Hétérogénéïté Génétique des Cancer du sein

Hétérogénéïté Génétique
des Cancer du sein
Pr. X Pivot
CHRU Besançon
Inca provided blood & tumour samples from ~ 150 paGents Basis ER+, HER-­‐ Inca provided blood & tumour samples from ~ 50 paGents Fr HER+ Inca leads the project for this subgroup ~ 150 paGents 75 Whole Genomes 30 Whole Exomes 75 RNASeq Uk Triple Neg. Total sequenced & analyzed 560 tumours (~140 from INCa) Études sein INCa
Mai 2006
Juillet 2010
PHARE
3400 patientes HER2+
Pharmacogénétique
PHARE
650 patientes HER2 + sang
•  Suivi clinique pour 5 ans
•  Echantillon de sang (optionnel)
Mai 2009
Octobre 2011
SIGNAL
3000 patientes HER2+ sang
6000 patientes HER2- sang
SIGNAL2-ICGC
500 tumeurs HER2+
2000 tumeurs HER2-
Mai 2009
? 2014
•  Suivi clinique pour 5 ans
•  Questionnaire épidémiologique SIGNAL
•  Echantillon de sang +
•  Tumeur pour SIGNAL2-ICGC-BASIS
doi:10.1038/nature17676
Landscape of somatic mutations in 560
breast cancer whole-genome sequences
Serena Nik-Zainal1,2, Helen Davies1, Johan Staaf3, Manasa Ramakrishna1, Dominik Glodzik1, Xueqing Zou1, Inigo Martincorena1,
Ludmil B. Alexandrov1,4,5, Sancha Martin1, David C. Wedge1, Peter Van Loo1,6, Young Seok Ju1, Marcel Smid7, Arie B. Brinkman8,
Sandro Morganella9, Miriam R. Aure10,11, Ole Christian Lingjærde11,12, Anita Langerød10,11, Markus Ringnér3, Sung-Min Ahn13,
Sandrine Boyault14, Jane E. Brock15, Annegien Broeks16, Adam Butler1, Christine Desmedt17, Luc Dirix18, Serge Dronov1,
Aquila Fatima19, John A. Foekens7, Moritz Gerstung1, Gerrit K. J. Hooijer20, Se Jin Jang21, David R. Jones1, Hyung-Yong Kim22,
Tari A. King23, Savitri Krishnamurthy24, Hee Jin Lee21, Jeong-Yeon Lee25, Yilong Li1, Stuart McLaren1, Andrew Menzies1,
Ville Mustonen1, Sarah O’Meara1, Iris Pauporté26, Xavier Pivot27, Colin A. Purdie28, Keiran Raine1, Kamna Ramakrishnan1,
F. Germán Rodríguez-González7, Gilles Romieu29, Anieta M. Sieuwerts7, Peter T. Simpson30, Rebecca Shepherd1,
Lucy Stebbings1, Olafur A. Stefansson31, Jon Teague1, Stefania Tommasi32, Isabelle Treilleux33, Gert G. Van den Eynden18,34,
Peter Vermeulen18,34, Anne Vincent-Salomon35, Lucy Yates1, Carlos Caldas36, Laura van’t Veer16, Andrew Tutt37,38,
Stian Knappskog39,40, Benita Kiat Tee Tan41,42, Jos Jonkers16, Åke Borg3, Naoto T. Ueno24, Christos Sotiriou17, Alain Viari43,44,
P. Andrew Futreal1,45, Peter J. Campbell1, Paul N. Span46, Steven Van Laere18, Sunil R. Lakhani30,47, Jorunn E. Eyfjord31,
Alastair M. Thompson28,48, Ewan Birney9, Hendrik G. Stunnenberg8, Marc J. van de Vijver20, John W. M. Martens7,
Anne-Lise Børresen-Dale10,11, Andrea L. Richardson15,19, Gu Kong22, Gilles Thomas44 & Michael R. Stratton1
ARTICLE RESEARCH
We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring
clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer
genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have
distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational
signature analysis was extended to genome rearrangements and
revealed
twelve base substitution and six rearrangement
B
560
whole-genome
signatures. ThreeArearrangement signatures, characterized by tandem duplications or deletions, appear associated with
sequenced
breast
cancers
defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient
BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across
34%
exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and
progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
ER pos
320
The mutational theory of cancer proposes that changes in DNA
sequence, termed ‘driver’ mutations, confer proliferative advantage on a cell, leading to outgrowth of a neoplastic clone1. Some
driver mutations are inherited in the germline, but most arise in
36%
10%
21%
somatic cells during the lifetime of the cancer patient, together with
ERmutations
neg not implicated in cancer development1.
