IARC Interim Annual Report 2012 6 December 2012 SC/49/2

SC/49/2
GC/55/2
6 December 2012
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Foreword
This Interim Annual Report contains many examples of the high-quality, interdisciplinary
collaborative research that IARC conducts worldwide. It serves as an illustration of the relevance
of the Agency’s work to cancer control and is a testimony to how its core mission of promoting
international cooperation in cancer research is being achieved. This is ever more valuable as
recognition grows of the rising burden of cancer and its implications for sustainable
development in the coming decades.
The United Nations High-Level Meeting of September 2011 focused the attention of the world’s
leaders on the impending crisis of non-communicable diseases (NCDs), including cancer. The
Political Declaration of the Meeting reflected not only the realization of the need for a swift and
coordinated response involving all sectors of society, but also the recognition that “prevention
must be the cornerstone of the global response to non-communicable diseases”1.
The scale of the projected rise in the burden of cancer, particularly in low- and middle-income
countries, is such that the only realistic response from a public health perspective, as well as
from an economic and social one, is a strong commitment to prevention and early detection.
IARC’s contribution to this global effort is both to produce the scientific evidence that underpins
policy development and to support the translation of evidence into practice through cooperation
with its network of partners in the scientific community and in civil society.
IARC is well positioned to respond to these challenges; supporting cancer prevention and
control, particularly in low-resource settings, has been at the core of the Agency’s purpose since
its inception, and through its relationship with WHO it has a direct channel for translation of its
research into practice. In addition, IARC has increasingly directed its research activities in
support of cancer prevention by focusing on four priority areas:
• cancer surveillance – describing the global cancer burden to assist the definition of regional
and local priorities for cancer prevention and control, and for monitoring the effectiveness
of specific interventions and public health programmes
• cancer etiology – using a multidisciplinary approach that incorporates the insights about the
mechanisms of carcinogenesis into population-based studies, to characterize and evaluate
the causes of human cancers and to inform policies for primary prevention
• cancer prevention – evaluating the effectiveness of interventions for prevention and early
detection of cancer, in particular of simple, affordable methods and policies that can be
appropriately implemented in low-resource settings
• implementation research – identifying the most effective approaches for the successful
implementation of prevention programmes as well as the barriers to the participation of
target populations in specific socioeconomic and cultural contexts.
To ensure the effective implementation of this overall strategy and the achievement of specific
objectives in individual research sections, the Agency continued to build a broad support
platform through an ongoing programme of investment and developments in:
• scientific leadership – attracting excellent scientists to lead research programs; recruitment
of committed mid-career scientists, highly experienced senior visiting scientists, and
motivated postdocs from around the world; creation of a collegiate and dynamic research
environment
1
Paragraph 34 – Political Declaration of the High-Level Meeting of the General Assembly on the Prevention and
Control of Non-communicable Diseases. United Nations General Assembly; New York, 16 September 2011.
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•
•
•
•
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infrastructure – investment in scientific equipment and IT capacity to ensure IARC’s
research remains competitive; a programme of building renovation and ongoing discussions
regarding the projects for a new building; review and optimization of business processes
and administrative support to research
resources – new Participating States; increase in competitive extra-budgetary sources;
establishment of bilateral agreements and other voluntary contributions
partnerships – expansion of the network of collaborations with national centres and
international partners; establishment of relations with regional cancer networks; supporting
and coordination with WHO regarding initiatives on NCD agenda
communication – a renewed focus on external communication; completely redesigned web
site; public profile and media relations.
The combination of excellent people, facilities, and collaborators is the foundation on which the
cancer research described in this report is based. The next few years offer many opportunities,
but at a time of severe economic constraints on research globally. This will require the Agency
to be focused, efficient, and creative in response. However, I am confident that through its
scientific strategy, its scientific leadership, the dedication of its researchers and support staff,
and its wide network of collaborators and partners, IARC is well equipped and well placed to
make a significant contribution to this global effort.
Dr Christopher Wild
IARC Director
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Section of Cancer Information (CIN)
IARC is the definitive reference source for the provision of information about global statistics on
the burden of cancer, and this activity is coordinated within the Section of Cancer Information
(CIN). The monitoring of cancer occurrence provides baseline information for the development
of cancer control planning, for the evaluation of public health interventions, and for etiological
research programmes. The systematic recording of incidence, mortality, prevalence, and survival
at national and regional levels provides estimates of the cancer burden that are relevant across
the domains of cancer control, providing information about the underlying risk of disease as well
as the efficacy of prevention, early detection, and treatment in different populations.
To undertake this activity, CIN coordinates the systematic collection, analysis, and dissemination
of data from population-based cancer registries (PBCRs) worldwide. CIN also conducts a
programme of research making use of these and other data for analyses of geographical
patterns, time trends, and estimation of the future burden of the disease. These objectives can
only be accomplished through the collaboration and support of cancer registries worldwide. CIN
provides the secretariat for the International Association of Cancer Registries (IACR;
http://www.iacr.com.fr) and the European Network of Cancer Registries (ENCR;
http://www.encr.com.fr). The 34th IACR Annual Meeting was held in Cork, Ireland, in
September 2012, hosted by the Irish National Cancer Registry under the scientific theme of
“Better cancer control through better information”. The ENCR Scientific Meeting that followed
highlighted the most significant achievements of the Network over the previous 5 years.
To increase the worldwide coverage and quality of PBCR data, CIN leads, on behalf of IARC, the
Global Initiative for Cancer Registry Development in Low- and Middle-Income Countries (GICR),
a multi-agency programme to support capacity building in countries seeking to establish highquality PBCRs. Several IARC Regional Hubs for Cancer Registration are being launched in
selected locations in Africa, Asia, and Latin America and the Caribbean to put the GICR
principles into practice through regional programmes of training, direct support, advocacy, and
research.
GLOBOCAN (http://globocan.iarc.fr) is the unique database and online analysis tool for the
provision of global, regional, and national estimates of the burden of cancer, currently for 2008.
These estimates were enhanced in 2012 by the inclusion of two additional indicators, prevalence
and disability-adjusted life years (DALYs). The prevalence figures provide a global estimate of
almost 29 million persons living with cancer in 2008 diagnosed within the previous 5 years. This
is supplemented in GLOBOCAN by estimates of cancer DALYs, with the global figure of
169 million years of healthy life lost due to cancer in 2008 indicative of the combined impact of
fatal cancer and disabling non-fatal disease outcomes. These indicators, alongside incidence,
mortality, and survival, provide a solid basis for determining the resource needs of patients in
different regions of the world (Bray et al., 2012a; Soerjomataram et al., 2012a, 2012b).
Numerous studies from CIN have made use of the GLOBOCAN 2008 data set, and these include,
in collaboration with the American Cancer Society (ACS), a detailed examination of cancer
patterns in Africa (Jemal et al., 2012; see also ACS, 2011), and an analysis of the female global
cancer burden highlighting the major differences in the sex-specific cancer profiles worldwide
(McCormack et al., 2012). Another research direction has been to use the GLOBOCAN 2008 data
in the estimation of burden of cancer associated with specific risk factors. In collaboration with
ICE, we have estimated the attributable fraction of cancers associated with established
infectious causes both worldwide and regionally (de Martel et al., 2012). This showed that
2 million (16.1%) of the total 12.7 million new cancer cases estimated in 2008 were attributable
mainly to four major infections: human papilloma virus (HPV), hepatitis B and C virus, and
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Helicobacter pylori. This fraction is higher in less developed countries (22.9%) than in more
developed countries (7.4%). An analogous study on the burden of cancer associated with
obesity has commenced in collaboration with NME and BST.
CIN is responsible for the production of Cancer Incidence in Five Continents (CI5;
http://ci5.iarc.fr). Produced in collaboration with the IACR, this serial publication contains
comparable cancer incidence data made available by high-quality PBCRs worldwide. Work has
been progressing on the development of the tenth volume in this series, to be published in
2013, and meetings of the Editorial Board have reviewed data sets supplied by more than
350 cancer registries in 81 countries, reporting incident cancers in the period 2003–2007. Work
is also proceeding on a similar timescale for the third volume in the companion series,
International Incidence of Childhood Cancer (IICC; http://iicc.iarc.fr).
The CancerMondial web site provides access to these and other databases (including the WHO
mortality database and NORDCAN) and serves as a basis for descriptive epidemiological
research. CIN has provided up-to-date reports on the global patterns and trends for several
specific cancer sites in 2012. International variation in time trends of malignant melanoma
incidence was examined using age–period–cohort models, in collaboration with ENV (Erdmann
et al., 2012), while prostate cancer incidence and mortality rates were evaluated using joinpoint regression, in collaboration with the ACS (Center et al., 2012). Two other studies making
use of CI5-derived data, both with United States National Cancer Institute investigators, involve
analyses of variation in the age-incidence pattern of Burkitt lymphoma (Mbulaiteye et al., 2012)
and in the incidence of male breast cancer (Ly et al., 2012). There have also been international
comparative studies of oropharyngeal cancer (de Camargo Cancela et al., 2012) and human
immunodeficiency virus (HIV)-associated cancers in Africa (Chaabna et al., 2012).
Global and regional overviews, making use of all the data sources available to CIN, have been
published on HPV-associated cancers (Bray et al., 2012b; Forman et al., 2012). An innovative
study recently focused on cancer in relation to current levels of human development and the
changing global cancer burden and profile as a result of the ongoing epidemiological transition
worldwide (Bray et al., 2012c). This review evaluated cancer incidence and mortality in relation
to the Human Development Index, a more comprehensive indicator of social and economic
development than those used hitherto. Also incorporated were assessments of the future
burden of cancer, building in estimates of future changes in risk of the major types of the
disease to those resulting from population ageing and population growth.
CIN continues its practice of collaborating with individual PBCRs to provide support in data
analysis and interpretation and has recently worked with the Croatia national registry to
investigate trends in testicular cancer (Sincić et al., 2012; Znaor and Bray, 2012); with the
Shanghai, China, registry on hepatocellular carcinoma (Gao et al., 2012); and with the Mumbai,
India, registry on breast cancer (Dikshit et al., 2012a). Other collaborative work has had a more
applied methodological focus, for example examining cure models to determine the proportion
of cured patients and the median survival of fatal cases for different cancer types (Cvancarova
et al., 2012) and the value of verbal autopsy procedures in making mortality estimates in India
(Dikshit et al., 2012b). The former study provided key data for use in estimating cancer DALYs
worldwide (Soerjomataram et al., 2012a, 2012b).
CIN is exploring new approaches to the visual presentation of global cancer statistics to reach
out to a broader audience and, in collaboration with Cancer Research United Kingdom and the
Union for International Cancer Control (UICC), has produced a new World Cancer Factsheet
using novel graphical descriptions (Cancer Research UK, 2012). Similarly, the adoption of up-todate web technology has been used in a major relaunch of the European Cancer Observatory
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(ECO) web site (http://eco.iarc.fr), which has provided enhanced and flexible user-friendly
access to data provided by more than 110 European regional and national PBCRs, as well as
new 2012 estimates for the burden of cancer incidence, mortality, and prevalence in
40 European countries. This was partly funded through the EU FP7 EUROCOURSE ERA-NET
project (http://www.eurocourse.org), and the technology used will be applied across the range
of web sites hosted by CIN to modernize our overall web presence, and specifically the main
platform CancerMondial.
Project work within CIN was initiated in 2012 on a new study, CAN EVOLUTION (funded by the
EU Marie Curie programme), to investigate the global impact of population ageing on the
changing dynamics of cancer patterns. A further project established in 2012 has been the
International Research Network investigating Cancer among Indigenous Peoples (IRNCIP) with a
study launched to compare cancer rates within such populations in Australia, Canada, New
Zealand, and the USA combined with literature reviews of cancer in indigenous peoples in Latin
America and the Caribbean, the circumpolar region, and Oceania. CIN contributes to the EU
FP7-funded European Network for Cancer Research in Children and Adolescents (ENCCA;
http://www.encca.eu) and PanCare Childhood and Adolescent Cancer Survivor Care and FollowUp Studies (PanCareSurFup; http://www.pancaresurfup.eu) by coordinating an investigation into
the feasibility of extending PBCR data collection in Europe, as a means to facilitate short- and
long-term follow-up of these patients, and thus improve outcomes.
The GICR (http://gicr.iarc.fr) was formally launched in November 2011 to ensure the further
establishment of PBCRs globally and to prioritize the specific needs of low- and middle-income
countries. The overall objective is to bring about year-on-year incremental increases in the
reporting of cancer data to a population-based standard so that these may inform national
cancer control policies and, in the longer term, reach a quality that might be considered for
publication in CI5. The GICR has coordinated the publication of advocacy material and, together
with UICC, the development of a fundraising programme.
A key component of the GICR is the development of IARC Regional Hubs for Cancer
Registration, which will offer a localized means to provide registries with direct support, training,
research, and advocacy, and enable regional networking. A hub has been formally inaugurated
in Mumbai, India, in October 2012 to cover South, Central, and East Asia. The establishment of
Collaborative Research Agreements with registries in Sri Lanka, Indonesia, and Mongolia in 2012
provides a direct means of support to these registries with a high potential of becoming
population-based. Site visits to Nepal in 2012 and Bhutan early in 2013 should provide key
information on the status of the respective registries and may pave the way for future
collaborative support. Agreements have been reached to launch by the end of 2012 a further
hub in Izmir, Turkey, to cover Western Asia and Northern Africa. In collaboration with the
International Network for Cancer Treatment and Research, an agreement will develop the
African Cancer Registry Network into a regional hub covering sub-Saharan Africa. Active
discussions are under way regarding a hub initiative for Central and South America.
CIN has provided a long-standing programme in the provision of training for PBCR staff at the
annual IARC Summer School and also in regional courses. Now being integrated within GICR
training developments, regional courses have been held in Cairo, Egypt (in French; November
2011); Mumbai, India (February 2012); Cali, Colombia (in Spanish; October 2012); and Abuja,
Nigeria (November 2012). A major element in training is to provide guidance in the use of and
transition to the IARC registration software, CanReg5, and during 2012, CIN has designed a
series of webinars on CanReg5 use, reflecting a commitment to developing distance learning
tools to deliver training. More generally, relevant course components have been recorded; their
potential as online audiovisual training materials is being explored.
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Bray F, Jemal A, Grey N et al. (2012c). Global cancer transitions according to the Human Development Index
(2008–2030): a population-based study. Lancet Oncol, 13:790–801. doi:10.1016/S1470-2045(12)70211-5
PMID:22658655
Bray F, Lortet-Tieulent J, Znaor A et al. (2012b). Burden of HPV infection-related diseases in Central and
Eastern Europe and Central and Western Asia. Vaccine, in press.
Bray F, Ren JS, Masuyer E, Ferlay J (2012a). Global estimates of cancer prevalence for 27 sites in the adult
population in 2008. Int J Cancer, [Epub ahead of print]. doi:10.1002/ijc.27711 PMID:22752881
Cancer Research UK, 2012. World Cancer Factsheet. IARC, UICC, and Cancer Research UK. Available at
http://gicr.iarc.fr/files/resources/20120906-WorldCancerFactSheet.pdf.
Center MM, Jemal A, Lortet-Tieulent J et al. (2012). International variation in prostate cancer incidence and
mortality rates. Eur Urol, 61:1079–1092. doi:10.1016/j.eururo.2012.02.054 PMID:22424666
Chaabna K, Boniol M, de Vuyst H et al. (2012). Geographical patterns of Kaposi’s sarcoma, nonHodgkin
lymphomas, and cervical cancer associated with HIV infection in five African populations. Eur J Cancer
Prev, 21:1–9. doi:10.1097/CEJ.0b013e32834a802a PMID:21955799
Cvancarova M, Aagnes B, Fosså SD et al. (2012). Proportion cured models applied to 23 cancer sites in
Norway. Int J Cancer, [Epub ahead of print]. doi:10.1002/ijc.27802 PMID:22927104
de Camargo Cancela M, de Souza DL, Curado MP (2012). International incidence of oropharyngeal cancer: a
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Dikshit R, Gupta PC, Ramasundarahettige C et al.; Million Death Study Collaborators (2012b). Cancer
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Dikshit RP, Yeole BB, Nagrani R et al. (2012a). Increase in breast cancer incidence among older women in
Mumbai: 30-year trends and predictions to 2025. Cancer Epidemiol, 36:e215–e220.
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Erdmann F, Lortet-Tieulent J, Schüz J et al. (2012). International trends in the incidence of malignant
melanoma 1953–2008 – are recent generations at higher or lower risk? Int J Cancer, [Epub ahead of
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Forman D, de Martel C, Lacey C et al. (2012). Global burden of human papillomavirus and related diseases.
Vaccine, in press.
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Jemal A, Bray F, Forman D et al. (2012). Cancer burden in Africa and opportunities for prevention. Cancer,
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Mbulaiteye SM, Anderson WF, Ferlay J et al. (2012). Pediatric, elderly, and emerging adult-onset peaks in
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Section of IARC Monographs (IMO)
In 2012, the IARC Monographs Programme organized three international Working Group
meetings of experts in carcinogenesis and public health, to develop new IARC Monographs. In
addition, two Workshops were organized as a follow-up to the recently completed Volume 100
of the IARC Monographs, “A review of human carcinogens”. The purpose, scope, and outcome
of these meetings are summarized below.
Monographs Working Groups convened at IARC, each for a period of 8 days, in February, June,
and October. The reviews and evaluations of these Working Groups will be published in book
and electronic form as Volumes 104, 105, and 106 of the IARC Monographs series.
IARC Monographs Working Group on “Polyomaviruses (SV40, BK, JC, and Merkel cell
viruses) and malaria”, Volume 104, 7–14 February 2012
The World Health Organization estimates the annual incidence of malaria cases at 216 million,
the majority of which (> 90%) are due to infection with the protozoan parasite Plasmodium
falciparum. Most deaths occur in children younger than 5 years, predominantly in sub-Saharan
Africa and in Papua New Guinea. In these regions the transmission is holoendemic, which is
defined as a parasite prevalence of > 75% in the 1-year age group.
“Malaria caused by infection with Plasmodium falciparum in holoendemic areas” was classified
as “probably carcinogenic to humans” (Group 2A). The evaluation was based on limited
epidemiological evidence that malaria is associated with endemic Burkitt lymphoma (eBL) and
strong mechanistic evidence that P. falciparum disturbs the immature immune system in young
children and reactivates the ubiquitous Epstein–Barr virus, a necessary agent for the
development of eBL.
BK virus (BKV) and JC virus (JCV) are highly prevalent viruses in humans worldwide and are
responsible for lethal non-cancerous diseases in immunosuppressed individuals (haemorrhagic
cystitis and nephropathy for BKV, multifocal leukoencephalopathy for JCV). Based on “sufficient
evidence” in experimental animals and “inadequate evidence” in humans, both viruses were
classified as “possibly carcinogenic to humans” (Group 2B).