many ‘passenger’
Multiple mutational
167processes, including endogenous and exogenous mutagen exposures, aberrant DNA editing, replication errors
substitutions
46
27
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. 2East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK.
rearrangements
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund SE-223 81, Sweden. 4Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory,
of
Los Alamos, NM 87545, New Mexico, USA. 5Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA. 6Department of Human Genetics, University indels
Leuven, B-3000 Leuven, Belgium. 7Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam 3015CN,
The Netherlands. 8Radboud University, Department of Molecular Biology, Faculties of Science and Medicine, 6525GA Nijmegen, The Netherlands. 9European Molecular Biology Laboratory, copy number aberrations
European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. 10Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital,
The Norwegian Radium Hospital, Oslo 0310, Norway. 11K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo 0310, Norway. 12Department of
Computer Science, University of Oslo, Oslo, Norway. 13Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea. 14Translational Research
Chr12
Lab, Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon Cedex Chr1
08, France. 15Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA. 16The Netherlands
Cancer Institute, 1066 CX Amsterdam, The Netherlands. 17Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000
Antwerp, Antwerp, 2.0e+07
Belgium. 19Dana-Farber
Cancer
Brussels, Belgium. 18Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of 0.0e+00
4.0e+07
6.0e+07
8.0e+07
0.0e+00
5.0e+07
1.0e+08
1.5e+08
2.0e+08
2.5e+08
Chr13
Institute, Boston, Massachusetts 02215, USA. 20Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. 21Department of Pathology, Asan
Chr2
Medical Center, College of Medicine, Ulsan University, Ulsan, South Korea. 22Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, South Korea. 23Memorial Sloan
Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA. 24Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson
0e+00
2e+07
4e+07
6e+07
26
and Biopharmaceutical Research
Cancer Center, 1515 Holcombe
Texas 77030, USA. 25Institute
0.0e+00
5.0e+07 Boulevard., Houston,
1.0e+08
1.5e+08for Bioengineering2.0e+08
2.5e+08 (IBBR), Hanyang University, Seoul, South Korea. Institut
0
500
HER2 pos
1.0e+08
1.2e+08
500
3
0
1
27
0
500
0
500
0
ARTICLE
Chr14
8e+07
1e+08
ARTICLE
ER positive
doi:10.1038/nature17676
Landscape of somatic mutations in 560
breast cancer whole-genome sequences
b
Fraction of samples
with driver
100 80 60 40 20 0
Serena Nik-Zainal1,2, Helen Davies1, Johan Staaf3, Manasa Ramakrishna1, Dominik Glodzik1, Xueqing Zou1, Inigo Martincorena1,
Ludmil B. Alexandrov1,4,5, Sancha Martin1, David C. Wedge1, Peter Van Loo1,6, Young Seok Ju1, Marcel Smid7, Arie B. Brinkman8,
Sandro Morganella9, Miriam R. Aure10,11, Ole Christian Lingjærde11,12, Anita Langerød10,11, Markus Ringnér3, Sung-Min Ahn13,
Sandrine Boyault14, Jane E. Brock15, Annegien Broeks16, Adam Butler1, Christine Desmedt17, Luc Dirix18, Serge Dronov1,
Aquila Fatima19, John A. Foekens7, Moritz Gerstung1, Gerrit K. J. Hooijer20, Se Jin Jang21, David R. Jones1, Hyung-Yong Kim22,
Tari A. King23, Savitri Krishnamurthy24, Hee Jin Lee21, Jeong-Yeon Lee25, Yilong Li1, Stuart McLaren1, Andrew Menzies1,
Ville Mustonen1, Sarah O’Meara1, Iris Pauporté26, Xavier Pivot27, Colin A. Purdie28, Keiran Raine1, Kamna Ramakrishnan1,
F. Germán Rodríguez-González7, Gilles Romieu29, Anieta M. Sieuwerts7, Peter T. Simpson30, Rebecca Shepherd1,
Lucy Stebbings1, Olafur A. Stefansson31, Jon Teague1, Stefania Tommasi32, Isabelle Treilleux33, Gert G. Van den Eynden18,34,
Peter Vermeulen18,34, Anne Vincent-Salomon35, Lucy Yates1, Carlos Caldas36, Laura van’t Veer16, Andrew Tutt37,38,
Stian Knappskog39,40, Benita Kiat Tee Tan41,42, Jos Jonkers16, Åke Borg3, Naoto T. Ueno24, Christos Sotiriou17, Alain Viari43,44,
P. Andrew Futreal1,45, Peter J. Campbell1, Paul N. Span46, Steven Van Laere18, Sunil R. Lakhani30,47, Jorunn E. Eyfjord31,
Alastair M. Thompson28,48, Ewan Birney9, Hendrik G. Stunnenberg8, Marc J. van de Vijver20, John W. M. Martens7,
Anne-Lise Børresen-Dale10,11, Andrea L. Richardson15,19, Gu Kong22, Gilles Thomas44 & Michael R. Stratton1
ER positive
We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring
clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer
genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have
distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational
signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement
signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with
defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient
BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across
exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and
progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
The mutational theory of cancer proposes that changes in DNA
sequence, termed ‘driver’ mutations, confer proliferative advantage on a cell, leading to outgrowth of a neoplastic clone1. Some
driver mutations are inherited in the germline, but most arise in
1
somatic cells during the lifetime of the cancer patient, together with
many ‘passenger’ mutations not implicated in cancer development1.
Multiple mutational processes, including endogenous and exogenous mutagen exposures, aberrant DNA editing, replication errors
RESEARCH ARTICLE
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. 2East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK.
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund SE-223 81, Sweden. 4Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory,
Los Alamos, NM 87545, New Mexico, USA. 5Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA. 6Department of Human Genetics, University of
Leuven, B-3000 Leuven, Belgium. 7Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam 3015CN,
The Netherlands. 8Radboud University, Department of Molecular Biology, Faculties of Science and Medicine, 6525GA Nijmegen, The Netherlands. 9European Molecular Biology Laboratory,
European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. 10Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital,
The Norwegian Radium Hospital, Oslo 0310, Norway. 11K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo 0310, Norway. 12Department of
Computer Science, University of Oslo, Oslo, Norway. 13Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea. 14Translational Research
Lab, Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon Cedex 08, France. 15Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA. 16The Netherlands
Cancer Institute, 1066 CX Amsterdam, The Netherlands. 17Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000
Brussels, Belgium. 18Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium. 19Dana-Farber Cancer
Institute, Boston, Massachusetts 02215, USA. 20Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. 21Department of Pathology, Asan
Medical Center, College of Medicine, Ulsan University, Ulsan, South Korea. 22Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, South Korea. 23Memorial Sloan
Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA. 24Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson
Cancer Center, 1515 Holcombe Boulevard., Houston, Texas 77030, USA. 25Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, South Korea. 26Institut
National du Cancer, Research Division, Clinical Research Department, 52 avenue Morizet, 92513 Boulogne-Billancourt, France. 27University Hospital of Minjoz, INSERM UMR 1098, Bd Fleming,
Besançon 25000, France. 28Pathology Department, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. 29Oncologie Sénologie, ICM Institut Régional du Cancer, Montpellier, France.
30
The University of Queensland, UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland 4059, Australia. 31Cancer Research Laboratory, Faculty of Medicine, University
of Iceland, 101 Reykjavik, Iceland. 32IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy. 33Department of Pathology, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cédex 08, France.