Merkel cell virus (MCV) has been recently discovered in a rare human skin cancer, Merkel cell
carcinoma (MCC). An etiological role of MCV in MCC is supported by a small number of case–
control studies, several case series, and strong mechanistic data. MCV was classified as
“probably carcinogenic to humans” (Group 2A).
In the 1950s and early 1960s, millions of people across the world received vaccines against
poliovirus that were contaminated with Simian virus 40 (SV40), a virus that naturally infects the
rhesus monkey. SV40 was subsequently shown to induce tumours in newborn hamsters. The
potential infection of humans raised serious concerns that this virus may cause cancer in
humans. Reviewing the extensive data available, the Working Group did not find compelling
evidence that SV40 infects humans or that transmission from human to human exists. SV40 was
evaluated as “not classifiable as to its carcinogenicity to humans” (Group 3).
IARC Monographs Working Group on “Diesel and gasoline engine exhausts and some
nitroarenes”, Volume 105, 5–12 June 2012
Diesel engines are used for on-road and non-road transport (e.g. trains, ships) and (heavy)
equipment in various industrial sectors (e.g. mining, construction), and in electricity generators,
particularly in developing countries. Gasoline engines are used for cars and hand-held
equipment (e.g. chainsaws). The qualitative and quantitative composition of combustion-engine
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exhausts depends on the fuel, the type and age of the engine, the state of its tuning and
maintenance, the emission control system, and the pattern of use. Exhausts from diesel engines
with no or limited emission controls contain more particulate matter. In the past two decades,
progressively tighter emission standards for on-road vehicles, introduced in North America,
Europe, and elsewhere, have triggered advances in diesel technology that resulted in lower
emission of particulate matter, nitrogen oxides, and hydrocarbons. Emission standards in nonroad applications are lagging and therefore these emissions are still largely uncontrolled today.
Moreover, in many less developed countries standards are not in place for both on-road and
non-road use of diesel and gasoline engines.
The most influential epidemiological studies assessing cancer risks associated with diesel engine
exhausts investigated occupational exposure among non-metal miners, railroad workers, and
workers in the trucking industry. For each of these groups, the studies support a causal
association between exposure to diesel engine exhaust and lung cancer. An increased risk for
bladder cancer was noted in many case–control studies but not in the cohort studies. The
Working Group concluded that there was “sufficient evidence” in humans for the carcinogenicity
of diesel engine exhaust.
With respect to animal cancer studies, the Working Group concluded that there was “sufficient
evidence” in experimental animals for the carcinogenicity of whole diesel engine exhaust, of
diesel engine exhaust particles, and of extracts of diesel engine exhaust particles. Positive
genotoxicity biomarkers of exposure and effect were also observed in humans exposed to diesel
engine exhaust. The Working Group concluded that there is “strong evidence” for the ability of
whole diesel engine exhaust to induce cancer in humans through genotoxicity.
The association between exposure to gasoline engine exhaust and cancer risk was investigated
in only a few epidemiological studies and, because of the difficulty of separating the effects of
diesel and gasoline exhaust, the evidence for carcinogenicity was evaluated as “inadequate”. As
to studies in experimental animals, the Working Group concluded that there was “sufficient
evidence” for the carcinogenicity of condensates of gasoline engine exhaust.
Overall, the Working Group classified diesel engine exhaust as “carcinogenic to humans” (Group
1) and gasoline engine exhaust as “possibly carcinogenic to humans” (Group 2B).
The Working Group also evaluated 10 nitroarenes that occur in diesel engine exhaust.
Biomonitoring studies have shown that workers and the general population are exposed to these
substances. All the nitroarenes were genotoxic to various extents in different assays. The
Working Group reaffirmed the Group 2B classification of seven of them. Strong evidence for
genotoxicity led to an upgrade of 3-nitrobenzanthrone to Group 2B, and similar findings in
human cells led to an upgrade of 1-nitropyrene and 6-nitrochrysene to Group 2A.
IARC Monographs Working Group on “Trichloroethylene, some other chlorinated
solvents, and their metabolites”, Volume 106, 2–9 October 2012
Several chlorinated solvents (trichloroethylene, tetrachloroethylene, 1,1,1,2-tetrachloroethane,
or 1,1,2,2-tetrachloroethane) and some of their metabolites (dichloroacetic acid, trichloroacetic
acid, and chloral hydrate) were reviewed by the Volume 106 Working Group.
Trichloroethylene (TCE) is a chlorinated solvent that was widely used for degreasing metal parts
until the 1990s, and in dry cleaning from the 1930s to 1950s. It is still used to remove stains
from fabric, but it is primarily used in chlorinated chemical production. The general population is
exposed through consumer products, including food, and through TCE-contaminated water.
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The Working Group classified TCE as “carcinogenic to humans” (Group 1) on the basis of an
increased risk of kidney cancer; there was also limited evidence for an association between TCE
exposure and liver cancer or non-Hodgkin lymphoma (NHL). Several case–control studies of
renal cell carcinoma, adjusted for tobacco smoking and other potential confounders, and a
meta-analysis provide consistent and robust evidence for a positive association with TCE
exposure. Experimental studies consistently show that metabolites of TCE formed via
glutathione conjugation (by glutathione S-transferase [GST] enzymes) are genotoxic,
particularly in kidney cells, where in situ metabolism occurs. The Working Group concluded that
there was “sufficient evidence” for carcinogenicity in experimental animals, and the findings
were remarkably consistent with the human data. Notably, an increased incidence of tumours of
the liver, kidney, lung, testes, and haematopoietic system were observed in both sexes of mice
and rats by both oral and inhalation routes of exposure in multiple studies.
Tetrachloroethylene is among the most widely used chlorinated solvents worldwide. From the
1950s to 1980s, its main use was in dry cleaning, for which it is still widely used. It was used to
a lesser extent in metal degreasing, but its current primary use is for chlorofluorocarbon
production. Current sources of exposure to the general population are from dry cleaning and
environmental contaminations (through outdoor or indoor air, and drinking-water).
The majority of the epidemiological studies reported an increased risk of bladder cancer, after
adjustment for tobacco smoking and other potential confounders. However, the epidemiological
evidence was evaluated as limited because employment in dry cleaning was the only indicator of
exposure to tetrachloroethylene in most studies, the number of exposed cases was small, and
evidence for an exposure–response relationship was weak. The Working Group concluded that
there was “sufficient evidence” for carcinogenicity in experimental animals. Tetrachloroethylene
was classified as “probably carcinogenic to humans” (Group 2A).
Chloral hydrate (CH) is used as a sedative before medical procedures and also occurs as a byproduct of water disinfection together with other chemicals. Evidence for the carcinogenicity of
CH was evaluated to be “inadequate” in humans and “sufficient” in experimental animals.
CH was upgraded to Group 2A, on the basis of strong evidence of its genotoxicity in most
experimental systems and exposed humans.
Multiple chronic bioassays in mice demonstrated that dichloroacetic acid, trichloroacetic acid,
1,1,1,2-tetrachloroethane, or 1,1,2,2-tetrachloroethane increased the incidence of hepatocellular
tumours. These agents were classified as “possibly carcinogenic to humans” (Group 2B) based
on “sufficient evidence” for carcinogenicity in experimental animals.
Workshops on “Tumour concordance and mechanisms of carcinogenesis”
(16–18 April 2012 and 28–30 November 2012)
These two Workshops will develop scientific publications that build on the reviews of the human
carcinogens in the Volume 100 series of the IARC Monographs. The two major topics are
“Tumour concordance between humans and experimental animals” and “Mechanisms involved in
human carcinogenesis”. A group of experts with broad expertise in epidemiology, animal cancer
studies, and toxicology, most of whom have participated in the Volume 100 series, was invited
to participate in both Workshops and to consider the two topics in conjunction, realizing that a
discussion on concordance and discordance would necessarily include mechanistic
considerations.
Before the first Workshop, a start was made with the extraction of animal cancer data from
Volume 100, which would lead to a database for the analysis of concordance and discordance.
The first Workshop opened with invited lectures on key issues and recent insights in toxicology
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and carcinogenesis, followed by discussions in subgroups and in plenary sessions, exploring how
analyses of and insights from tumour concordance and mechanisms can benefit from each
other, and which additional data analyses should be done in preparation for the second
Workshop. Agreement was reached on the fine-tuning of the animal cancer data, and on the
development of a data set on mechanisms, based on a list of key terms identifying the most
important mechanistic pathways. A draft table of contents with writing assignments for different
chapters was also discussed.
In the two months after the first Workshop, the data sets were finalized and made available to
all participants for further analysis. The second Workshop will discuss the results of these
analyses and their interpretation, and aim to reach consensus on the conclusions with regard to
future hazard identification.
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Section of Mechanisms of Carcinogenesis (MCA)
The broad long-term goal of the Section of Mechanisms of Carcinogenesis (MCA) is to advance
understanding of mechanisms of carcinogenesis and to contribute to cancer prevention. This is
achieved through a multifaceted programme investigating interactions between genes, the
epigenome, and the environment. In collaboration with epidemiology groups, MCA contributes
to the development of translational studies through the discovery and validation of biomarkers
of tumorigenesis and environmental exposures. The Section also aims to promote the
development of cancer research relevant, although not exclusive, to low- and medium-resource
countries and common cancers related to these regions of the world. Another focus of MCA is
the development of genetic/epigenetic methods that are applicable to biobanks associated with
case–control and population-based studies.
Molecular Mechanisms and Biomarkers Group (MMB)
MMB conducts studies aimed at improving understanding of molecular mechanisms of
carcinogenesis and identifying biomarkers applicable in molecular epidemiology and cancer
prevention. This is achieved through studies of molecular and genetic changes, gene function,
and gene–environment interactions. MMB also aims to investigate the effects of environmental
exposures on molecular changes to discover and validate new cancer biomarkers. MMB also
maintains and publishes on the web a comprehensive database of all TP53 mutations published
in the literature.
Role of TP53 somatic mutations as prognostic and predictive markers in breast
cancer
The TP53 gene has a major tumour suppressor role in breast cancer and is inactivated by
mutation in about 30% of breast tumours. While several studies have demonstrated the
prognostic value of TP53 mutations, the predictive role of p53 status in patients treated with a
controlled treatment regimen in the context of a clinical trial has not been investigated. In
collaboration with the BIG clinical network, we have assessed the prognosis and predictive value
of TP53 somatic mutations in the BIG 02-98 randomized phase III trial, in which women with
node-positive breast cancer were treated with adjuvant doxorubicin-based chemotherapy with
or without docetaxel (ClinicalTrials.gov identifier NCT00174655). While overall TP53 mutations
were not associated with prognosis or time to recurrence, truncating mutations showed
significant independent prognostic value, with an increased recurrence risk compared with
patients with other types of mutations or no mutations (hazard ratio = 3.21, 95% CI = 1.740–
5.935, P = 0.0002). p53 status had no significant predictive value for response to docetaxel.
These results confirmed that loss of wild-type p53 through protein-truncating mutations is
associated with poor prognosis in breast cancer, but could not identify a significant predictive
role for p53 status regarding docetaxel (Fernández-Cuesta et al., 2012).
TP53 R249S mutation, genetic variations in HBX, and risk of hepatocellular
carcinoma
In regions with high prevalence of chronic hepatitis B virus (HBV) infection and dietary aflatoxin
exposure, hepatocellular carcinomas (HCCs) often contain TP53 mutation at codon 249 (R249S).
Interestingly, R249S mutations can be detected in asymptomatic subjects (Villar et al., 2011).
We evaluated the association between R249S and HBX status in relation to HCC in a West
African population. HBX (complete or 3′-truncated) and HBS genes were assessed in cell-free
DNA (CFDNA) from plasma of subjects recruited in a hospital-based case–control study
conducted in The Gambia. These samples had been previously analysed for R249S and HBV
serological status. Complete HBX sequence was frequently detected in CFDNA of HCC-R249S
positive (77%) compared with HCC-R249S negative cases (44%). Conversely, the proportion of
3′-truncated HBX gene was significantly higher in HCC-R249S negative than positive cases (34%
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vs 12%). Moreover, HBV mutation analysis revealed that double mutation at nucleotides
1762T/1764A was associated with diagnosis of cirrhosis or HCC (Gouas et al., 2012). These
findings suggest that in HCCs from The Gambia, complete HBX sequences are often associated
with the presence of TP53 R249S mutation.
Preferential occurrence of TP53 R249S-mutated DNA in liver cancer developing in
the absence of cirrhosis
Most HCCs are associated with chronic HBV infection, while a G→T mutation at codon 249 of
the TP53 gene, R249S, specific for exposure to aflatoxin, is also detected in a significant fraction
of tumours. Previous studies showed that circulating free DNA (CFDNA) from plasma is a
suitable surrogate source of liver-derived DNA for detection of R249S mutations (Gormally et al.,
2007). In this study, plasma samples collected in a case-referent design at the National Cancer
Institute, Bangkok, were used to evaluate the association of R249S-mutated DNA plasma
concentrations with the occurrence of HCC, cholangiocarcinoma (CC), or chronic liver disease.
The short oligonucleotide mass analysis (SOMA) assay was used to quantify free circulating
R249S-mutated DNA in plasma samples. Plasma R249S-mutated DNA was detectable at low
concentrations (≥ 67 copies/mL) in 53–64% of patients with primary liver cancer or chronic liver
disease and in 19% of controls. Also, 44% of patients with HCC and no evidence of cirrhosis had
plasma concentrations of R249S-mutated DNA ≥ 150 copies/mL, compared with 21% of patients
with both HCC and cirrhosis, 22% of CC patients, and 12% of patients with non-cancer chronic
liver disease. Thus, plasma concentrations of R249S-mutated DNA ≥ 150 copies/mL tended to
be more common in patients with HCC developing without pre-existing cirrhosis (Villar et al.,
2012). These results support the preferential occurrence of R249S-mutated DNA in HCC
developing in the absence of cirrhosis in a context of chronic HBV infection.
Disseminating knowledge on the master tumour suppressor gene TP53
MMB maintains a public molecular epidemiology database, the IARC TP53 Database
(http://www-p53.iarc.fr), an internationally recognized resource in the field for the analysis and
interpretation of human TP53 mutation in sporadic and inherited cancers. With the advent of
next-generation sequencing technologies and the flood of sequencing data, the interpretation of
gene variations and the identification of driver mutations rely on annotations compiled in
databases such as the IARC TP53 Database. The database provides extensive annotations on
the prevalence, type, phenotype, and predicted or experimentally assessed functional impact of
TP53 mutations, which are useful to identify functional variants. Recent database developments
have aimed at (1) extending the scope of annotations, (2) improving data accessibility by
redesigning the web interface, and (3) sharing and integrating data with central genetic
resources such as COSMIC, NCBI dbSNP, or UniProtKB/Swiss-Prot. In 2012, the group has
produced a book describing how research on p53 has advanced our understanding of the
molecular basis of human cancer, and how this knowledge is starting to affect cancer
management and therapy (Hainaut et al., 2012).
Epigenetics Group (EGE)
Over the past decade, research in epigenetics has been making it into mainstream research,
owing to the fact that epigenetic changes have emerged as key mechanisms in cancer
development and progression. The ubiquity and intrinsic reversibility make epigenetic events
attractive subjects for biomarker discovery and strategies for cancer prevention (Herceg and
Vaissière, 2011; Nogueira da Costa and Herceg, 2012). The EGE Group conducts research projects
aiming to (i) gain a better mechanistic understanding of tumorigenesis and (ii) discover and
validate new epigenetic biomarkers. This programme exploits new concepts in cancer
epigenetics and recent technological advances in epigenetics and epigenomics, and is carried
out in close collaboration with IARC laboratory scientists and epidemiologists as well as external
groups and consortia.
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Epigenetic mechanisms in control of cellular processes and cancer
We have previously shown that histone modifications and remodelling are important to provide
accessibility to DNA lesions and for efficient DNA repair (Murr et al., 2006; Gospodinov et al.,
2011). In this study, we have identified TRRAP, a critical component of histone acetyltransferase
(HAT) complexes, as a novel target of proteolytic degradation in a cell-cycle dependent manner.
TRRAP overexpression or mutation-induced stabilization resulted in multiple mitotic defects,
including lagging chromosomes, chromosome bridges, lack of sister chromatid cohesion, and
impaired chromosome condensation. We further found that mitotic defects are associated with a
global histone H4 hyperacetylation, indicating that TRRAP and TRRAP-mediated histone
acetylation are necessary for proper condensation of chromatin, chromosome segregation, and
genomic stability (Ichim et al., submitted). Together with recent findings of recurrent mutations
in the TRRAP gene in several cancer types, such as melanoma, pancreatic adenocarcinomas,
and HCC, our results argue that deregulation of TRRAP/HATs and histone acetylation and
consequent changes in chromatin compaction states may represent an important mechanism of
chromosome instability and tumorigenesis.
Epigenetic changes associated with risk factors in upper aerodigestive tract (UADT)
cancer
Deregulation of the epigenome by environmental, dietary, and lifestyle exposure is believed to
disrupt different cellular processes and contribute to cancer risk. We combined quantitative
profiling of DNA methylation states in a wide panel of cancer-associated genes using Illumina
microarray technology or high-throughput pyrosequencing with case–control studies of UADT
cancer. The aim of this study was to examine the global deregulation of epigenetic (DNA
methylation) states in oesophageal squamous cell carcinoma (ESCC) and identify potential early
cancer biomarkers. We performed a large-scale analysis of promoter methylation in ESCC and
normal surrounding tissues as well as in oesophageal mucosa from healthy individuals. To this
end, we used a bead array analysis of more than 800 cancer-related genes. A total of 37 CpG
sites were found to be differentially methylated between tumours and surrounding tissues.
These CpG sites were significantly enriched in genes related to several pathways, including the
IL-10 anti-inflammatory signalling pathway and cell communication pathway (Lima et al., 2011;
manuscript in preparation). This is the first study to address methylation changes in ESCC in a
large panel of genes. These data may prove to be the reference for future studies identifying
potential biomarkers and molecular targets in ESCC.
We further analysed changes in DNA methylation in UADT cancers and their potential
association with primary risk factors. To this end, we have taken advantage of a case–control
study of UADT cancer involving seven centres in South America, using detailed lifestyle
information and quantitative analysis of DNA methylation in a panel of cancer-associated genes.
Our analyses revealed a high frequency of aberrant hypermethylation of specific genes, among
which we identified new genes (including the nicotinic acetylcholine receptor gene, CHRN3, and
the downstream of tyrosine kinases 1 gene, DOK1), suggesting that epigenetic deregulation of
these genes may promote the development of UADT cancer (Mani et al., 2012; Saulnier et al.,
2012; Siouda et al., 2012). Importantly, we found that sex and age are associated with the
methylation states, whereas tobacco smoking and alcohol intake may also influence the
methylation levels in specific genes (Mani et al., 2012).
Together, these studies identify aberrant DNA methylation patterns in UADT and gastric cancer
and suggest a potential mechanism by which environmental factors may deregulate key cellular
genes involved in tumour suppression and contribute to these common human cancers.