34
Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium. 35Institut Curie, Department of Pathology and INSERM U934, 26 rue d’Ulm, 75248 Paris Cedex 05, France. 36Cancer
Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. 37Breast Cancer Now Toby Robin’s Research Unit, King’s College London,
London SE1 9RT, UK. 38Breast Cancer Now Toby Robin’s Research Centre, Institute of Cancer Research, London SW3 6JB, UK. 39Department of Clinical Science, University of Bergen, 5020
Bergen, Norway. 40Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway. 41National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore. 42Singapore General
Hospital, Outram Road, 169608, Singapore. 43Equipe Erable, INRIA Grenoble-Rhône-Alpes, 655, Avenue de l’Europe, 38330 Montbonnot-Saint Martin, France. 44Synergie Lyon Cancer, Centre
Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France. 45Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, Texas 77230, USA. 46Department of Radiation Oncology,
Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands. 47Pathology Queensland, The Royal Brisbane and Women’s Hospital, Brisbane,
Queensland 4029, Australia. 48Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, Texas 77030, USA.
3
a
80,000
5,000
1,200
20
Substitutions
*
Indels
Rearrangements
0 0 M O N T H 2 0 1 6 | VO L 0 0 0 | NAT U R E | 1
Driver mutations
ER positive
b
*
Fraction of samples
with driver
100 80 60 40 20 0
Enrichment
log P value
–10 0 10
ER negative
Fraction of samples
with driver
0 20 40 60 80 100
Enrichment
log P value
–10 0 10
TP53
PIK3CA
MYC
CCND1
PTEN
ERBB2
ZNF703/FGFR1
GATA3
RB1
MAP3K1
MAP2K4
ZNF217
CDH1
MLL3
ARID1B
CDKN2A
MLLT4
AKT1
FBXW7
ARID1A
CCND3
CBFB
MDM2
CCNE1
CDKN2B
NCOR1
SF3B1
SPEN
TBX3
IGF1R
BRCA2
NF1
PIK3R1
EGFR
KRAS
ESR1
FOXA1
MED23
CDK6
NOTCH2
AKT2
BRCA1
CTCF
KDM6A
SETD2
CREBBP
DNMT3A
FOXP1
MLL2
RUNX1
USP9X
XBP1
PDGFRA
ATR
ERBB3
FGFR2
PALB2
RHOA
SMAD4
ATM
ATRX
AXIN1
BCOR
10 CDKN1B
CUX1
GNAS
MLH1
NOTCH1
PHF6
SMARCA4
STAG2
ZFP36L1
APC
CASP8
CBLB
CNOT3
ECT2L
MEN1
MSH2
NRAS
PBRM1
PMS2
STK11
TET2
ASXL1
BRAF
BUB1B
CIC
ERCC4
HRAS
NF2
PRDM1
PREX2
Figure 1 | Cohort and catalogue of somatic mutations in 560 breast
cancers. a, Catalogue of base substitutions, insertions/deletions,
rearrangements and driver mutations in 560 breast cancers (sorted by
total substitution burden). Indel axis limited to 5,000(*). b, Complete list
of curated driver genes sorted by frequency (descending). Fraction of ERpositive (left, total 366) and ER-negative (right, total 194) samples carrying
a mutation in the relevant driver gene presented in grey. log P value of
enrichment of each driver gene towards the ER-positive or ER-negative
cohort is provided in black. Highlighted in green are genes for which there
is new or further evidence supporting these as novel breast cancer genes.
and defective DNA maintenance, are responsible for generating
these mutations1–3.
Over the past five decades, several waves of technology have advanced
the characterization of mutations in cancer genomes. Karyotype
analysis revealed rearranged chromosomes and copy number
alterations. Subsequently, loss of heterozygosity analysis, hybridization
of cancer-derived DNA to microarrays and other approaches provided
higher resolution insights into copy number changes4–8. Recently, DNA
sequencing has enabled systematic characterization of the full repertoire of mutation types including base substitutions, small insertions/
ER negative
Fraction of samples
with driver
0 20 40 60 80 100
ER negative
the charac
analysis r
alterations
of cancer-d
higher reso
sequencin
toire of mu
deletions,
substantia
processes o
As for m
genome se
there has b
intronic an
to the mol
of activatin
genes/prot
as observe
role of dri
genome20,
human dis
the possib
was highlig
TERT gene
the somat
question h
on genom
tion mutat
signatures
Here we
address th
hensive un
mutations
Cancer g
The whol
tissue fro
sequence
We detecte
and 77,695
of each bet
Transcripto
ber and DN
To ident
and indels
constitutin
clustering
genes were
(MED23, F
tions indic
a dominan
ARTICLE
ER positive
b
doi:10.1038/nature17676
Landscape of somatic mutations in 560
breast cancer whole-genome sequences
Fraction of samples
with driver
100 80 60 40 20 0
Serena Nik-Zainal1,2, Helen Davies1, Johan Staaf3, Manasa Ramakrishna1, Dominik Glodzik1, Xueqing Zou1, Inigo Martincorena1,
Ludmil B. Alexandrov1,4,5, Sancha Martin1, David C. Wedge1, Peter Van Loo1,6, Young Seok Ju1, Marcel Smid7, Arie B. Brinkman8,
Sandro Morganella9, Miriam R. Aure10,11, Ole Christian Lingjærde11,12, Anita Langerød10,11, Markus Ringnér3, Sung-Min Ahn13,
Sandrine Boyault14, Jane E. Brock15, Annegien Broeks16, Adam Butler1, Christine Desmedt17, Luc Dirix18, Serge Dronov1,
Aquila Fatima19, John A. Foekens7, Moritz Gerstung1, Gerrit K. J. Hooijer20, Se Jin Jang21, David R. Jones1, Hyung-Yong Kim22,
Tari A. King23, Savitri Krishnamurthy24, Hee Jin Lee21, Jeong-Yeon Lee25, Yilong Li1, Stuart McLaren1, Andrew Menzies1,
Ville Mustonen1, Sarah O’Meara1, Iris Pauporté26, Xavier Pivot27, Colin A. Purdie28, Keiran Raine1, Kamna Ramakrishnan1,
F. Germán Rodríguez-González7, Gilles Romieu29, Anieta M. Sieuwerts7, Peter T. Simpson30, Rebecca Shepherd1,
Lucy Stebbings1, Olafur A. Stefansson31, Jon Teague1, Stefania Tommasi32, Isabelle Treilleux33, Gert G. Van den Eynden18,34,
Peter Vermeulen18,34, Anne Vincent-Salomon35, Lucy Yates1, Carlos Caldas36, Laura van’t Veer16, Andrew Tutt37,38,
Stian Knappskog39,40, Benita Kiat Tee Tan41,42, Jos Jonkers16, Åke Borg3, Naoto T. Ueno24, Christos Sotiriou17, Alain Viari43,44,
P. Andrew Futreal1,45, Peter J. Campbell1, Paul N. Span46, Steven Van Laere18, Sunil R. Lakhani30,47, Jorunn E. Eyfjord31,
Alastair M. Thompson28,48, Ewan Birney9, Hendrik G. Stunnenberg8, Marc J. van de Vijver20, John W. M. Martens7,
Anne-Lise Børresen-Dale10,11, Andrea L. Richardson15,19, Gu Kong22, Gilles Thomas44 & Michael R. Stratton1
ER positive
We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring
clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer
genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have
distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational
signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement
signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with
defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient
BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across
exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and
progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
The mutational theory of cancer proposes that changes in DNA
sequence, termed ‘driver’ mutations, confer proliferative advantage on a cell, leading to outgrowth of a neoplastic clone1. Some
driver mutations are inherited in the germline, but most arise in
A
30
PIK3CA
25
GATA3
promoter
PLEKHS1
TP53
20
15
10
intergenic
intron
GPR126
PIK3CA
SF3B1
GATA3
intergenic
TP53
AKT1
XBP1
5
0
1
2
3
4
5
6
7
8
9
10
11
12 13 14 15 16 17 18 19 20 22
X Y
0 0 M O N T H 2 0 1 6 | VO L 0 0 0 | NAT U R E | 1
chromosome
B
lncRNA MALAT1
lncRNA NEAT1
sub
indel
● ●●
●●
65,190,000
●
● ●
●
●
●
●●●●●●
●
●●
●
● ●
● ●●●● ● ● ●● ●● ●●
●
65,200,000
chr11 coordinate (Mbp)
●
●●
● ●
●
65,210,000
sub
–10 0 10
TP53
PIK3CA
MYC
CCND1
PTEN
ERBB2
ZNF703/FGFR1
GATA3
RB1
MAP3K1
MAP2K4
ZNF217
CDH1
MLL3
ARID1B
CDKN2A
MLLT4
AKT1
FBXW7
ARID1A
CCND3
CBFB
MDM2
CCNE1
CDKN2B
NCOR1
SF3B1
SPEN
TBX3
IGF1R
BRCA2
NF1
PIK3R1
EGFR
KRAS
ESR1
FOXA1
MED23
CDK6