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Epigenetic changes in surrogate tissue as cancer biomarkers
Because DNA methylation profiles of the human genome are tissue-specific, we tested the
possibility that global methylation levels in surrogate tissues, such as blood, may be exploited in
epidemiologic studies. We used two independent but complementary methods to assess global
methylation levels in peripheral blood DNA from a well-characterized population-based case–
control study (the Long Island Breast Cancer Study Project [LIBCSP], with more than 2100
peripheral blood samples). Our results obtained by pyrosequencing-based assay (LUMA) and
genome-wide methylation (Illumina Infinium arrays) profiling revealed greater promoter
hypermethylation in breast cancer cases, while methylation levels in repetitive elements (as
revealed by LINE-1 methylation assay) were not associated with breast cancer risk (Xu et al.,
2012). This study shows that global promoter hypermethylation measured in peripheral blood
may be used in breast cancer risk assessment. Further studies on the samples from a
prospective cohort (EPIC) are under way to assess the value of this marker and address the
potential influence of the disease onset (reverse causality) and one-carbon metabolism on the
methylome of blood DNA (Demetriou et al., 2012, submitted).
References
Fernández-Cuesta L, Oakman C, Falagan-Lotsch P et al. (2012). Prognostic and predictive value of TP53
mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxanebased adjuvant therapy: results from the BIG 02-98 phase III trial. Breast Cancer Res, 14:R70.
doi:10.1186/bcr3179 PMID:22551440
Gormally E, Caboux E, Vineis P, Hainaut P (2007). Circulating free DNA in plasma or serum as biomarker
of carcinogenesis: practical aspects and biological significance. Mutat Res, 635:105–117.
doi:10.1016/j.mrrev.2006.11.002 PMID:17257890
Gospodinov A, Vaissiere T, Krastev DB et al. (2011). Mammalian Ino80 mediates double-strand break
repair through its role in DNA end strand resection. Mol Cell Biol, 31:4735–4745.
doi:10.1128/MCB.06182-11 PMID:21947284
Gouas DA, Villar S, Ortiz-Cuaran S et al. (2012). TP53 R249S mutation, genetic variations in HBX and risk
of hepatocellular carcinoma in The Gambia. Carcinogenesis, 33:1219–1224.
doi:10.1093/carcin/bgs135 PMID:22759751
Hainaut P, Olivier M, Wiman KG, eds (2012). p53 in the Clinics. New York: Springer Science+Business
Media, in press. doi:10.1007/978-1-4614-3676-8
Herceg Z, Vaissière T (2011). Epigenetic mechanisms and cancer: an interface between the environment
and the genome. Epigenetics, 6:804–819. doi:10.4161/epi.6.7.16262 PMID:21758002
Lima SC, Hernández-Vargas H, Simão T et al. (2011). Identification of a DNA methylome signature of
esophageal squamous cell carcinoma and potential epigenetic biomarkers. Epigenetics, 6:1217–1227.
doi:10.4161/epi.6.10.17199 PMID:21946330
Mani S, Szymańska K, Cuenin C et al. (2012). DNA methylation changes associated with risk factors in
tumors of the upper aerodigestive tract. Epigenetics, 7:270–277. doi:10.4161/epi.7.3.19306
PMID:22430803
Murr R, Loizou JI, Yang Y-G et al. (2006). Histone acetylation by Trrap-Tip60 modulates loading of repair
proteins and repair of DNA double-strand breaks. Nat Cell Biol, 8:91–99. doi:10.1038/ncb1343
PMID:16341205
Nogueira da Costa A, Herceg Z (2012). Detection of cancer-specific epigenomic changes in biofluids:
Powerful tools in biomarker discovery and application. Mol Oncol, 6:704–715.
doi:10.1016/j.molonc.2012.07.005 PMID:22925902
Saulnier A, Vaissiere T, Yue J et al. (2012). Inactivation of the putative suppressor gene DOK1 by
promoter hypermethylation in primary human cancers. Int J Cancer, 130:2484–2494.
doi:10.1002/ijc.26299 PMID:21796618
Siouda M, Yue J, Shukla R, et al. (2012). Transcriptional regulation of the human tumor suppressor DOK1 by
E2F1. Mol Cell Biol, 32:4877–4890. doi:10.1128/MCB.01050-12 PMID:23028047
Villar S, Le Roux-Goglin E, Gouas DA et al. (2011). Seasonal variation in TP53 R249S-mutated serum DNA
with aflatoxin exposure and hepatitis B virus infection. Environ Health Perspect, 119:1635–1640.
doi:10.1289/ehp.1103539 PMID:21768053
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Villar S, Ortiz-Cuaran S, Abedi-Ardekani B et al. (2012). Aflatoxin-induced TP53 R249S mutation in
hepatocellular carcinoma in Thailand: association with tumors developing in the absence of liver
cirrhosis. PLoS One, 7:e37707. doi:10.1371/journal.pone.0037707 PMID:22675488
Xu X, Gammon MD, Hernandez-Vargas H et al. (2012). DNA methylation in peripheral blood measured by
LUMA is associated with breast cancer in a population-based study. FASEB J, 26:2657–2666.
doi:10.1096/fj.11-197251 PMID:22371529
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Section of Molecular Pathology (MPA)
Molecular pathology of tumours
The Section of Molecular Pathology (MPA) focuses on the elucidation of the molecular basis and
genetic pathways of human neoplasms, in particular brain tumours, with the objectives of
correlating histologically recognized phenotypes with genotypes, and identifying reliable
molecular markers for classification and progression of tumours. Some highlights of 2012 are
described below.
Molecular mechanisms of mesenchymal differentiation in gliosarcomas
Gliosarcoma is a rare variant of glioblastoma that is characterized by a biphasic tissue pattern
with alternating areas displaying glial or mesenchymal differentiation. We compared genomewide chromosomal imbalances using array CGH (105K) in glial and mesenchymal tumour areas
of 13 gliosarcomas. Patterns of gain and loss were similar, except for gain at 13q13.3–q14.1
(log2 ratio > 3.0), which was restricted to the mesenchymal tumour area of a single
gliosarcoma. Further analyses of 64 gliosarcomas using quantitative polymerase chain reaction
(PCR) showed amplification of the STOML3, FREM2, and LHFP genes at 13q13.3–q14.1 in 14
(21%), 10 (15%), and 7 (11%) of mesenchymal tumour areas, respectively, but not in glial
tumour areas. Immunohistochemistry confirmed that overexpression of STOML3 and FREM2 was
more extensive in mesenchymal than in glial tumour areas. We also assessed 40 gliosarcomas
for immunoreactivity of Slug, Twist, MMP-2, and MMP-9, which are involved in epithelial–
mesenchymal transition (EMT). Nuclear expression of Slug was observed in > 50% of neoplastic
cells in mesenchymal tumour areas of 33 (83%) gliosarcomas, but not in glial tumour areas.
Nuclear expression of Twist was observed in > 50% of neoplastic cells in mesenchymal tumour
areas of 35 (88%) gliosarcomas, but glial tumour areas were largely negative. Expression of
MMP-2 and MMP-9 was also significantly more extensive in mesenchymal than in glial tumour
areas. None of 20 ordinary glioblastomas showed expression of Slug or Twist in > 10% of
neoplastic cells. These results suggest that mesenchymal components of a small fraction of
gliosarcomas may be derived from glial cells that have acquired genetic alterations that
distinguish them from other glial cells in the tumour, and that mechanisms involved in EMT in
epithelial neoplasms may also play roles in mesenchymal differentiation in gliosarcoma (Nagaishi
et al., 2012a, 2012b).
BRAF gain and the BRAF-KIAA1549 fusion gene in low-grade diffuse gliomas
Chromosomal 7q34 duplication and BRAF-KIAA1549 fusion are characteristic genetic alterations
in pilocytic astrocytomas. Gain of 7q34 appears to be common in diffuse astrocytomas, but its
significance is unclear. We assessed BRAF gain and BRAF mutations in 123 low-grade diffuse
gliomas (diffuse astrocytomas, oligoastrocytomas, and oligodendrogliomas). Quantitative PCR
revealed BRAF gain in 34% of oligodendrogliomas, a significantly higher frequency than in
diffuse astrocytomas (13%). BRAF gain was common in low-grade diffuse gliomas with 1p/19q
loss (39%) and those lacking any of the genetic alterations analysed (31%), but was rare in
those with TP53 mutations (2%). Logistic regression analysis showed a significant positive
association between 1p/19q loss and BRAF gain, and a significant negative association between
TP53 mutations and BRAF gain. These results suggest that low-grade diffuse gliomas with
1p/19q loss have frequent BRAF gains (Kim et al., 2012). We also found the BRAF-KIAA1549
fusion gene in 17 out of 185 diffuse gliomas cases (9%), suggesting that, as in pilocytic
astrocytomas, the KIAA1549-BRAF fusion gene may be responsible for deregulation of the RasRAF-ERK signalling pathway in a small fraction of diffuse gliomas (Badiali et al., 2012).
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Pace of malignant progression from diffuse astrocytoma to secondary glioblastoma
Most glioblastomas develop with a short clinical history, without evidence for less malignant
precursor lesions (primary glioblastomas); in contrast, secondary glioblastomas develop slowly
via progression from diffuse astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO
grade III). IDH1 mutations reliably distinguish between primary glioblastomas (without IDH1
mutations) and secondary glioblastomas (with IDH1 mutations) (Kleihues et al., 2012; Ohgaki,
2012). The time to progression and the clinical outcome of diffuse astrocytomas vary
significantly among patients. The ability to predict the pace of progression from low-grade
diffuse astrocytoma to secondary glioblastoma, which is however not possible
histopathologically, would be clinically very important, giving oncologists a rational basis for
deciding whether and at what stage to administer adjuvant radiotherapy.
Despite possessing distinctive genetic alterations, primary and secondary glioblastomas have
similar histological features, which may be attributable to those genetic alterations that are
common to both subtypes. The most frequent genetic alteration shared by primary and
secondary glioblastomas is loss of heterozygosity (LOH) at 10q (up to 60% of cases). When we
searched for commonly deleted genes at 10q25-qter in The Cancer Genome Atlas (TCGA), 10
genes were identified with log-ratio thresholds of –1.0. Of these, DMBT1 at 10q26.13 was the
only homozygously deleted gene in glioblastomas with or without IDH1 mutations (12.5% vs
8.0%). We demonstrated the presence of DMBT1 homozygous deletion at a similar frequency in
an independent set of primary and secondary glioblastomas (20% vs 21%). A small fraction
(11%) of diffuse astrocytomas also showed homozygous deletion of DMBT1, and this was
significantly associated with shorter overall patient survival (Motomura et al., 2012). A similar
approach was used to search for commonly amplified genes in glioblastomas with and without
IDH1 mutations in the TCGA database. A total of 25 genes were identified, of which 21 were
located at 7q31–34. Further analyses revealed gain of the MET gene at 7q31.2 in primary
glioblastomas (47%) and secondary glioblastomas (44%). Interestingly, MET gain is also
common in diffuse astrocytomas (38%), and is associated with shorter survival. These results
indicate that several genetic alterations that are frequent in both primary and secondary
glioblastomas may be responsible for the identical histological phenotype and, if already present
in diffuse astrocytomas, may predict unfavourable clinical outcome (Pierscianek et al., 2012).
Genetic alterations in microRNAs in medulloblastomas
MicroRNAs (miRNAs) regulate a variety of cellular processes via the regulation of multiple target
genes. We screened 48 medulloblastomas for mutation, deletion, and amplification of 9 miRNA
genes that were selected on the basis of the presence of potential target sequences within the
3′-untranslated region of the MYCC mRNA. Differential PCR revealed deletions in miR-186
(15%), miR-135a-1 (33%), miR-548d-1 (42%), miR-548d-2 (21%), and miR-512-2 (33%)
genes, whereas deletion or amplification was detected in miR-135b (23%) and miR-135a-2
(15%). In miR-33b, deletion, amplification, or a mutation at the precursor miRNA were detected
in 10% of medulloblastomas. Overall, 35 out of 48 (73%) medulloblastomas had at least one
alteration. Real-time RT-PCR revealed MYCC overexpression in 11 out of 37 (30%)
medulloblastomas, and there was a significant correlation between MYCC overexpression and
miR-512-2 gene deletion. Antisense-based knockdown of miR-512-5p (mature sequence of miR512-2) resulted in significant upregulation of MYCC expression in HeLa and A549 cells, while
forced overexpression of miR-512-2 in medulloblastoma/primitive neuroectodermal tumour
(PNET) cell lines DAOY, UW-228-2, and PFSK resulted in downregulation of MYCC protein.
Furthermore, the results of luciferase reporter assays suggested that miR-512-2 targets the
MYCC gene. These results indicate that alterations in the miRNA genes may be an alternative
mechanism leading to MYCC overexpression in medulloblastomas (Lv et al., 2012).
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WHO Classification of Tumours series
MPA is responsible for the publication of the 4th edition of the WHO Classification of Tumours
series (WHO Blue Books). The objective of this project is to establish a histological and genetic
classification of tumours that reflects recent advances in histopathology and cancer genetics,
and that is accepted and used worldwide. These authoritative, concise reference books provide
an international standard for oncologists and pathologists and serve as indispensable guides for
the design of studies monitoring response to therapy and clinical outcome.
WHO Classification of Tumours of the Breast
The 4th volume of the 4th edition of the WHO Classification of Tumours series, this book was
prepared by 90 authors from 24 countries, and was published in June 2012. The volume editors
are Dr Sunil R. Lakhani, The Royal Brisbane and Women's Hospital, Brisbane, Australia; Dr
Ian Ellis, Nottingham University Hospitals, Nottingham, United Kingdom; Dr Stuart Schnitt,
Harvard Medical School, Boston, USA; Dr Puay Hoon Tan, Singapore General Hospital,
Singapore; and Dr Marc J. van de Vijver, Academic Medical Center, Amsterdam,
The Netherlands.
WHO Classification of Tumours of Soft Tissue and Bone
This is the 5th volume of the 4th edition, edited by Dr Christopher D. M. Fletcher, Brigham and
Women’s Hospital, Boston, USA; Dr Julia A. Bridge, Nebraska Medical Center, Omaha, USA;
Dr Pancras C.W. Hogendoorn, Leiden University Medical Center, Leiden, The Netherlands; and
Dr Fredrik Mertens, Lund University, Lund, Sweden. In July 2011, 156 experts from 23 countries
were invited to contribute. The Consensus and Editorial Meeting was held in April 2012 in
Zurich, Switzerland, in collaboration with and with the support of the University of Zurich and
the Charles Rodolphe Brupbacher Foundation. Publication is scheduled for early 2013.
WHO Classification of Tumours of Female Reproductive Organs
This will be the 6th volume of the 4th edition. The volume editors, invited in spring 2012, are
Dr Robert J. Kurman, Johns Hopkins University, Baltimore, USA; Dr Maria Luisa Carcangiu,
Istituto Nazionale dei Tumori, Milano, Italy; Dr Simon Herrington, Ninewells Hospital and Medical
School, Dundee, United Kingdom; and Dr Robert H. Young, Massachusetts General Hospital,
Harvard Medical School, Boston, USA. We are currently preparing the draft WHO Classification,
the structure of the book, and the list of contributors to be invited. The Consensus and Editorial
Meeting for this volume is scheduled for early summer 2013.
References
Badiali M, Gleize V, Paris S et al. (2012). KIAA1549-BRAF fusions and IDH mutations can coexist in diffuse
gliomas of adults. Brain Pathol, 22:841–847. doi:10.1111/j.1750-3639.2012.00603.x PMID:22591444
Kim YH, Nonoguchi N, Paulus W et al. (2012). Frequent BRAF gain in low-grade diffuse gliomas with 1p/19q
loss. Brain Pathol, 22:834–840. doi:10.1111/j.1750-3639.2012.00601.x PMID:22568401
Kleihues P, Rushing E, Ohgaki H (2012). The WHO Classification of Tumours of the Central Nervous
System. In: Batchelor T, Nishikawa R, Tarbell N, Weller M, eds. Textbook in Neuro-Oncology. Oxford
University Press.
Lv S-Q, Kim YH, Giulio F et al. (2012). Genetic alterations in microRNAs in medulloblastomas. Brain Pathol,
22:230–239. doi:10.1111/j.1750-3639.2011.00523.x PMID:21793975
Motomura K, Mittelbronn M, Paulus W et al. (2012). DMBT1 homozygous deletion in diffuse astrocytomas is
associated with unfavorable clinical outcome. J Neuropathol Exp Neurol, 71:702–707.
doi:10.1097/NEN.0b013e31825f2e5d PMID:22805772
Nagaishi M, Kim YH, Mittelbronn M et al. (2012a). Amplification of the STOML3, FREM2, and LHFP genes is
associated with mesenchymal differentiation in gliosarcoma. Am J Pathol, 180:1816–1823.
doi:10.1016/j.ajpath.2012.01.027 PMID:22538188
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Nagaishi M, Paulus W, Brokinkel B et al. (2012b). Transcriptional factors for epithelial–mesenchymal
transition are associated with mesenchymal differentiation in gliosarcoma. Brain Pathol, 22:670–676.
doi:10.1111/j.1750-3639.2012.00571.x PMID:22288519
Ohgaki H (2012). Contribution of molecular biology to the classification of low-grade diffuse glioma. In:
Duffau, H, ed. Diffuse Low-Grade Gliomas in Adults: Natural History, Interaction with the Brain, and
New Individualized Therapeutic Strategies. Springer, in press.
Pierscianek D, Kim Y-H, Motomura K et al. (2012). MET gain in diffuse astrocytomas is associated with
poorer outcome. Brain Pathol, [Epub ahead of print]. doi:10.1111/j.1750-3639.2012.00609.x
PMID:22672415
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Section of Infections (INF)
The Section of Infections (INF) comprises the Infections and Cancer Biology Group (ICB) and
the Infections and Cancer Epidemiology Group (ICE). Both Groups focus on infectious agents
and different aspects of the infection/cancer relationship, including worldwide distribution and
trends over time of cancer-associated infections; range of tumours associated with infection,
and strength of the association; transformation mechanisms; meaning of viral variants; role of
innate and acquired immunity; and new virological and bacteriological tests for epidemiological
studies. Agents studied are mucosal and cutaneous human papillomavirus (HPV) types; human
immunodeficiency virus (HIV), in combination with other cancer-associated viruses; Helicobacter
species; hepatitis B and C virus (HBV/HCV); Epstein–Barr virus (EBV); and Merkel cell
polyomavirus (MCV). Some aspects are exclusive to ICB (transformation mechanisms) or ICE
(worldwide distribution and trends). On other aspects (role of innate and acquired immunity,
different HPV variants), collaborations are possible with the increasing availability in ICB of tests
suitable for large-scale application. One of INF’s greatest assets is collaboration on
methodology. ICB provides advice about decisions on INF biological protocols; ICE provides
guidance on statistical matters in INF protocols and publications. In 2012, INF has had
60 articles published, covering a wide range of topics.