NOTCH2
AKT2
BRCA1
CTCF
KDM6A
SETD2
CREBBP
DNMT3A
FOXP1
MLL2
RUNX1
USP9X
XBP1
PDGFRA
ATR
ERBB3
FGFR2
PALB2
RHOA
SMAD4
ATM
ATRX
AXIN1
BCOR
CDKN1B
CUX1
GNAS
MLH1
NOTCH1
PHF6
SMARCA4
STAG2
ZFP36L1
APC
CASP8
CBLB
CNOT3
ECT2L
MEN1
MSH2
NRAS
PBRM1
PMS2
STK11
TET2
ASXL1
BRAF
BUB1B
CIC
ERCC4
HRAS
NF2
PRDM1
PREX2
ARTICLE RESEARCH
somatic cells during the lifetime of the cancer patient, together with
many ‘passenger’ mutations not implicated in cancer development1.
Multiple mutational processes, including endogenous and exogenous mutagen exposures, aberrant DNA editing, replication errors
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. 2East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK.
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund SE-223 81, Sweden. 4Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory,
Los Alamos, NM 87545, New Mexico, USA. 5Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA. 6Department of Human Genetics, University of
Leuven, B-3000 Leuven, Belgium. 7Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam 3015CN,
The Netherlands. 8Radboud University, Department of Molecular Biology, Faculties of Science and Medicine, 6525GA Nijmegen, The Netherlands. 9European Molecular Biology Laboratory,
European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. 10Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital,
The Norwegian Radium Hospital, Oslo 0310, Norway. 11K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo 0310, Norway. 12Department of
Computer Science, University of Oslo, Oslo, Norway. 13Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea. 14Translational Research
Lab, Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon Cedex 08, France. 15Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA. 16The Netherlands
Cancer Institute, 1066 CX Amsterdam, The Netherlands. 17Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000
Brussels, Belgium. 18Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium. 19Dana-Farber Cancer
Institute, Boston, Massachusetts 02215, USA. 20Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. 21Department of Pathology, Asan
Medical Center, College of Medicine, Ulsan University, Ulsan, South Korea. 22Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, South Korea. 23Memorial Sloan
Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA. 24Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson
Cancer Center, 1515 Holcombe Boulevard., Houston, Texas 77030, USA. 25Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, South Korea. 26Institut
National du Cancer, Research Division, Clinical Research Department, 52 avenue Morizet, 92513 Boulogne-Billancourt, France. 27University Hospital of Minjoz, INSERM UMR 1098, Bd Fleming,
Besançon 25000, France. 28Pathology Department, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. 29Oncologie Sénologie, ICM Institut Régional du Cancer, Montpellier, France.
30
The University of Queensland, UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland 4059, Australia. 31Cancer Research Laboratory, Faculty of Medicine, University
of Iceland, 101 Reykjavik, Iceland. 32IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy. 33Department of Pathology, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cédex 08, France.
34
Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium. 35Institut Curie, Department of Pathology and INSERM U934, 26 rue d’Ulm, 75248 Paris Cedex 05, France. 36Cancer
Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. 37Breast Cancer Now Toby Robin’s Research Unit, King’s College London,
London SE1 9RT, UK. 38Breast Cancer Now Toby Robin’s Research Centre, Institute of Cancer Research, London SW3 6JB, UK. 39Department of Clinical Science, University of Bergen, 5020
Bergen, Norway. 40Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway. 41National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore. 42Singapore General
Hospital, Outram Road, 169608, Singapore. 43Equipe Erable, INRIA Grenoble-Rhône-Alpes, 655, Avenue de l’Europe, 38330 Montbonnot-Saint Martin, France. 44Synergie Lyon Cancer, Centre
Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France. 45Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, Texas 77230, USA. 46Department of Radiation Oncology,
Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands. 47Pathology Queensland, The Royal Brisbane and Women’s Hospital, Brisbane,
Queensland 4029, Australia. 48Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, Texas 77030, USA.