Infections and Cancer Biology Group (ICB)
ICB’s research is focused on the establishment of a causal role of specific infectious agents in
human cancer. Two complementary strategies are currently followed:
(i) Characterization of the biological properties of proteins from potential oncogenic viruses
using in vitro and in vivo model systems; and
(ii) Development and validation of laboratory assays for the detection of infections in human
specimens that can be used in epidemiological studies.
The following viruses are currently included in ICB studies: mucosal and cutaneous HPV types,
MCV and related polyomaviruses, and EBV.
Biological studies
One of the goals of the ICB Group is to evaluate the role of cutaneous β HPV types in the
development of non-melanoma skin cancer (NMSC). We have performed several studies to
characterize the biological properties of the main oncoproteins E6 and E7 from many β HPV
types (Chiantore et al., 2012; Cornet et al., 2012a). In particular, we observed that only E6 and
E7 from some β HPV types displayed in vitro transforming properties (i.e. HPV38 and HPV49),
supporting the hypothesis that β HPV types may differently impact on carcinogenesis. HPV49 E6
shares with mucosal high-risk HPV16 E6 the same mechanism in targeting the tumour
suppressor protein p53. Indeed, both viral proteins induce p53 degradation via the proteasome
pathway (Cornet et al., 2012a). In contrast, we have previously shown that HPV38 inactivates
the p53-regulated pathways inducing accumulation of ΔNp73α, a strong inhibitor of the p53
transcriptional functions. Interestingly, recent data from our group showed that also EBV, via
the oncoprotein LMP-1, inactivates p53 functions increasing ΔNp73α mRNA and protein levels
(Accardi et al., submitted). We are currently exploring whether additional oncogenic viruses
have the properties to target the p53-regulated transcription via accumulation of ΔNp73α.
Epidemiological studies
Another activity of the ICB Group is to perform epidemiological studies in collaboration with
colleagues at IARC and external researchers. We have developed novel assays for the detection
of more than 100 infectious agents, including 68 HPV types, all known polyomaviruses, and all
herpes viruses. These assays are based on the use of multiplex polymerase chain reaction (PCR)
protocols and bead-based technology (Luminex). Validation studies demonstrated the high
sensitivity and specificity of these assays, which allow the use of DNA extracted from a broad
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spectrum of biological specimens, e.g. saliva, paraffin-embedded tissue, urine, cervical cells, and
skin swabs (Comar et al., 2012; Deodhar et al., 2012; Gheit et al., 2012; Halec et al., 2012;
Iannacone et al., 2012). Case–control studies in Florida, where a high incidence of NMSC is
recorded, provided strong evidence for the association of β HPV infections with the development
of squamous cell carcinoma (SCC) (Iannacone et al., 2012). In an independent study in the
same population, we have observed that MCV infections increase the risk of SCC development
(Rollison et al., 2012). In addition to skin cancer, we have performed epidemiological studies to
evaluate the role of oncogenic virus infections in cancer of several anatomical regions, e.g. lung
and bladder (Gheit et al., 2012; Polesel et al., 2012).
Infections and Cancer Epidemiology Group (ICE)
ICE’s goal is to elucidate the contribution of infectious agents, such as HPV, HIV, HBV/HCV,
Kaposi sarcoma herpes virus (KSHV), and H. pylori, to the etiology of cancer.
HPV
In 2012, ICE’s main focus was HPV. For HPV vaccines and HPV-based screening to be
successful, accurate knowledge of the infection burden and type-specific distribution of HPV
types in different parts of the world is needed. ICE carried out new population-based HPV
prevalence surveys in Vanuatu (Aruhuri et al., 2012), the Islamic Republic of Iran (Khodakarami
et al., 2012), and Bhutan (manuscript in preparation). Work in Bhutan was the first step of a
multi-year project meant to demonstrate the early impact of successful implementation of
vaccination against HPV in two low-resource countries (the other being Rwanda). Bhutan and
Rwanda, in addition of having achieved the highest HPV vaccine coverage in developing
countries, are also committed to improving their screening programme through the introduction
of HPV test-based screening. ICE will therefore jointly evaluate the impact of vaccination and
screening. In addition, ICE released the first systematic comparison of the distribution of
individual HPV types in 115 789 HPV-positive women with and without cervical cancer or preneoplastic lesion (Guan et al., 2012). To further expand the study of factors that influence the
geographical variability and different prognosis of HPV infections, HPV16 variants were
evaluated, in collaboration with ICB (Cornet et al., 2012b).
The contribution of HPV infection to cancer of the head and neck is controversial and varies
substantially by population. ICE took advantage of registry-based data from the USA to show
that the presence of HPV was high (50%) and was associated with better survival exclusively in
oropharyngeal sites (Sethi et al., 2012). Tobacco smoking was also, however, a very strong
prognostic factor.
HIV/AIDS
Cancer risk in people with HIV/AIDS (PWHA) is a very important subject to ICE now that highly
active antiretroviral therapy (HAART) has improved survival in PWHA as well as the age-related
cancer burden. A new record-linkage study from the Swiss HIV Cohort suggested that the
approximately 3-fold excess of lung cancer in people with HIV compared with the general
population was not clearly associated, among HIV-positive people, with the severity of
immunosuppression. Lung cancer excess is mainly attributable to heavy smoking (Clifford et al.,
2012).
A second line of research has focused on how HIV infection modifies the cancer potential of HPV
infections in countries at very high risk for both infections (Kenya and South Africa) (De Vuyst et
al., 2012b). A study of 498 HIV-positive women in Nairobi, Kenya, showed that the burden of
high-risk HPV (hrHPV) and cervical intraepithelial neoplasia grade 2 or worse (CIN2/3) was high
and was related to immunosuppression level. Use of combination antiretroviral therapy (cART)
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for 2 years or longer had a favourable effect on hrHPV prevalence but not on CIN2/3. cART use
in our population may have been started too late to prevent CIN2/3 (De Vuyst et al., 2012a).
Finally, better statistical methods were devised to evaluate and project the benefits of HPV
vaccination and screening in HIV-negative and HIV-positive women. Concerns were, for
instance, expressed on the lack of specificity of HPV testing in African women and, notably, HIVpositive women, due to very high hrHPV prevalence. We showed that the positive predictive
value (PPV) for CIN2/3 of HPV testing in high-risk populations was very high, notably in women
aged 45 years or older as CIN2/3 accumulates over time if adequate screening for women is
lacking (Giorgi-Rossi et al., 2012). High PPV demonstrates the effectiveness and potential costeffectiveness of HPV testing in high-risk women despite low test specificity.
Global burden of cancer attributable to infections
ICE, in collaboration with CIN, used data from GLOBOCAN and a variety of literature sources to
calculate the fraction of cancer attributable to infection worldwide and in eight geographical
regions (de Martel et al., 2012). Overall, 2 million (16.1%) of the total 12.7 million new cancer
cases that occurred in 2008 are attributable to infections. This fraction is higher in less
developed countries (22.9%) than in more developed countries (7.4%) and varies 10-fold by
region, from 3.3% in Australia/New Zealand to 32.7% in sub-Saharan Africa. The most
important infectious agents are H. pylori, HBV/HCV, and HPV, which together are responsible for
1.9 million cases of gastric, liver, and cervix uteri cancers, respectively. Application of existing
public health methods for infection prevention, such as vaccination, safer injection practice, or
antimicrobial treatments, could have a major impact on the future burden of cancer worldwide.
References
Aruhuri B, Tarivonda L, Tenet V et al. (2012). Prevalence of cervical human papillomavirus (HPV) infection in
Vanuatu. Cancer Prev Res (Phila), 5:746–753. doi:10.1158/1940-6207.CAPR-11-0515 PMID:22427345
Chiantore MV, Vannucchi S, Accardi R et al. (2012). Interferon-β induces cellular senescence in cutaneous
human papilloma virus-transformed human keratinocytes by affecting p53 transactivating activity. PLoS
One, 7:e36909. doi:10.1371/journal.pone.0036909 PMID:22615843
Clifford GM, Lise M, Franceschi S et al.; Swiss HIV Cohort Study (2012). Lung cancer in the Swiss HIV Cohort
Study: role of smoking, immunodeficiency and pulmonary infection. Br J Cancer, 106:447–452.
doi:10.1038/bjc.2011.558 PMID:22240797
Comar M, Cuneo A, Maestri I et al. (2012). Merkel-cell polyomavirus (MCPyV) is rarely associated to B-chronic
lymphocytic leukemia (1 out of 50) samples and occurs late in the natural history of the disease. J Clin
Virol, 55:367–369. doi:10.1016/j.jcv.2012.08.011 PMID:22959215
Cornet I, Bouvard V, Campo MS et al. (2012a). Comparative analysis of transforming properties of E6 and E7
from different beta human papillomavirus types. J Virol, 86:2366–2370. doi:10.1128/JVI.06579-11
PMID:22171257
Cornet I, Gheit T, Franceschi S et al.; IARC HPV Variant Study Group (2012b). Human papillomavirus type 16
genetic variants: phylogeny and classification based on E6 and LCR. J Virol, 86:6855–6861.
doi:10.1128/JVI.00483-12 PMID:22491459
de Martel C, Ferlay J, Franceschi S et al. (2012). Global burden of cancers attributable to infections in 2008: a
review and synthetic analysis. Lancet Oncol, 13:607–615. doi:10.1016/S1470-2045(12)70137-7
PMID:22575588
De Vuyst H, Mugo NR, Chung MH et al. (2012a). Prevalence and determinants of human papillomavirus
infection in HIV-positive women in Nairobi, Kenya. Br J Cancer, 107:1624–1630. doi:10.1038/bjc.2012.441
De Vuyst H, Ndirangu G, Moodley M et al. (2012b). Prevalence of human papillomavirus in women with
invasive cervical carcinoma by HIV status in Kenya and South Africa. Int J Cancer, 131:949–955.
doi:10.1002/ijc.26470 PMID:21960453
Deodhar K, Gheit T, Vaccarella S et al. (2012). Prevalence of human papillomavirus types in cervical lesions
from women in rural Western India. J Med Virol, 84:1054–1060. doi:10.1002/jmv.23310 PMID:22585722
Gheit T, Muñoz JP, Levican J et al. (2012). Merkel cell polyomavirus in non-small cell lung carcinomas from
Chile. Exp Mol Pathol, 93:162–166. doi:10.1016/j.yexmp.2012.04.008 PMID:22537543
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Giorgi-Rossi P, Franceschi S, Ronco G (2012). HPV prevalence and accuracy of HPV testing to detect highgrade cervical intraepithelial neoplasia. Int J Cancer, 130:1387–1394. doi:10.1002/ijc.26147
PMID:21520039
Guan P, Howell-Jones R, Li N et al. (2012). Human papillomavirus types in 115,789 HPV-positive women: a
meta-analysis from cervical infection to cancer. Int J Cancer, 131:2349–2359. doi:10.1002/ijc.27485
PMID:22323075
Halec G, Schmitt M, Dondog B et al. (2012). Biological activity of probable/possible high-risk human
papillomavirus types in cervical cancer. Int J Cancer, 131:63–71. doi:10.1002/ijc.27605 PMID:22514107
Iannacone MR, Gheit T, Waterboer T et al. (2012). Case–control study of cutaneous human papillomaviruses
in squamous cell carcinoma of the skin. Cancer Epidemiol Biomarkers Prev, 21:1303–1313.
doi:10.1158/1055-9965.EPI-12-0032 PMID:22707711
Khodakarami N, Clifford GM, Yavari P et al. (2012). Human papillomavirus infection in women with and
without cervical cancer in Tehran, Iran. Int J Cancer, 131:E156–E161. doi:10.1002/ijc.26488
PMID:22038830
Polesel J, Gheit T, Talamini R et al. (2012). Urinary human polyomavirus and papillomavirus infection and
bladder cancer risk. Br J Cancer, 106:222–226. doi:10.1038/bjc.2011.519 PMID:22116302
Rollison DE, Giuliano AR, Messina JL et al. (2012). Case–control study of Merkel cell polyomavirus infection
and cutaneous squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev, 21:74–81. doi:10.1158/10559965.EPI-11-0764 PMID:22016472
Sethi S, Ali-Fehmi R, Franceschi S et al. (2012). Characteristics and survival of head and neck cancer by
HPV status: a cancer registry-based study. Int J Cancer, 131:1179–1186. doi:10.1002/ijc.26500
PMID:22020866
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Section of Environment and Radiation (ENV)
The overall objectives of the Section of Environment and Radiation (ENV) are to investigate
environmental, lifestyle, occupational, and radiation-related causes of cancer in human
populations. ENV investigates these exogenous factors with the aim of contributing to primary
prevention of cancer and to increasing the understanding of biological mechanisms of
carcinogenesis. These objectives are achieved through collaborative international
epidemiological studies using a multidisciplinary approach when possible or through the
initiation of individual analytical epidemiological studies. A second approach used by ENV is the
coordination of international consortia of epidemiological studies.
Investigation of external environmental exposures such as pollutants and occupational
exposures are core tasks of ENV. One major area of research is pesticides. ENV coordinates the
newly established consortium of agricultural cohort studies (AGRICOH), allowing the
investigation of various research questions. In addition, ENV conducts studies on testicular
cancer and childhood cancer in the offspring of parents exposed to pesticides; both these
research questions are addressed with multiple but complementary study designs. Another large
effort is ENV’s coordination of a consortium of case–control studies on occupational risk factors
for lung cancer (SYNERGY). ENV coordinates a pooling project of European cohort studies
investigating cancer risks in workers in the contemporary rubber industry and participates in
further investigation of asbestos-related cancer risks.
Research on lifestyle-related factors comprises tobacco and other drugs of abuse, specifically
qat chewing, for which a pilot study has started in Ethiopia. Lifestyle-related questions are also
part of comprehensive studies of particular cancers when there is potential interplay between
environmental and other factors. Further research comprises the launch of studies on the
etiology of oesophageal and breast cancer as well as childhood cancer in low- and middleincome countries. Cancers of particular interest in ENV in the context of ongoing studies are
brain tumours, testicular cancer, upper digestive tract cancer (particularly oesophageal cancer),
childhood cancer, and breast cancer, the latter also in a broader context of using
mammographic density as an intermediate marker of risk. A future aim of ENV is to launch
studies in Africa, where some environmental and occupational exposures are higher and
people’s protection is less rigorous than in high-income countries, to address the rapidly
increasing cancer burden in that continent (McCormack and Schüz, 2012).
Related to ionizing radiation, ENV has projects on the effects of protracted low doses of external
ionizing radiation from medical diagnostic examinations (cohort study of children and
adolescents exposed to computed tomography [EPI-CT]) and from occupational activities
(follow-up of the international study of cancer risk among radiation workers in the nuclear
industry); studies of populations exposed to Chernobyl fallout (development of the Agenda for
Research on Chernobyl Health [ARCH], thyroid cancer risk in clean-up workers); studies on in
utero exposure to ionizing radiation in the Southern Urals (SOLO); and studies on the interaction
between ionizing radiation and genetic factors (e.g. case–control study of thyroid cancer in
young people in the wake of the Chernobyl accident). In the GENE-RAD-RISK project on
radiation exposures at an early age, the impact of genotype on breast cancer risk is
investigated.
With regard to non-ionizing radiation, research activities include a large international
collaborative case–control study on mobile phone use and the risk of brain tumours, acoustic
neuroma, and salivary gland tumours (INTERPHONE); collaboration in a Danish cohort study of
mobile phone subscribers; a pilot study to set up a prospective cohort study of mobile phone
users in France; and collaboration in studies on extremely low-frequency magnetic fields and
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childhood cancer. The INTERPHONE study and collaboration in an international study on brain
tumours in teenagers and adolescents (CEFALO) allows the investigation of various possible
environmental and genetic risk factors of brain tumours.
Consortium of agricultural cohort studies (AGRICOH)
Agricultural worker populations in many countries show distinctive exposure and disease
profiles. These populations appear to have lower risk of some diseases, including colon and lung
cancer, which has been attributed to frequent exposure to microbial agents and healthier habits,
including reduced tobacco use and increased physical activity. In contrast, regular exposure to
certain pesticides, ultraviolet radiation, diesel exhaust and solvents, and high dust levels has
been reported to be associated with increased risks of several cancer types. The purpose of
AGRICOH is to promote and sustain collaboration and data sharing/pooling to assess the
association between various agricultural exposures and a wide range of health outcomes, with a
particular focus on those associations that cannot easily be investigated in individual studies
because of rare exposures or relatively rare outcomes (Leon et al., 2011). As of mid-2012,
26 cohorts from 5 continents are included in AGRICOH. Recently launched projects, both led by
ENV, are on overall cancer risks in various agricultural activities and on the risk of
haematological malignancies in farmers.
Consortium of case–control studies on occupational exposures and lung cancer risk
(SYNERGY)
The aim of the SYNERGY project is to estimate joint effects of five selected occupational
carcinogens (asbestos, respirable crystalline silica [RCS], polycyclic aromatic hydrocarbons
[PAHs], chromium, and nickel) in the development of lung cancer. The results should provide a
scientific basis for recognition of lung cancer as an occupational disease in workers with
exposures to more than one lung carcinogen in combination with tobacco smoking. A total of
17 705 lung cancer cases and 21 813 controls are available from 14 case–control studies. The
quantitative job-exposure matrix SYN-JEM was created based on a database of exposure
measurements for the five selected carcinogens, containing 360 000 measurements from
multiple countries covering more than 50 years. Analyses are in the process of being finalized.
In an analysis on occupational diesel motor exhaust (DME), cumulative DME was associated with
a significant 30% increase in lung cancer risk, comparing highest exposure versus unexposed,
and a significant exposure–response relationship, adjusted for smoking habits (Olsson et al.,
2011).
Studies on the carcinogenicity of asbestos
Quantifying the asbestos-related lung cancer burden is difficult due to this disease’s multiple
causes. Researchers led by ENV explored two methods to estimate this burden using
mesothelioma deaths as a proxy for asbestos exposure, using published data from the follow-up
of 55 asbestos cohorts. Ratios varied by asbestos type, but all types of asbestos fibres kill at
least twice as many people through lung cancer than through mesothelioma, except for
crocidolite (McCormack et al., 2012). For chrysotile, widely consumed today, asbestos-related
lung cancers could not be robustly estimated.
A retrospective cohort study of employees at the world’s largest currently operating chrysotile
asbestos mine and the affiliated processing mills, situated in the town of Asbest, Sverdlovsk
Oblast, Russian Federation, has recently been initiated. The overall aim of the study is to more
precisely characterize and quantify the risks of cancer mortality associated with exposure to this
particular asbestiform mineral. Although the carcinogenicity of chrysotile asbestos is established,
this study seizes the opportunity to further characterize its carcinogenicity using a unique,
relevant, and – due to its comprehensive study base of job details and historical dust
measurements – informative setting.
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International paediatric CT scan study (EPI-CT)
Diagnostic radiation represents an indispensable tool for modern medicine. Physicians see
benefits of using CT scanning in their daily clinical practice. The growing use of CT technology
raises concerns in radiological protection. Children are generally more sensitive to the
carcinogenic effects of ionizing radiation than are adults. In addition, they may receive even
higher radiation doses from a CT procedure than adults. The long-term risk of radiation-induced
cancer or other health effects after CT scanning has not been directly assessed. EPI-CT,
coordinated by ENV, involves 18 centres from 11 countries cooperating in this project to enrol
approximately 1 million patients.
Risk of thyroid cancer in clean-up workers after the Chernobyl nuclear accident
A collaborative case–control study nested within cohorts of Belarusian, Russian, and Baltic
liquidators after the Chernobyl nuclear accident in 1986 was conducted to evaluate the
radiation-induced risk of thyroid cancer. The study included 107 cases and 423 controls.
A statistically significant dose–response relationship was found with total thyroid dose. Although
recall bias and uncertainties in doses could have affected the magnitude of the risk estimates,
the findings of this study contribute to better characterize the risk of thyroid cancer after
radiation exposure in adulthood (Kesminiene et al., 2012).
Mobile phone use and the risk of brain tumours
Scientific evidence on whether use of mobile phones is associated with an increased risk of brain
tumours is still controversial. The question has been addressed using three different
epidemiological study designs that complement one another: case–control, cohort, and
incidence time trend studies. An update of the largest study led by ENV, i.e. a Danish
nationwide cohort study of mobile phone subscribers, did not show any association with brain
tumour risk (Frei et al., 2011; Schüz et al., 2011); although this was reassuring for overall
mobile phone use, no information was available on amount of use, leaving open the possibility
that heavy use of mobile phones still poses a risk. Indeed, such a risk increase has been
reported from the largest and most comprehensive case–control study series in 13 countries,
INTERPHONE, coordinated by ENV; a 40% risk increase was observed in the 10% heaviest
users of mobile phones for glioma (INTERPHONE Study Group, 2010) and likewise for acoustic
neuroma (INTERPHONE Study Group, 2011). Due to reliance in case–control studies on selfreported use of mobile phones and high participation, evidence of bias in those studies
precluded firm conclusions. The first case–control study on teenagers and adolescents on this
topic (CEFALO) also did not show an overall association (Aydin et al., 2011), but questions
remain. ENV also conducted incidence time trend studies; while showing that incidence time
trends of brain tumours in the Nordic countries were stable (Deltour et al., 2012), and thereby
confirming that any large risk increase can be ruled out, they do not allow final judgement on
risks restricted to heavy mobile phone users, as the resulting number of excess brain tumours
would still be too small.
References
Aydin D, Feychting M, Schüz J et al. (2011). Mobile phone use and brain tumors in children and
adolescents: a multicenter case–control study. J Natl Cancer Inst, 103:1264–1276.
doi:10.1093/jnci/djr244 PMID:21795665
Deltour I, Auvinen A, Feychting M et al. (2012). Mobile phone use and incidence of glioma in the Nordic
countries 1979–2008: consistency check. Epidemiology, 23:301–307.
doi:10.1097/EDE.0b013e3182448295 PMID:22249239
Frei P, Poulsen AH, Johansen C et al. (2011). Use of mobile phones and risk of brain tumours: update of
Danish cohort study. BMJ, 343:d6387. doi:10.1136/bmj.d6387 PMID:22016439
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INTERPHONE Study Group (2010). Brain tumour risk in relation to mobile telephone use: results of the
INTERPHONE international case–control study. Int J Epidemiol, 39:675–694. doi:10.1093/ije/dyq079
PMID:20483835
INTERPHONE Study Group (2011). Acoustic neuroma risk in relation to mobile telephone use: results of
the INTERPHONE international case–control study. Cancer Epidemiol, 35:453–464.
doi:10.1016/j.canep.2011.05.012 PMID:21862434
Kesminiene A, Evrard AS, Ivanov VK et al. (2012). Risk of thyroid cancer among Chernobyl liquidators.
Radiat Res, 178:425–436. doi:10.1667/RR2975.1 PMID:22998226
Leon ME, Beane Freeman LE, Douwes J et al. (2011). AGRICOH: a consortium of agricultural cohorts. Int
J Environ Res Public Health, 8:1341–1357. doi:10.3390/ijerph8051341 PMID:21655123
McCormack V, Peto J, Byrnes G et al. (2012). Estimating the asbestos-related lung cancer burden from
mesothelioma mortality. Br J Cancer, 106:575–584. doi:10.1038/bjc.2011.563 PMID:22233924
McCormack VA, Schüz J (2012). Africa’s growing cancer burden: environmental and occupational
contributions. Cancer Epidemiol, 36:1–7. doi:10.1016/j.canep.2011.09.005 PMID:21996568
Olsson AC, Gustavsson P, Kromhout H et al. (2011). Exposure to diesel motor exhaust and lung cancer
risk in a pooled analysis from case–control studies in Europe and Canada. Am J Respir Crit Care Med,
183:941–948. doi:10.1164/rccm.201006-0940OC PMID:21037020
Schüz J, Steding-Jessen M, Hansen S et al. (2011). Long-term mobile phone use and the risk of vestibular
schwannoma: a Danish nationwide cohort study. Am J Epidemiol, 174:416–422.
doi:10.1093/aje/kwr112 PMID:21712479
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Section of Nutrition and Metabolism (NME)
Diet, nutrition, metabolic/hormonal imbalances, excess energy consumption, obesity, and
physical inactivity are thought to be important contributors to increasing cancer incidence rates
worldwide. However, the mechanisms of action of these factors remain poorly understood. In
addition, the contributing influence of dietary transitions from traditional to Western-type diets,
which is taking place in low- and middle-income countries (e.g. Latin America), and exposures in
fetal life/early infancy are not well studied.
Thus, the main objective of the Section of Nutrition and Metabolism (NME) is to address these
issues by evaluating the association of diet (including dietary patterns), nutrition, physical
activity, and energy imbalance with cancer risk in high- and medium-to-low–resource countries
using cohort and case–control designs or human intervention studies. Among others, the NME
Section plays a leading role in the coordination and maintenance of the European Prospective
Investigation into Cancer and Nutrition (EPIC), a large ongoing prospective cohort initiated by
IARC. Emphasis is on improving the accuracy, understanding, and interpretation of dietary
exposures; developing, validating, and disseminating standardized dietary methodologies
relevant to international study settings; applying biomarkers and metabolomics to study cellular,
biochemical, and physiological changes; and consideration of gene–diet/nutrient/environment
interactions. Ultimately, the translation of findings into public health recommendations and the
development of appropriate cancer prevention strategies are of major importance to the NME
Section.
Nutritional Epidemiology Group (NEP)
The overall objective of this Group, in close interaction with DEX and BMA, is to determine the
role of diet, nutrition (micronutrient deficiency, under/over-nutrition), hormonal factors, physical
activity, and energy balance on cancer risk and development, particularly with consideration of
biomarkers and gene–diet/nutrient/environment interactions.
Studies in high-resource settings (the EPIC project)
For colorectal cancer (CRC), major recent publications include: increased risk with higher
oxidative stress levels (Leufkens et al., 2012); decreased risk with higher concentrations of
soluble leptin receptor (Aleksandrova et al., 2012b) and adiponectin (Aleksandrova et al., 2012a);
and lower overall and CRC-specific mortality with higher baseline vitamin D concentration
(Fedirko et al., 2012a). In collaboration with BMA, an analysis of phospholipid fatty acid
concentrations and risk of gastric cancer was published (Chajès et al., 2011), as well as an
association between obesity and higher risk of differentiated thyroid cancer in women (Rinaldi et
al., 2012). For liver cancer, contributions of smoking, alcohol, and hepatitis infection to risk were
confirmed (Trichopoulos et al., 2011), as were those of obesity (Schlesinger et al., 2012) and
higher simple sugar and lower dietary fibre consumption (Fedirko et al., 2012b). Other analyses
in liver cancer are ongoing. For breast cancer (BC), recent efforts have concentrated on risk
assessment for molecular subtypes, showing that high glycemic load and carbohydrate intake
are positively associated with increased risk of ER– and ER–/PR– cancers in postmenopausal
women (Romieu et al., 2012), while higher intake of dietary fibre is inversely associated (Ferrari
et al., 2012a). Analyses on fatty acids, folate, polyphenols, and healthy lifestyle index are
ongoing.
Studies in low- and middle-resource settings
BC is the major female cancer in developed countries, and its incidence and mortality are rising
in lower-resource countries. The Group is using large cohorts and multicentre case–control
studies to identify the roles and mechanisms by which diet, physical activity, obesity, and
metabolic disorders affect BC incidence and survival. The Group is collaborating with the
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National Institute of Public Health (INSP) and the National Cancer Institute (INCan) in Mexico on
a multicentre BC case–control study (CAMA) of Mexican women and a large cohort of Mexican
teachers (EsMaestras) selected in nine Mexican states. In CAMA, analyses show an inverse BC
risk for higher circulating vitamin D (Fedirko et al., 2012c) and higher n-3 PUFA intake, but
increased risk for more n-6 PUFA consumption (Chajès et al., 2012). Studies using fatty acid
biomarkers are in progress. In EsMaestras, larger silhouettes are associated with high intakes of
carbohydrates, sweet drinks, and refined foods (Romieu et al., 2011). A similar study on dietary,
metabolic, and hormonal determinants of mammographic density, a strong BC risk factor, is
progressing. Efforts are advancing to develop a multicountry study (Brazil, Chile, Colombia,
Costa Rica, Mexico) of molecular subtypes of premenopausal BC, with the objective of
evaluating the distribution of specific subtypes and identifying the roles and mechanisms by
which diet, physical activity, obesity, and metabolic disorders affect incidence and survival. The
Group recently published a review paper on the potential role of epigenetics in BC in young
women (Teegarden et al., 2012) and is planning studies on the topic in EsMaestras as well as in
EPIC.
Gene–nutrient interactions
The Group was involved in a successful FP7 application by the Micronutrient Genomics Project to
study carotenoid– and vitamin C–gene interactions using existing data. In EPIC, other studies
are ongoing on CRC (iron–HFE gene mutations) and BC (folate and alcohol intake and folate
metabolism genes).
Alcohol and cancer
The Group is continuing its contribution to systematic meta-analyses on alcohol and risk of
various cancers, recently confirming that light alcohol drinking is associated with higher risk of
oropharyngeal, oesophageal squamous cell, and female BC, but not CRC, liver, or larynx
tumours (Bagnardi et al., 2012). Within EPIC, the rs1573496 (ADH7) polymorphism was shown to
modulate the alcohol–CRC relationship (Ferrari et al., 2012b). In addition, the group is exploring
the application of competing risks approaches to the role of alcohol intake on non-communicable
diseases and reanalysing the role of alcohol intake on BC within EPIC in view of a potential
interaction with folate status.
Determinants of healthy ageing
The Group leads the cancer-specific work package as a partner in a major FP7 project
(CHANCES), which brings together 13 international cohorts to conduct pooled analyses of
determinants of cancer risk and survival in elderly populations. After 2 years of harmonization of
variables, analyses are set to start, with the Group leading efforts on socioeconomic status, and
a competing risks approach for alcohol intake.
Nutritional metabolomics
The Group is continuing its projects of NMR metabolomic profiling in pancreatic and liver
cancers, as well as targeted analyses for a large array of metabolites in close collaboration with
the BMA Group.
Early-life and metabolic disorders
To study the effects of fetal and early-life exposures on health later in life, a consortium of Latin
American birth cohorts has been established. The effects of maternal nutrition and early
nutritional status on the child’s biological/metabolic profiles and as predictors of later disease
risk are under study.
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Dietary Exposure Assessment Group (DEX)
The overall goal of the DEX Group is to improve the accuracy, understanding, and interpretation
of dietary exposure (and changes thereof) in studies on diet and cancer and other intermediate
diseases. This Group has a leading role in the development of dietary methodologies to monitor
changes in dietary exposures and improve their integrated analyses in relation to diseases,
particularly in international study settings.
International methodologies and (web-) infrastructure to support nutritional studies
A comprehensive web-based platform, the dietary e-Standardized Methodologies Platform
(e-SMP), for use and dissemination of the DEX international research dietary methodologies, is
currently being implemented in a stepwise approach. As a key element of the e-SMP, the
standardised 24-hour dietary recall program (EPIC-Soft®) initially developed for international
epidemiological studies (EPIC) has been adapted for use as a reference instrument in panEuropean monitoring surveys within the EFCOVAL project (Slimani et al., 2011). More recently, a
data entry version of EPIC-Soft (PANCAKE project) that is better suited for data entry of
repeated consecutive days of food consumption data as collected by food diaries among children
(but also among the elderly) has also been successfully developed and tested (manuscript in
preparation).
Additional software tools and facilities are also under development or planned through recently
granted projects, for example an e-SMP module for matching food consumption data with
nutrient and other occurrence databases or training and new e-facilities to support distance
training.
The development of new dietary tools also includes the enrichment of the standardized EPIC
Nutrient Databases (ENDB) previously developed by the DEX Group (Slimani et al., 2007). A new
folate database has been compiled (Bouckaert et al., 2011) as well as a database on flavonoids
in collaboration with Spanish colleagues, which will be revised and extended through a broader
cross-sectional project on polyphenols initiated by Drs Romieu (NEP) and Scalbert (BMA).
The Group was also involved as a task leader in the IDAMES project to evaluate measurement
properties of dietary assessment tools and the applicability of innovative e-dietary assessment
technologies for large-scale epidemiological studies (Illner et al., 2012).
Applying DEX methodologies in international monitoring and epidemiological studies
In view of the first pan-European monitoring survey involving the 27 Member States in a rolling
system where the DEX methodology is used as a reference tool, a pilot study in adults has been
launched. Within the two complementary projects, the EMP-PANEU and PILOT-PANEU projects,
funded by the European Food Safety Authority (EFSA), the DEX methodology has been
successfully implemented in five EU Member States (Bulgaria, Hungary, Finland, Portugal, and
Poland) and tested in their respective local feasibility studies. In addition, e-training facilities
were developed at IARC and tested under real study conditions.
As an extension of this successful experience in Europe, the implementation of the DEX
methodologies for research and monitoring purposes in Latin America is under consideration,
starting with Brazil and Mexico as two pilot countries (local and National Institutes of Health
grants have been submitted and are still under evaluation). In parallel, collaboration with the
Korean National Cancer Centre has been established to develop a Korean version of the DEX
methodologies.
Validation and descriptive analyses on dietary exposures and their related biomarkers
(e.g. plasma fatty acids, acrylamide/glycidamide haemoglobin adducts, folates) are ongoing or
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have already been completed in collaboration with researchers within or outside the NME
Section (see list of publications).
Integrated dietary analyses to study diet–disease associations
In parallel with the improvement and standardization of dietary methodologies, the DEX Group,
in close collaboration with the Biostatistics Group (BST) and other, external partners, initiated a
methodological project on analysing nutrient and biological patterns in international study
contexts with planned applications to colorectal cancer (granted project), breast cancer
(ongoing WCRF grant), and diabetes (Interact project). Two methodological papers that
describe the rationale and procedures to derive nutrient patterns and an innovative approach to
ease the interpretation and description of the derived nutrient patterns, particularly in an
international study context, are in preparation.
To consolidate the future DEX activities worldwide, important collaborations/contacts were
established with several EU Member States already using the DEX methodologies in their
national monitoring surveys, (cancer) research/public health centres in Latin America and Korea,
EFSA, WHO headquarters, FAO, and other key players or networks in these nutritional areas. In
addition, an important network of African countries (22 representatives, 35 researchers) was
formed to conduct a full inventory on the local situations regarding dietary and physical activity
assessment methodologies and infrastructures used/needed. This inventory will serve to develop
a road map for prioritizing support infrastructure needed for international nutritional research to
be initiated in Africa.
Biomarkers Group (BMA)
The major objectives of the Group, created 2 years ago, are to develop new biomarkers to
improve assessment of diet, metabolism, and exposure to environmental risk factors, including
food contaminants and hormonal status, and to apply these biomarkers to large cohort and
case–control studies in relation to cancer risk (in close interaction with DEX and NEP) as well as
to small-scale dietary interventions in humans. This approach will allow a better understanding
of the mechanisms and metabolic pathways by which biomarkers of diet, food contaminants,
and hormones affect cancer and intermediate end-points at the cellular and physiological levels.
Special emphasis is given to metabolomic approaches to identify novel biomarkers and to
provide more comprehensive measurements of exposure to cancer risk factors in metabolomewide association studies.
Establishment of a new laboratory for metabolomics studies
A new analytical platform has been developed to analyse the human metabolome and has been
installed at IARC in two fully renovated laboratories. Novel equipment includes a high-resolution
mass spectrometer (QTof 6550 from Agilent) and a tandem mass spectrometer (QTrap 5500
from AB Sciex), both coupled to an ultrahigh-performance liquid chromatography system, a gas
chromatograph, and a robot for solid-phase extraction. Computing capacity was developed to
allow storage and treatment of metabolomics data. Staff have been trained to run this new
equipment, and two young researchers highly skilled in metabolomics have been recruited.
Metabolomics and discovery of biomarkers of exposure to cancer risk factors
New research activities have been started to identify new biomarkers of dietary and
environmental exposure through metabolomics approaches (grants NutriTech FP7, EXPOsOMICS
FP7, EUROCAN). The metabolome is being analysed in urine and plasma samples in large-scale
cohort studies and in specifically designed intervention studies to identify biomarkers of intake
for a large diversity of foods and of environmental exposure. Databases on food constituents
and their metabolites and on biomarkers of dietary exposure are being built to speed up the
identification of biomarkers in complex metabolomic profiles.
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Hormones
A series of hormone analyses have been undertaken within large cohort studies, such as EPIC
and the Mexican EsMaestras cohort (led by Dr Romieu). Analyses of thyroid hormones, thyroid
stimulating hormone, thyroglobulin, and antibodies against thyroglobulin in serum samples have
been finalized in a large case–control study nested within the EPIC cohort on thyroid cancer risk
(in collaboration with Dr Franceschi [ICE]; manuscript in preparation). A study on the
repeatability of these hormones over time has also been initiated. Measurements of growth
factors, adipokines and cytokines, estrogens, and C-peptide have been performed on serum
samples from the EsMaestras cohort, to study the relationship between these biomarkers,
obesity, and mammographic density in women, in collaboration with the NEP Group (led by Dr
Romieu; manuscripts in preparation).
Fatty acids
A method has been developed to routinely analyse 60 fatty acids in blood samples. It has been
optimized for complete resolution of trans fatty acid isomers from industrial and natural dietary
sources. New research activities have been started integrating these measurements for
application in large-scale epidemiological studies in relation to cancer risk in low- to high-income
countries (Chajès et al., 2011).
Polyphenols
A database on all known metabolites of polyphenols, major antioxidants in the diet, has been
developed (Rothwell et al., 2012), and an in-depth characterization of all polyphenols detectable
in urine and plasma samples from cohort studies is ongoing. A novel method of quantification
based on metabolite coding with labelled dansyl chloride is being developed and will be applied
to a first nested case–control study to identify polyphenols associated with risk of colorectal
cancer (grant from Institut National du Cancer).
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Aleksandrova K, Boeing H, Jenab M et al. (2012a). Total and high-molecular weight adiponectin and risk of
colorectal cancer: the European Prospective Investigation into Cancer and Nutrition Study.
Carcinogenesis, 33:1211–1218. doi:10.1093/carcin/bgs133 PMID:22431719
Aleksandrova K, Boeing H, Jenab M et al. (2012b). Leptin and soluble leptin receptor in risk of colorectal
cancer in the European Prospective Investigation into Cancer and Nutrition Cohort. Cancer Res,
72:5328–5337. doi:10.1158/0008-5472.CAN-12-0465 PMID:22926557
Bagnardi V, Rota M, Botteri E et al. (2012). Light alcohol drinking and cancer: a meta-analysis. Ann Oncol,
[Epub ahead of print]. doi:10.1093/annonc/mds337 PMID:22910838
Bouckaert KP, Slimani N, Nicolas G et al. (2011). Critical evaluation of folate data in European and
international databases: recommendations for standardization in international nutritional studies. Mol
Nutr Food Res, 55:166–180. doi:10.1002/mnfr.201000391 PMID:21207520
Chajès V, Jenab M, Romieu I et al. (2011). Plasma phospholipid fatty acid concentrations and risk of
gastric adenocarcinomas in the European Prospective Investigation into Cancer and Nutrition (EPICEURGAST). Am J Clin Nutr, 94:1304–1313. doi:10.3945/ajcn.110.005892 PMID:21993438
Chajès V, Torres-Mejía G, Biessy C et al. (2012). ω-3 and ω-6 Polyunsaturated fatty acid intakes and the
risk of breast cancer in Mexican women: impact of obesity status. Cancer Epidemiol Biomarkers Prev,
21:319–326. doi:10.1158/1055-9965.EPI-11-0896 PMID:22194528
Fedirko V, Lukanova A, Bamia C et al. (2012b). Glycemic index, glycemic load, dietary carbohydrate, and
dietary fiber intake and risk of liver and biliary tract cancers in Western Europeans. Ann Oncol, [Epub
ahead of print]. doi:10.1093/annonc/mds434 PMID:23123507
Fedirko V, Riboli E, Tjønneland A et al. (2012a). Prediagnostic 25-hydroxyvitamin D, VDR and CASR
polymorphisms, and survival in patients with colorectal cancer in Western European populations.
Cancer Epidemiol Biomarkers Prev, 21:582–593. doi:10.1158/1055-9965.EPI-11-1065 PMID:22278364
Fedirko V, Torres-Mejía G, Ortega-Olvera C et al. (2012c). Serum 25-hydroxyvitamin D and risk of breast
cancer: results of a large population-based case-control study in Mexican women. Cancer Causes
Control, 23:1149–1162. doi:10.1007/s10552-012-9984-z PMID:22622862
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Ferrari P, McKay J, Jenab M et al. (2012b). Alcohol dehydrogenase and aldehyde dehydrogenase gene
polymorphisms, alcohol intake and the risk of colorectal cancer in the European Prospective
Investigation into Cancer and Nutrition study. Eur J Clin Nutr, [Epub ahead of print].
doi:10.1038/ejcn.2012.173
Ferrari P, Rinaldi S, Jenab M et al. (2012a). Dietary fiber intake and risk of hormonal receptor defined breast
cancer in the European Prospective Investigation into Cancer and Nutrition study (EPIC). Am J Clin Nutr, in
press.
Illner AK, Freisling H, Boeing H et al. (2012). Review and evaluation of innovative technologies for
measuring diet in nutritional epidemiology. Int J Epidemiol, 41:1187–1203. doi:10.1093/ije/dys105
PMID:22933652
Leufkens AM, van Duijnhoven FJ, Woudt SH et al. (2012). Biomarkers of oxidative stress and risk of
developing colorectal cancer: a cohort-nested case-control study in the European Prospective
Investigation Into Cancer and Nutrition. Am J Epidemiol, 175:653–663. doi:10.1093/aje/kwr418
PMID:22422922
Rinaldi S, Lise M, Clavel-Chapelon F et al. (2012). Body size and risk of differentiated thyroid carcinomas:
findings from the EPIC study. Int J Cancer, 131:E1004–E1014. doi:10.1002/ijc.27601 PMID:22511178
Romieu I, Escamilla-Núñez MC, Sánchez-Zamorano LM et al. (2011). The association between body shape
silhouette and dietary pattern among Mexican women. Public Health Nutr, 15:116–125.
doi:10.1017/S1368980011001182 PMID:21875454
Romieu I, Ferrari P, Rinaldi S et al. (2012). Dietary glycemic index and glycemic load and breast cancer
risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Am J Clin Nutr,
96:345–355. doi:10.3945/ajcn.111.026724 PMID:22760570
Rothwell JA, Urpi-Sarda M, Boto-Ordoñez M et al. (2012). Phenol-Explorer 2.0: a major update of the
Phenol-Explorer database integrating data on polyphenol metabolism and pharmacokinetics in humans
and experimental animals. Database (Oxford), 2012:bas031. PMID:22879444
Schlesinger S, Aleksandrova K, Pischon T et al. (2012). Abdominal obesity, weight gain during adulthood
and risk of liver and biliary tract cancer in a European cohort. Int J Cancer, [Epub ahead of print].
doi:10.1002/ijc.27645 PMID:22618881
Slimani N, Casagrande C, Nicolas G et al.; EFCOVAL Consortium (2011). The standardized computerized 24h dietary recall method EPIC-Soft adapted for pan-European dietary monitoring. Eur J Clin Nutr, 65
Suppl 1:S5–S15. doi:10.1038/ejcn.2011.83 PMID:21731006
Slimani N, Deharveng G, Unwin I et al. (2007). The EPIC nutrient database project (ENDB): a first attempt
to standardize nutrient databases across the 10 European countries participating in the EPIC study.
Eur J Clin Nutr, 61:1037–1056. doi:10.1038/sj.ejcn.1602679 PMID:17375121
Teegarden D, Romieu I, Lelièvre SA (2012). Redefining the impact of nutrition on breast cancer incidence:
is epigenetics involved? Nutr Res Rev, 25:68–95. doi:10.1017/S0954422411000199 PMID:22853843
Trichopoulos D, Bamia C, Lagiou P et al. (2011). Hepatocellular carcinoma risk factors and disease burden
in a European cohort: a nested case-control study. J Natl Cancer Inst, 103:1686–1695.
doi:10.1093/jnci/djr395 PMID:22021666
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Section of Genetics (GEN)
The Section of Genetics (GEN) comprises three Groups with the overall mission of identifying
genes involved in cancer, characterizing the spectrum of pathogenic sequence variants that they
harbour, and understanding how they interact with non-genetic factors. These are the Genetic
Epidemiology Group (GEP), the Genetic Cancer Susceptibility Group (GCS), and the Biostatistics
Group (BST). GEP is mainly involved in coordinating large population-based epidemiological
studies and analysis of multiple common genetic variants to identify new susceptibility loci.
Cancers of primary interest include those of the lung and upper aerodigestive tract (including
the nasopharynx) as well as kidney cancer. GCS hosts the Genetic Services Platform and uses a
combination of bioinformatics and sequencing approaches to aid the identification of
susceptibility variants or mutations. BST provides overall statistical and bioinformatics support to
GEP and GCS while serving as a focal point for statistical activity within the Agency. GEP is also
responsible for two large cohorts that were developed by IARC: the Golestan cohort of
50 000 individuals and the Russian cohort of 150 000 individuals.
Biostatistics Group (BST)
The BST Group contributed to the design and analysis of various studies throughout
the Agency. A selection of these projects is listed below, by collaborating Section and Group.
With the Section of Environment and Radiation (ENV)
Thyroid cancer risk in Chernobyl clean-up workers
BST was responsible for evaluating the effects of uncertainties in the radiation exposure
measurements (Kesminiene et al., 2012).
Asbestos-related lung cancer risk
Mesothelioma was used as a proxy for asbestos exposure, to estimate the attributable fraction
of asbestos in lung cancer (McCormack et al., 2012).
With the Section of Nutrition and Metabolism (NME)
Dietary reporting errors
Errors in reports of dietary consumption, as judged by physiologically implausible caloric intakes,
were found to be strongly associated with body mass index (BMI). This suggests the presence
of strong systematic biases in dietary exposure measures (Freisling et al., 2012).
Body size and differentiated thyroid cancers
The risk of differentiated thyroid cancer was found to be associated with obesity in women,
whether measured by BMI or waist-to-hip ratio. In men, the association was with height,
directly and also via leg length (Rinaldi et al., 2012).
With the Genetic Cancer Susceptibility Group (GEN/GCS)
Optimizing high-throughput classification of rare variants
It was shown that using a transformed version of continuous measure of variant tolerability
produced by the SIFT program can outperform the standard binary classification when applied
to multiple variants in a gene (Delahaye et al., submitted).
Radiation and genetic risk factors for papillary thyroid cancer (PTC)
In a study of those exposed to radiation subsequent to the Chernobyl accident, several genetic
factors were seen to increase the risk of PTC in conjunction with radiation. The effect of
radiation and genetic factors appeared to be multiplicative (which may or not be described as an
interaction depending on scale) (Damiola et al., submitted).
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With the Genetic Epidemiology Group (GEN/GEP)
Opium consumption and mortality – see GEP section below (Khademi et al., 2012a).
Alarm symptoms for upper gastrointestinal tract (UGI) malignancies
An optimal decision tool is being developed for patients presenting with dyspepsia in the context
of high rates of UGI malignancy (Khademi et al., 2012b).
Genetic variants, cotinine, and lung cancer risk
Measurements of cotinine were used to calibrate self-reported smoking rates and so obtain
modified estimates of the direct effect of 15q25 variants on lung cancer risk (Timofeeva et al.,
2011).
Outside IARC
University of Melbourne: Cancer risk of computed tomography (CT) scans of children and young
adults
A study of a cohort of 11 million young Australians to estimate risks of cancer resulting from CT
scans in the first 19 years of life (Mathews et al., submitted).
University of Helsinki: Trends in breast cancer mortality
A study of breast cancer mortality trends in Sweden, using the staged introduction of screening
to obtain an alternative estimate of the benefit of screening (Haukka et al., 2011).
Genetic Cancer Susceptibility Group (GCS)
In 2012, GCS has studied the contribution of rare variants to cancer susceptibility and further
exploited the genome-wide association study (GWAS) approach to investigate the contribution
of common genetic variants. We have also focused on the installation and optimization of the
laboratory and bioinformatics aspects of next-generation sequencing.
Rare variants in XRCC2 and breast cancer susceptibility
An exome (the coding part of the genome)-sequencing study of families with multiple breastcancer-affected individuals identified two families with mutations in the homologous
recombination-related DNA repair gene XRCC2, one protein-truncating mutation and one
probably deleterious missense substitution. To further investigate this gene, 689 families with
multiple breast cancer cases were screened for mutations at the University of Melbourne, and at
IARC we screened 1308 breast cancer patients with an early age of cancer onset and
1120 controls. The replication phase identified eight additional breast cancer cases carrying a
protein-truncating or a probably deleterious (as predicted by in silico tools) rare missense
variants in XRCC2. This number of variants was more than expected by chance, implicating
XRCC2 in breast cancer susceptibility. This is the first breast cancer susceptibility gene to be
identified using such an approach. This study demonstrates the potential that massively parallel
sequencing, in combination with appropriate study designs, has to discover new cancer
susceptibility genes.
Incorporating prior probabilities to assist ranking of a GWAS of oral cancers
We have undertaken a GWAS of oral cancer in 791 cases and 7012 controls. We developed a
Bayesian method, AdAPT, that allows prior probabilities for genetic variants to be considered in
the ranking of GWAS results. Higher prior probabilities were placed on genetic variants that
keyword-based, automated text screening of the medical literature identified as potentially
relevant to oral cancers. The top five genetic variants ranked using AdAPT were studied further
in an additional 1046 oral cancer cases and 2131 controls. Only one variant, rs991316, ranked
77th by P value and 3rd using AdAPT, displayed statistically significant association in the
replication phase (Preplication = 0.003). The rs991316 variant is located in the ADH gene cluster on
4q23, and appears to be restricted to oral cancers, with little evidence for association with other
upper aerodigestive tract cancer sites. The GCS Group is now exploring the possibility of
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incorporating additional sources of information to generate prior probabilities within AdAPT, for
example genomics information produced by the Genetic Services Platform.
Genetic Services Platform (GSP)
By maintaining and further developing the genetic technical platform and related Laboratory
Information Management System (LIMS), the GSP provides a suite of laboratory services to
support IARC genomics projects. The platform integrates several multipurpose liquid-handling
robots into the laboratory processes in combination with the use of a LIMS to track the progress
of samples as they pass through the laboratory workflows. Recent developments of GSP include
the installation of two next-generation sequencers (a Life Technologies SOLiD 5500XL and an
Ion Torrent PGM) and a high-performance computing cluster.
The main GSP capabilities are:
• Exome and targeted sequencing using massively parallel sequencing
• SNP genotyping using TaqMan, high-resolution melting curve analysis, or Illumina microarrays
• Gene expression, copy number variation, and whole-genome methylation profiling using
Illumina microarrays.
GSP coordinates collaborative efforts with IARC Groups (GCS, GEP, EGE, ICB, MPA, MMB) and
external partners. Some examples of recent relevant projects are:
• Exome sequencing of nasopharyngeal cancer patients from an extended Malaysian pedigree
(GCS)
• Exome sequencing of lung cancer patient tumours and corresponding germline DNAs
(collaboration with GEP)
• Whole-genome expression profiling by RNA-seq of total cellular RNA from Epstein–Barr virus
(EBV)-infected cells with pLXSN, anti DNp73a anti-sense oligonucleotide and the sense
oligonucleotide (collaboration with ICB)
• Exome sequencing of schwannoma patients (collaboration with MPA)
• Exome sequencing of formalin-fixed, paraffin-embedded (FFPE) triple-negative breast cancers
and corresponding germline DNAs (collaboration with MMB)
• Whole-genome methylation profiling using Illumina 450K microarrays on blood samples from
children exposed to aflatoxin (collaboration with EGE)
• Whole-genome methylation profiling using Illumina 450K microarrays on large series of blood
samples from breast cases and controls from the EPIC cohort (collaboration with EGE).
Genetic Epidemiology Group (GEP)
Notable results from GEP in 2012 include the following.
Lung cancer genome-wide analyses
Recent GWASs have identified common genetic variants at 5p15.33, 6p21–6p22, and 15q25.1
associated with lung cancer risk. To identify additional novel risk variants for lung cancer, we
have recently performed a meta-analysis of 16 GWASs, totalling 14 900 cases and 29 485
controls of European descent (Timofeeva et al., 2012). This international collaboration, with the
analysis hosted at IARC, provided increased support for previously identified risk loci at 5p15,
6p21, and 15q25. Furthermore, we demonstrated histology-specific effects for 5p15, 6p21, and
12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus
for squamous cell carcinoma at 9p21, which was replicated in a series of 5415 Han Chinese.
This large analysis provides additional evidence for the role of inherited genetic susceptibility to
lung cancer and insight into biological differences in the development of the different
histological types of lung cancer.
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Renal cancer genome-wide analyses
Along with colleagues from the United States National Cancer Institute and MD Anderson Cancer
Center, we have extended our previous GWA analysis of renal cancer, published in 2011
(Purdue et al., 2011), with an extended analysis that involved an additional 984 cases and
1516 controls (Wu et al., 2012). This analysis resulted in the identification of a fourth
susceptibility locus for renal cancers at 12p11.23, implicating the ITPR2 gene. The other primary
focus for this year has been to bring together a series of 2000 cases and a similar number of
controls, who will undergo dense genome-wide genotyping.
Hodgkin lymphoma genome-wide analyses
In 2012 we finalized a GWAS of 1200 classical Hodgkin lymphoma (cHL) patients and more than
6000 control subjects, with validation in an independent replication series, to identify common
genetic variants associated with total cHL and subtypes defined by tumour EBV status (Urayama
et al., 2012). Two novel loci associated with total cHL irrespective of EBV status were identified
in the major histocompatibility complex region; one resides adjacent to MICB and the other at
HLA-DRA, with both results confirmed in an independent replication series. Associations were
also found between EBV-positive cHL and genetic variants within the class I HLA region and
between EBV-negative cHL and variants within the class II region. Evidence for an association
between EBV-negative cHL and the 5q31 region (comprising the IL13 gene – previously linked
to psoriasis and asthma) was also observed.
Opium consumption and mortality within the Golestan cohort
The 50 000 individuals of the Golestan cohort, recruited between 2004 and 2008, were followed
up to mid-2011, at which point 2145 deaths had been reported. An initial analysis on the role of
opium in all-cause mortality was finalized and published in 2012 (Khademi et al., 2012a),
reporting a nearly 2-fold increased risk for the 17% of the population who had reported opium
use at baseline. Opium consumption was significantly associated with increased risks of deaths
from several causes, including circulatory diseases (hazard ratio, 1.81) and cancer (1.61). The
strongest associations were seen with deaths from asthma, tuberculosis, and chronic obstructive
pulmonary disease (11.0, 6.22, and 5.44, respectively). After exclusion of people who selfprescribed opium after the onset of major chronic illnesses, the associations remained strong
with a dose–response relation.
References
Freisling H, van Bakel MM, Biessy C et al. (2012). Dietary reporting errors on 24 h recalls and dietary
questionnaires are associated with BMI across six European countries as evaluated with recovery
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SC/49/2 & GC/55/2
Section of Early Detection and Prevention (EDP)
Prevention and early detection are major interventions in reducing the burden of and controlling
cancer. The Section of Early Detection and Prevention (EDP) consists of three groups: the
Prevention and Implementation Group (PRI), the Quality Assurance Group (QAS), and the
Screening Group (SCR). Together, their aim is to make significant contributions through focused
research to the development of cost-effective and resource-appropriate public health policies for
early detection and prevention, as well as evidence-based and quality-assured strategies to
further augment prevention and early detection programmes for breast, cervical, colorectal,
oral, and gastric cancers globally, with particular emphasis on less-developed countries. To
achieve this objective, the Section investigates various early detection and prevention
approaches and addresses the development of quality assurance guidelines and the integration
of the different prevention and early detection strategies as part of routine health services.
There is a continuing emphasis on developing, updating, and expanding training resources to
augment human resources for cancer prevention and early detection initiatives and on the scaleup of prevention and early detection services by contributing to the development of local health
systems within the limitations of the research studies.
Prevention and Implementation Group (PRI)
PRI conducts studies to evaluate the efficacy, population impact, and feasibility of interventions
aimed at the primary and secondary prevention of cervical, anal, oral, and gastric cancer,
particularly in low- and middle-income countries. In addition, we collaborate with public health
institutions and governments to implement and evaluate effective interventions for cancer
prevention. The main focus of PRI has been the development and implementation of safe and
effective vaccines against human papillomavirus (HPV)-related cancers and the evaluation of the
potential impact of Helicobacter pylori (H. pylori) eradication on gastric cancer incidence and
mortality. In addition, a multicentre evaluation of methods to triage HPV-positive women in the
context of cervical cancer screening is planned, to start in the near future.
Cervical cancer studies in Guanacaste, Costa Rica
The Guanacaste Project (PEG) is a long-term collaboration with the United States National
Cancer Institute and Costa Rican investigators to investigate the natural history of HPV
infections and associated neoplasia, in addition to new preventive strategies. The Costa Rica
Vaccine Trial (CVT) is part of this effort. Between 2004 and 2005, CVT recruited approximately
7500 women aged 18–25 years to participate in a randomized controlled trial of the bivalent
HPV vaccine (HPV 16/18) to evaluate its efficacy against cervical infections and cervical
intraepithelial neoplasia (CIN2+). The initial 4-year follow-up has been completed, and initial
results on prevention of 1-year persistent infections published (Herrero et al., 2011). A report on
efficacy to prevent CIN2+ has been submitted to the United States Food and Drug
Administration. We observed approximately 80% protection against CIN2+ regardless of HPV
type in the according-to-protocol cohort of naive women. The long-term follow-up of the
vaccinated cohort continues, mainly to evaluate long-term protection (10 years), safety,
immunogenicity, and HPV type-replacement.
Epidemiology and prevention of anal and oral HPV infection
At the 4-year visit in the Costa Rica Vaccine Trial, we obtained anal specimens for HPV testing
from sexually active women. We detected 22% of anal oncogenic HPV infection in this group of
relatively young women (Castro et al., 2012). Current plans include long-term follow-up of anal
HPV-positive women with HPV testing, anal cytology, and anoscopy, to define the natural history
of these infections. We have already reported on the efficacy of the vaccine to prevent anal HPV
infection 4 years after recruitment (Kreimer et al., 2011), and the long-term follow-up will permit
assessment of long-term efficacy. Oral HPV detection was relatively low (1.9%), but we
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observed lower prevalence among vaccinated women 4 years after vaccination (unpublished
results). Follow-up is under way to investigate the natural history of these infections.
Multicentre study of HPV screening and triage (ESTAMPA)
We have put together a group of Latin American investigators to conduct a large multicentre
study including more than 50 000 women to evaluate multiple triage techniques among HPVpositive women. Women aged 30–64 years will be recruited at centres in at least seven Latin
American countries and screened with an HPV test. All HPV-positive women and a sample of
HPV-negative women will be referred for colposcopy, biopsy, and final diagnosis, with follow-up
at 18 months. Visual, cytological, and molecular triage methods should allow the definition of
specific strategies to select women requiring more intensive follow-up and treatment. The study
is in its final phases of preparation.
Clinical trial of H. pylori infection in Latin America
We have completed the initial follow-up phase of our Latin American randomized clinical trial to
evaluate efficacy of three different treatment regimens against H. pylori in seven centres in
Latin America, conducted in collaboration with the Southwest Oncology Group (SWOG) in the
USA. The results of eradication at 6 weeks after treatment have been published (Greenberg et
al., 2011), and we have now completed analysis of the 1-year follow-up data. The
recurrence/reinfection rate appears larger than expected, and detailed analysis of its
determinants is under way.
Medellin, Colombia, ASCUS trial
In collaboration with the University of Antioquia, we are participating in a randomized trial to
evaluate different strategies for clinical management of women with atypical squamous cells of
unknown significance (ASCUS) cytology. The trial is well under way, with close to 1500 women
recruited. Recruitment will continue for at least another year.
Support of HPV vaccination and screening programmes in Latin America
In the context of the Argentina national screening programme to implement HPV-based
screening, extensive political and educational meetings, development of guidelines and
educational material, setting up of laboratories, etc., have been completed for the first province
to implement the programme (Jujuy). A protocol to evaluate the acceptability and performance
of self-collected specimens was recently initiated. Extension to new areas is now being planned.
The materials developed and the experience gained should be useful for implementing other
programmes in the region. We have participated in meetings with local authorities from Mexico,
Costa Rica, Chile, Colombia, Peru, and Paraguay and with the Network of Latin American Cancer
Institutes to promote implementation of new cervical cancer screening approaches and HPV
vaccination.
Quality Assurance Group (QAS)
Quality assurance aims to ensure that a given endeavour leads to the outcome for which it is
intended. It is highly relevant to complex systems, such as screening and primary prevention
programmes that are designed to lower the burden of cancer in the population. The activities of
the QAS Group aim to expand and effectively disseminate knowledge key to assuring the
successful implementation of primary and secondary prevention programmes as a tool for
comprehensive cancer control. The focus is on programmes and evidence-based interventions
for large segments of the population in which the majority of currently preventable cancer cases
and deaths occur. The efforts of the Group are particularly relevant to continuous improvement
in comprehensive control of cancer. They cover not only primary and secondary prevention but
also tertiary prevention, because the process of screening involves diagnosis, treatment, and
also subsequent care of patients identified through screening.
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SC/49/2 & GC/55/2
The same principles of quality assurance and successful implementation of cancer prevention
programmes apply in all cultural and resource settings (see, e.g., Hill and Dixon, 2010; Kania and
Kramer, 2011; Hanleybrown et al., 2012; Lynge et al., 2012; von Karsa et al., 2012a). Through
coordination of international networks, the Group promotes exchange of experience and
collaboration in quality assurance and successful implementation of programmes in Europe and,
increasingly, in other regions of the world.
Guidelines for cancer screening
The WHO guidelines on Comprehensive cervical cancer control were published by WHO in 2006.
The QAS Group has collaborated with the Department of Chronic Diseases Prevention and
Management and the Department of Reproductive Health and Research in a project co-financed
by the French National Cancer Institute to update the WHO guidelines.
The fourth edition of the European guidelines for quality assurance in breast cancer screening
and diagnosis was published by the European Commission in 2006 (Perry et al., 2006; see also
Perry et al., 2008). A full revision of the European guidelines for quality assurance in breast
cancer screening and diagnosis is now under way, and the new, fifth edition is planned for
publication in 2014 or 2015. In the meantime, supplements to the current, fourth edition have
been prepared in a project coordinated by the QAS Group and co-financed by the EU Health
Programme. These supplements have been developed to address those fields that the editors
felt warranted an earlier update of the standards, protocols, and best practice
recommendations, in particular digital mammography and pathology. The supplements also
include recommendations on implementation of population-based cancer screening programmes
that are relevant not only to breast cancer screening but also to cervical and colorectal cancer
screening.
The Group has collaborated with experts in quality assurance and evaluation of breast cancer
screening in the preparation and publication of a series of 10 papers based on the results of
population-based service screening programmes in the EU (Broeders et al., 2012; Giordano et al.,
2012a, 2012b; Hackshaw 2012; Hofvind et al., 2012; Moss et al., 2012b; Njor et al., 2012; Paci and
EUROSCREEN Working Group, 2012; Puliti et al., 2012; Zappa and Federici, 2012). The papers
elucidate the balance between the key benefits and harms of breast cancer screening and show
that the results expected from the randomized trials have been achieved in service screening
programmes in Europe. Preparation of these publications has been co-financed by the EU Health
Programme.
Another series of 13 papers based on the individual chapters of the European guidelines for
quality assurance in colorectal cancer screening and diagnosis (Segnan et al., 2010) have been
prepared and published (Atkin et al., 2012; Austoker et al., 2012; Halloran et al., 2012; LansdorpVogelaar and von Karsa, 2012; Malila et al., 2012; Minozzi et al., 2012; Moss et al., 2012a; Quirke
et al., 2012; Steele et al., 2012a, 2012b; Valori et al., 2012; Vieth et al., 2012; von Karsa et al.,
2012b). Adherence to the principles, standards, and recommendations in the guidelines has the
potential to enhance the control of colorectal cancer through improvement of the quality and
effectiveness of screening programmes and services. Through these publications, the editors
hope to promote international discussion and collaboration by making the content of the new EU
guidelines known to a wider professional and scientific community. The preparation of the
recommendations in the EU guidelines has been co-financed by the EU Health Programme.
The second edition of the European guidelines for quality assurance in cervical cancer screening
was published by the European Commission in 2008 (Arbyn et al., 2008; see also Arbyn et al.,
2010). Supplements to the current, second edition have been prepared in a project coordinated
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Page 44
by the QAS group and co-financed by the EU Health Programme. These supplements deal with
fields that the editors felt warranted an update (primary screening through HPV testing) or
inclusion in the guidelines (HPV vaccination) before preparation of a third edition. The
supplements will be published in 2013.
Revision of the European Code Against Cancer
Work has begun on the revision of the European Code Against Cancer (Boyle et al., 2003). The
aim of the project, which is co-financed by the EU Health Programme, is to evaluate, revise, and
expand if necessary the previous recommendations for key lifestyle and public health
interventions that if adopted by average-risk members of the population may result in a
reduction in cancer incidence and mortality. The project is coordinated by the QAS and ENV
groups and involves several other sections and groups within the Agency (CIN, COM, IMO, INF,
PRI, SCR).
EU screening implementation report
The first Report on the Implementation of the Council Recommendation of 2 December 2003 on
Cancer Screening was published by the European Commission in 2008. Work has begun on the
second report in a project coordinated by the QAS group and co-financed by the EU.
Dissemination of knowledge on successful implementation of cancer screening
In addition to the above-mentioned guidelines publications, in bilateral projects the Group has
provided advice to the programmes and responsible authorities involved in breast and cervical
cancer screening in Belarus; in breast cancer screening in Estonia; and in breast, cervical, and
colorectal cancer screening in Turkey. The ongoing expert support to Belarus is provided in
collaboration with WHO (headquarters, WHO Regional Office for Europe, and country office).
The Group has also played a key role in the EUROMED project, providing advice in capacity
building in early diagnosis and training in quality assurance and implementation of cancer
screening programmes to 18 countries in the Mediterranean region, including the Middle East
and Northern Africa. This project is co-financed by Italy, France, and Spain and is jointly
coordinated by the Ministries of Health and Finance in these countries in collaboration with the
WHO headquarters (Department of Chronic Diseases Prevention and Management) and IARC
(QAS).
A two-week course on planning, management, and evaluation of population-based cancer
screening programmes has been developed, and piloting will begin in November 2012. This
project is co-financed by the EU Health Programme through the European Partnership for Action
Against Cancer and the EUROMED project.
Screening Group (SCR)
SCR conducts studies to evaluate the performance characteristics, effectiveness, and service
delivery aspects of different screening and early clinical diagnosis interventions for breast,
cervical, colorectal, and oral cancer control in low- and middle-income countries (LMICs). These
initiatives address the development and evaluation of pragmatic and feasible quality assurance
inputs, the methods by which screening services could be scaled up through routinely existing
health systems, the evaluation of population and service delivery determinants that influence
participation in intervention programmes, and the development of different training resources to
catalyse and augment trained human resources through close collaboration with the national
institutions and government health services in the countries. The Group aims to catalyse the
development of resource-appropriate screening, early diagnosis policies, and health systems to
deliver effective early services. Technical support is also provided to planned and ongoing
national early detection programmes in selected LMICs.
IARC Interim Annual Report 2012
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SC/49/2 & GC/55/2
Cervical cancer prevention and screening
As part of efforts to accelerate the introduction of HPV vaccination in low-resource countries, the
efficacy of two doses versus three doses of HPV vaccine, administered over 6 months, in
preventing cervical neoplasia is being evaluated in a clinical trial. Of the 17 729 unmarried girls
recruited, 4920 have received two doses and 4337 have received three doses over 180 days or
more; the remainder have received either a suboptimal single dose or two doses over 60 days.
Preliminary results indicate that the immunogenicity of two doses is non-inferior to the threedose regimen. No serious adverse events related to vaccination have been reported so far. The
study cohorts will be followed up to establish long-term immunogenicity, amnestic response,
HPV infection, and cervical neoplasia outcomes following the different dose regimes.
SCR continues to document cervical cancer incidence and mortality among the 230 000 women
in the Osmanabad and Dindigul district cervical screening trials in India, addressing the impact
of a single round of screening with HPV testing, cytology, or visual inspection with acetic acid
(VIA). The role of cytology and VIA to triage HPV-positive women is being evaluated in a
randomized trial involving 30 000 women in India. The effectiveness of different screening
approaches in preventing cervical neoplasia in human immunodeficiency virus (HIV)-infected
women is being addressed in a cross-sectional study in India (Joshi et al., 2012). A descriptive
evaluation of the Thailand national cytology screening programme has been completed,
highlighting the need to improve several programmatic aspects, and results have been
published (Khuhaprema et al., 2012). Technical support was provided to ongoing programmes in
Bangladesh, Guinea, India, Morocco, Republic of Congo, Sri Lanka, and Thailand. An evaluation
of cervical cancer screening in health services in Mali was completed (Teguete et al., 2012).
A high acceptability of HPV vaccination in the general population of Argentina was established in
a qualitative study (Arrossi et al., 2012). An overall assessment of visual inspection methods for
cervical screening was completed (Sankaranarayanan et al., 2012a). A meta-analysis of the
efficacy of cryotherapy in curing cervical intraepithelial neoplasia was completed (Sauvaget et al.,
2012).
Breast cancer screening
The second round of screening by clinical breast examination (CBE) has been completed, and
the third round has been initiated in a randomized controlled trial involving 116 000 women in
Trivandrum, India. A qualitative study addressing the factors influencing participation in the
various levels of the screening trial has been initiated. A study of the role of breast awareness in
improving early detection and survival of breast cancer patients was initiated in Mumbai in 2012
(Gadgil et al., 2012). We are currently evaluating the performance characteristics of new tools
based on near-infrared imaging and tactile imaging in India, China, and Thailand.
Oral cancer screening
Long-term results, after 15 years of follow-up, of the participants in the randomized trial of oral
visual screening in Kerala, India, indicate a 25% reduction in mortality among users of tobacco
and/or alcohol and a more than 80% reduction in mortality in those who complied with all four
rounds of screening (Sankaranarayanan et al., 2012b). We are currently evaluating the inputs
and outcome of a “social marketing” increased-awareness-based early detection programme in
Sri Lanka.
Colorectal cancer screening
SCR is technically supporting the integration and scaling up of a colorectal cancer screening
programme based on immunochemical faecal blood testing and triage colonoscopy in the
government health services in Lampang Province, Thailand. It has already covered 50% of the
150 000 target population aged 50–64 years and will inform and facilitate large-scale national
scaling up in the future.
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IARC Interim Annual Report 2012
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screening. Endoscopy, 44:SE140–SE150. doi:10.1055/s-0032-1309802 PMID:23012117
Steele RJC, Rey J-F, Lambert R (2012b). European guidelines for quality assurance in colorectal cancer
screening and diagnosis. First edition. Professional requirements and training. Endoscopy, 44:SE106–
SE115. doi:10.1055/s-0032-1309796 PMID:23012114
Teguete I, Muwonge R, Traore CB et al. (2012). Can visual cervical screening be sustained in routine health
services? Experience from Mali, Africa. BJOG, 119:220–226. doi:10.1111/j.1471-0528.2011.03122.x
PMID:21895956
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Valori R, Rey J-F, Atkin W et al. (2012). European guidelines for quality assurance in colorectal cancer
screening and diagnosis. First edition. Quality assurance in endoscopy in colorectal screening and
diagnosis. Endoscopy, 44:SE88–SE105. doi:10.1055/s-0032-1309795 PMID:23012124
Vieth M, Quirke P, Lambert R et al. (2012). European guidelines for quality assurance in colorectal cancer
screening and diagnosis. First edition. Annex - Annotations of colorectal lesions. Endoscopy,
44:SE131–SE139. doi:10.1055/s-0032-1309798 PMID:23012116
von Karsa L, Patnick J, Segnan N (2012a). European guidelines for quality assurance in colorectal cancer
screening and diagnosis. First edition. Executive summary. Endoscopy, 44:SE1–SE8. doi:10.1055/s0032-1309822 PMID:23012113
von Karsa L, Patnick J, Segnan N et al. (2012b). European guidelines for quality assurance in colorectal cancer
screening and diagnosis: Overview and introduction to the full Supplement publication. Endoscopy, in
press.
Zappa M, Federici A (2012). Introduction. J Med Screen, 19 Suppl 1:3–4. doi:10.1258/jms.2012.012075
PMID:22972805
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The Gambia Hepatitis Intervention Study Group (GHIS)
The Gambia Hepatitis Intervention Study aims to evaluate the effectiveness of vaccination
against hepatitis B virus in infancy for the prevention of cirrhosis and liver cancer in The
Gambia. It was initiated in 1986.
The three partners in this long-term project – IARC; the Medical Research Council, The Gambia
Unit; and the Government of The Gambia – met in January 2012 to review progress. They
endorsed plans for enhanced surveillance of chronic liver disease, including cancer, and reaffirmed their commitment to the study.
Dr Njie, the hepatologist now managing the project, has further developed clinical services for
those with liver disease and ensured that all the relevant information is captured by the National
Cancer Registry. To further strengthen the registry, one of the senior Tumour Registry Officers
attended the IARC Summer School on Cancer Epidemiology in Lyon.
Dr Ervik of IARC visited The Gambia to support the registry and to develop record-linkage
methods. The variability in spelling of both forenames and family names is a key issue,
particularly since this spelling may have changed between the time when the name was
recorded for the infant and now, when that infant is an adult giving their own name. A strategy
of generating a complete listing of possible spellings and using this for linkage is now being
evaluated. The final linkage is likely to require verification using the foot and palm prints
collected both for those in the vaccination study and for all subjects in the appropriate age
range recorded by the cancer registry. Once this has been validated, the linkage protocol can be
finalized.
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Laboratory Services and Biobank Group (LSB)
The biobank arm of the Laboratory Services and Biobank Group (LSB) is responsible for
managing biological resources and for providing biobanking services to IARC colleagues and
international collaborators. IARC stores more than 7 million biosamples – about 4 million from
370 000 participants in the EPIC study, and the remainder from collaborative projects involving
IARC-based scientists. LSB’s other role is to support core laboratory activities at IARC. Together
with the Laboratory Steering Committee (LSC), the laboratory services arm of LSB sets priorities
for investment in equipment and shared platforms.
Biobank
The main goals of the biobank arm of LSB are to maintain and manage a centralized IARC
Biobank in a safe and secure environment; to provide an up-to-date record of IARC’s resources;
to provide a reliable pre-analytical sample processing service for sample retrieval, DNA
extraction, and shipment according to international guidelines and protocols; and to contribute
its resources and services internationally, through established networks. For sample inventory
and cataloguing, to date, sample records for 47% of the IARC-based collections have been
checked and verified, and more than half of the verified records have been entered into the
centralized database (SAMI). A sample access policy has been developed in collaboration with
the Biobank Steering Committee (BSC), to provide information on how to access IARC’s
resources. In 2012 a review was conducted of the practices and procedures, including the
operational costs, of the biobank. As a result, the Material Transfer Agreement (MTA) and
sample shipment procedures have been revised in line with international guidelines and
protocols and for synergy with the sample access procedures. Through a tender process, a new
company has been identified that will provide liquid nitrogen at a much lower cost compared
with the previous contract.
Future priorities include working closely with the Section of Support to Research (SSR), LSC, and
BSC to develop the new laboratory and biobank infrastructure for IARC, and exploring the
possibility of coordinating a biobank network for low- and middle-income countries (LMICs) in
collaboration with the United States National Cancer Institute (NCI) and other international
societies and organizations. The aim is to work with LMIC partners to address shortfalls in
population cohorts and biobanking facilities, which are underdeveloped in resource-constrained
settings.
Laboratory Services
The main goal of the laboratory services arm of LSB is to manage the basic laboratory services
supporting research. This includes, in collaboration with LSC, coordinating equipment acquisition
and maintenance programmes; supervising laboratory safety and safe practice at work across
the Agency and providing technical advice to the Occupational Health and Safety Committee;
supporting specialized platforms and equipment, such as next-generation sequencing, mass
spectrometry, and Biosafety Level 3 facilities managed by specific research groups;
implementing and monitoring common quality tools such as the electronic laboratory notebook
(ELN) for recording experimental data; and standardization of standard operating practice
documents to enhance good laboratory practice for laboratory quality management.
The laboratory services web site, which will be launched at the end of 2012, will serve as a
central resource, containing laboratory protocols and providing information on facilities and
laboratory equipment. Future priorities include investing in new equipment, such as robotics for
sample preparation compatible with popular downstream applications such as qPCR,
microarrays, and next-generation sequencing platforms, and continuing to monitor good
laboratory and safety practices according to national and international guidelines.
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Education and Training Group (ETR)
Education and training in cancer research has been one of the statutory functions of the Agency
since its inception in 1966, complementing and supporting IARC’s research activities. Priority is
given to scientists from, or with a research interest relevant to, low- and middle-income
countries (LMICs). Since its establishment in 2010, the Education and Training Group (ETR) has
worked closely with the scientific groups to develop and implement training initiatives, under
two main programmes: Courses and Fellowships.
Courses
The activities of the Courses Programme comprise both the IARC Summer School on Cancer
Epidemiology and the organization of specialized courses run by the scientific Groups of the
Agency.
The Summer School is organized in Lyon each year in June and July. In 2012, more than
160 applications were received, of which 64 were accepted, with approximately 73% of the
participants from LMICs. A new Union for International Cancer Control (UICC)-IARC award was
successfully launched and will allow one of the most promising participants in the Summer
School to return to IARC for a period of 3 months to receive further training and to set up a
research collaboration. Additional financial support for the Summer School was provided by the
United States National Institutes of Health–National Cancer Institute (NIH-NCI) as well as by the
Nordic Cancer Union (NCU).
Specialized courses were also organized by scientific groups, often with the support of ETR.
As an example, courses on cancer registration were organized in Egypt (in French), in India (in
English), and in Colombia (in Spanish) in the framework of the Global Initiative for Cancer
Registry Development in Low- and Middle-Income Countries (GICR). Bringing such training to
the regions is supporting the establishment of regional hubs that will provide technical support
for cancer registries in the region and the establishment of a regional training programme.
On the distance learning front, renewed negotiations with the Programme of Action for Cancer
Therapy/Virtual University for Cancer Control (PACT/VUCCnet) would lead to development of an
e-learning module on Cancer Registration in 2013. In addition, two specialized courses, on
CanReg5 and EPIC-SOFT, have been run successfully 100% at distance by scientific groups,
through a webinar online tool. This approach will be extended to other IARC advanced courses
in the future.
Fellowships
IARC Fellowships provide excellent training and experience in an exceptional multicultural and
international environment to deserving postdoctoral fellows from around the world.
In 2012, eleven new postdoctoral fellowships were awarded and seven were extended for a
second year. Fellows came from Argentina, Australia, Brazil, Colombia, India, Lebanon,
Malaysia, Mexico, the Netherlands, South Africa, Spain, Sudan, Thailand, and the USA. One
Return Grant was granted to a fellow from China.
Additional funding came from the EC-FP7 Marie Curie Actions-People-COFUND programme. ETR
applied for a new EC-FP7 Marie Curie Actions-People-COFUND grant, to contribute to 40% of
the postdoctoral fellowship costs for 2014–2019. The proposal was favourably evaluated and is
now under negotiation.
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In addition, and under the bilateral agreement with the Cancer Council Australia, one IARCAustralia fellowship was awarded in 2012 and one extended for an additional year, and the
eligibility criteria for the IARC-Ireland fellowship launched with the Irish Cancer Society have
been widened to allow a greater number of applications. Other, similar partnerships are
currently under discussion with several institutions in Participating States.
One year after its implementation, the IARC Postdoctoral Fellowship Charter has met with
success, allowing a more structured approach to postdoctoral training at IARC, defining
expectations and including opportunities for generic training. In this respect, several generic
courses were organized at IARC, to equip postdoctoral researchers with essential skills to
enhance career prospects: Principles of Oncology, Biomedical Research Ethics, Project
Management, and Grant Writing.
The Agency also attracts top international cancer researchers, who spend various periods of
time contributing to the Agency’s programmes, making IARC the ideal environment for
education, training, and exchange. The Senior Visiting Scientist Award for 2012 was granted to
Dr Isabel Dos Santos Silva, London School of Hygiene and Tropical Medicine, London, United
Kingdom; Dr Terry Dwyer, Murdoch Childrens Research Institute, Parkville, Victoria, Australia;
and Steven Rappaport, Center for Occupational and Environmental Health, University of
California, Berkeley, California, USA.
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Communications Group (COM)
The Communications Group (COM) consists of several teams: the IARC publications programme,
library services, web services, editing and translation services, and the media team. Below are
some highlights of COM’s activities in 2012.
After testing and presenting a new format and design for IARC book collections, the IARC
publications team has helped prepare the following volumes.
IARC Monographs in PDF online:
Volume 101 (2012) Some Chemicals Present in Industrial and Consumer Products, Food and
Drinking-water
IARC Monographs in print:
Volume 100: A Review of Human Carcinogens (including a 6-book boxed set):
Volume 100A (2012) Pharmaceuticals
Volume 100B (2012) Biological Agents
Volume 100C (2012) Arsenic, Metals, Fibres, and Dusts
Volume 100D (2012) Radiation
Volume 100E (2012) Personal Habits and Indoor Combustions
Volume 100F (2012) Chemical Agents and Related Occupations
Other books:
Improving Public Health through Mycotoxin Control, IARC Scientific Publication No. 158.
WHO Classification of Tumours of the Breast, 4th edition.
In 2012, the library team has focused its activity and efforts on developing an open-access
policy for the Agency, and that should bear fruit in the next few months. It has prepared key
performance indicators for reporting to the IARC governing bodies and contributed the data for
the Staff Publications Database implemented by the web team. The Library team also
addressed collection preservation and access issues through ongoing weeding and space
rationalization projects. A range of library services and information management training
sessions were provided for IARC scientists, fellows, students, and staff.
The web team successfully launched an entirely redesigned IARC web site in May. The
enhanced web site includes a “Cancer Topics” section, a Search facility for IARC Staff
Publications stored in the IARC Reference Manager Database, and a “Who’s Who” section to
display detailed profile information about IARC staff. A dedicated effort has been made to align
all IARC web sites to the new visual identity. This team has also been developing the IARC Web
Strategy, outlining future directions in relation to promoting IARC’s work, and a practical
document with policies and procedures for use within the Sections/Groups.
The editing and translation team edited dozens of articles, book chapters, reports, and
grants, and translated the official documents from English into French. Training sessions on
effective writing were provided for Summer School participants.
The media team issued 51 IARC news items published on the web, and released
7 international news releases. It coordinated media efforts for World Cancer Day in February. It
also organized a major press conference on the outcome of the Monographs Working Group
evaluation of diesel engine exhaust in June.
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IARC Communications Strategy
In 2012, COM has been developing an Agency-wide communications strategy, which focuses on
the following as core elements of the dissemination of scientific information to the scientific
community and to the wider public.
– The IARC publications programme is being merged with library services to create a
Knowledge Management Centre, which integrates relevant services relating to information
creation, dissemination, and preservation.
– The web project is improving and introducing new technologies to ensure the dissemination
and visibility of the Agency’s research results, and thus a consistent corporate identity
throughout the organization’s web sites.
– The editing and translation services have merged, in order to bring similar interests
together and offer fast and efficient services to the IARC community.
– The media strategy has been prepared and, as this is considered to be a key area for the
Agency’s visibility, the Agency is recruiting a professional Press Officer to help the COM team
achieve its medium-term goals: restructuring the Group, ensuring open access to scientific
results and literature as much as is possible, making most of IARC’s scientific results available
through the media, and developing IARC’s influence in the media.
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Governing Council and Scientific Council
The International Agency for Research on Cancer (IARC) was established in May 1965 through a
resolution of the XVIIIth World Health Assembly, as an extension of the World Health
Organization, after a French initiative. It is governed by its own Governing bodies, the IARC
Governing Council and the IARC Scientific Council.
Governing Council
IARC's general policy is directed by a Governing Council, composed of the Representatives of
Participating States and of the Director-General of the World Health Organization. It meets
every year in ordinary session in Lyon, usually the week prior to the WHO World Health
Assembly. The Council elected Dr Christopher Wild in May 2008 to serve for a five-year term;
he took office on 1 January 2009. The Chairperson of the Governing Council prepares the
meetings together with the Secretariat and advises the Director throughout the year.
Scientific Council
The Scientific Council consists of highly qualified scientists, selected on the basis of their
technical competence in cancer research and allied fields. Members of the Scientific Council are
appointed as experts and not as representatives of Participating States. When a vacancy arises
on the Scientific Council, the Participating State that nominated the departing member may
nominate up to two experts to replace that member. Scientific Council members are appointed
for four-year terms by the Governing Council. The Scientific Council reviews the scientific
activities of the Agency and makes recommendations on its programme of permanent activities
and priorities. The Scientific Council meets every year in ordinary session in late January–early
February.
Budget
For the biennium 2012–2013, the IARC Governing Council voted a regular budget of
€39 419 315. A number of projects are also funded by extrabudgetary sources, both national
and international. In the 2010–2011 biennium, 28% of the Agency’s overall expenditure was
financed by extrabudgetary funds.
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Participating States and Representatives at IARC Governing Council
Fifty-fourth Session, 17–18 May 2012
Finland
Professor Pekka Puska, Chairperson
Director-General, National Institute for Health and Welfare
Helsinki
Dr Sakari Karjalainen
Secretary-General, Cancer Society of Finland
Helsinki
Professor Harri Vainio
Director-General, Finnish Institute of Occupational Health
Helsinki
United Kingdom of Great Britain and Northern Ireland
Dr Mark Palmer, Vice-Chairperson
Head, International Strategy, Medical Research Council
London
Switzerland
Dr Diane Steber Büchli, Rapporteur
Collaboratrice scientifique, Office fédéral de la santé publique
Bern
Australia
Professor Christopher Baggoley
Chief Medical Officer, Department of Health and Ageing
Canberra
Austria
Dr Hemma Bauer
Austrian Federal Ministry of Science and Research
Vienna
Belgium
M. Lieven De Raedt
Attaché Relations Internationales
SPF Santé publique, Sécurité de la Chaîne Alimentaire et Environnement
Brussels
Canada
Dr Morag Park
Scientific Director, Institute of Cancer Research
Canadian Institutes of Health Research
Montreal, Quebec
Ms Lucero Hernandez
Senior Policy Analyst, Multilateral Relations Division
International Affairs Directorate, Strategic Policy Branch, Health Canada
Ottawa, Ontario
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Denmark
Professor Herman Autrup
University of Aarhus School of Public Health
Aarhus
France
Professeur Agnès Buzyn
Présidente, Institut national du Cancer (INCa)
Boulogne-Billancourt
Germany
Dr Irene Keinhorst
Advisor, Division of Global Health, Federal Ministry of Health
Berlin
India
Professor G.K. Rath (unable to attend)
Chief, Dr B.R. Ambedkar Institute Rotary Cancer Hospital (DBRAIRCH)
All India Institute of Medical Sciences (AIIMS)
New Delhi
Ireland
Dr Tony Holohan (unable to attend)
Chief Medical Officer, Department of Health and Children
Dublin 2
Italy
No Representative
Japan
Dr Masato Mugitani
Assistant Minister for Global Health, Ministry of Health, Labour and Welfare
Tokyo
Dr Yukiko Nakatani
Deputy Director for Mental Health and Welfare Division
Ministry of Health, Labour and Welfare
Tokyo
Netherlands
Mr Jeroen Hulleman
Senior Policy Advisor, Public Health Directorate, Ministry of Health, Welfare and Sport
The Hague
Norway
Dr Henrietta Blankson
Senior Adviser, The Research Council of Norway
Oslo
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Republic of Korea
Dr Byung-Guk Yang
Director General, Bureau of Public Health Policy, Ministry of Health and Welfare
Seoul
Dr Soon-se Park
Deputy Director, Division of Disease Control Policy, Ministry of Health and Welfare
Seoul
Dr Jeongseon Kim
Division of Cancer Epidemiology and Prevention, National Cancer Center Research Institute
Gyeonggi-do
Russian Federation
Dr Oleg Salagay
Deputy Director, Department of Innovative Policy and Science
Ministry of Health and Social Development
Moscow
Dr Elena Skachkova
Deputy Director, Department of Medical Care Organisation and Healthcare Development
Ministry of Health and Social Development
Moscow
Ms Yulia Bakonina
Senior Specialist, Department of International Cooperation
Ministry of Health and Social Development
Moscow
Spain
Dr Carlos Segovia
Deputy Director for International Research Programmes
Instituto de Salud Carlos III, Ministry of Science and Innovation
Madrid
Sweden
Professor Mats Ulfendahl (unable to attend)
Secretary-General, Swedish Research Council – Medicine
Stockholm
Turkey
Professor Murat Tuncer
Director, Cancer Control Department, Ministry of Health
Ankara
United States of America
Dr Lisa Stevens
Deputy Director, Center for Global Health
National Cancer Institute, Department of Health and Human Services
Bethesda, Maryland
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Dr Joe B. Harford
Senior Advisor, Center for Global Health
National Cancer Institute, National Institutes of Health
Bethesda, Maryland
Dr Peter Mamacos
Multilateral Branch Chief, Office of Global Affairs
Department of Health and Human Services
Bethesda, Maryland
World Health Organization
Dr Oleg Chestnov
Assistant Director-General, Noncommunicable Diseases and Mental Health (NMH)
WHO Headquarters, Geneva, Switzerland
Mrs Joanne McKeough
Office of the Legal Counsel
WHO Headquarters, Geneva, Switzerland
Dr Cecilia Sepulveda
Senior Adviser Cancer Control, Chronic Diseases Prevention and Management
WHO Headquarters, Geneva, Switzerland
Dr Andreas Ullrich
Medical Officer, Chronic Diseases and Health Promotion
WHO Headquarters, Geneva, Switzerland
Observers
Scientific Council
Outgoing Chairperson, Scientific Council
Professor Ian Frazer
Incoming Chairperson, Scientific Council
Professor Mads Melbye
Union for International Cancer Control
Mr Cary Adams
Executive Director, Union for International Cancer Control (UICC)
Geneva, Switzerland
External Audit
Ms Usha S. Sankar
Additional Deputy Comptroller and Auditor General of India
New Delhi, India
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Scientific Council Members (2012)
Professor Ian Frazer (Chairperson)
CEO and Research Director, Translational Research Institute
Woolloongabba, Queensland, Australia
Professor Mads Melbye (Vice-Chairperson)
Director, Division of Epidemiology
Statens Serum Institut
Copenhagen, Denmark
Professor Giulio Superti-Furga (Rapporteur)
Director, Centre of Molecular Medicine of the Austrian Academy of Sciences
Vienna, Austria
Dr Ahti Anttila
Mass Screening Registry, Finnish Cancer Registry
Helsinki, Finland
Professor Bettina Borisch
Institute of Social and Preventive Medicine
University of Geneva Medical School
Geneva, Switzerland
Dr Florence Demenais
INSERM U946 – Genetic Variation and Human Diseases
Fondation Jean Dausset/CEPH
Paris, France
Dr Paul W. Dickman
Department of Medical Epidemiology and Biostatistics (MEB)
Karolinska Institutet
Stockholm, Sweden
Professor Richard Gallagher
BC Cancer Agency, Cancer Control Research
Vancouver, Canada
Dr Luca Gianni
Director, Department of Medical Oncology
Fondazione Centro San Raffaele del Monte Tabor
Milan, Italy
Dr Inger Torhild Gram
Institute for Community Medicine
University of Tromsø
Tromsø, Norway
Dr Murat Gültekin (unable to attend)
Cancer Control Department
Ministry of Health of Turkey
Ankara, Turkey
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Professor Karin Haustermans
Department of Radiation Oncology and Experimental Radiation
Catholic University Leuven/University Hospital Gasthuisberg Leuven
Leuven, Belgium
Dr In-Hoo Kim
Director, Research Institute
National Cancer Center
Gyeonggi-do, Republic of Korea
Professor Sir Alex Markham
University of Leeds
Institute of Molecular Medicine
Leeds, United Kingdom
Dr Deirdre Murray
National Cancer Control Programme
Department of Public Health
Cork, Ireland
Dr Hitoshi Nakagama
Deputy Director, National Cancer Center Research Institute
Tokyo, Japan
Dr Marina Pollán Santamaria
Centro Nacional de Epidemiologia
Instituto de Salud Carlos III
Madrid, Spain
Professor Thangarajan Rajkumar
Head, Department of Molecular Oncology
Cancer Institute (WIA)
Chennai, India
Professor Martyn Smith
Division of Environmental Health Sciences
School of Public Health, University of California
Berkeley, California, USA
Dr Sergei Tjulandin
Cancer Research Center (CRC)
Moscow, Russian Federation
Dr Cornelia (Neli) Ulrich
National Center for Tumor Diseases (NCT) Heidelberg
German Cancer Research Center
Heidelberg, Germany
Professor Piet A. van den Brandt
Department of Epidemiology, Maastricht University
Maastricht, The Netherlands
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IARC Publications 2012
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