3
−log10(pval)
1
Enrichment
log P value
● ● ●●
●●
● ● ●
indel
● ●● ● ●
● ●●● ●●
65,266,000
●
● ●●
●●
●
● ●
●
● ● ●● ●
●
65,270,000
chr11 coordinate (Mbp)
●
● ●
● ●●● ●
65,274,000
ER negative
Fraction of samples
with driver
0 20 40 60 80 100
ER negative
the charac
analysis r
alterations
of cancer-d
higher reso
sequencin
toire of mu
deletions,
substantia
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there has b
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to the mol
of activatin
genes/prot
as observe
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mutations
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and 77,695
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Transcripto
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To ident
and indels
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(MED23, F
tions indic
a dominan
0.2
ARTICLE
0.1
0.2
Signature 8
0.1
Signature 26
doi:10.1038/nature17676
0.2
Landscape of somatic mutations in 560
breast cancer whole-genome sequences
0.1
Serena Nik-Zainal1,2, Helen Davies1, Johan Staaf3, Manasa Ramakrishna1, Dominik Glodzik1, Xueqing Zou1, Inigo Martincorena1,
Ludmil B. Alexandrov1,4,5, Sancha Martin1, David C. Wedge1, Peter Van Loo1,6, Young Seok Ju1, Marcel Smid7, Arie B. Brinkman8,
Sandro Morganella9, Miriam R. Aure10,11, Ole Christian Lingjærde11,12, Anita Langerød10,11, Markus Ringnér3, Sung-Min Ahn13,
Sandrine Boyault14, Jane E. Brock15, Annegien Broeks16, Adam Butler1, Christine Desmedt17, Luc Dirix18, Serge Dronov1,
Aquila Fatima19, John A. Foekens7, Moritz Gerstung1, Gerrit K. J. Hooijer20, Se Jin Jang21, David R. Jones1, Hyung-Yong Kim22,
Tari A. King23, Savitri Krishnamurthy24, Hee Jin Lee21, Jeong-Yeon Lee25, Yilong Li1, Stuart McLaren1, Andrew Menzies1,
Ville Mustonen1, Sarah O’Meara1, Iris Pauporté26, Xavier Pivot27, Colin A. Purdie28, Keiran Raine1, Kamna Ramakrishnan1,
F. Germán Rodríguez-González7, Gilles Romieu29, Anieta M. Sieuwerts7, Peter T. Simpson30, Rebecca Shepherd1,
Lucy Stebbings1, Olafur A. Stefansson31, Jon Teague1, Stefania Tommasi32, Isabelle Treilleux33, Gert G. Van den Eynden18,34,
Peter Vermeulen18,34, Anne Vincent-Salomon35, Lucy Yates1, Carlos Caldas36, Laura van’t Veer16, Andrew Tutt37,38,
Stian Knappskog39,40, Benita Kiat Tee Tan41,42, Jos Jonkers16, Åke Borg3, Naoto T. Ueno24, Christos Sotiriou17, Alain Viari43,44,
P. Andrew Futreal1,45, Peter J. Campbell1, Paul N. Span46, Steven Van Laere18, Sunil R. Lakhani30,47, Jorunn E. Eyfjord31,
Alastair M. Thompson28,48, Ewan Birney9, Hendrik G. Stunnenberg8, Marc J. van de Vijver20, John W. M. Martens7,
Anne-Lise Børresen-Dale10,11, Andrea L. Richardson15,19, Gu Kong22, Gilles Thomas44 & Michael R. Stratton1
0.2 Signature 30
0.1
Signature 5
100,000
b
0
100%
RESEARCH ARTICLE
We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring
clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer
genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have
distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational
signature analysis was extended
genome rearrangements
revealed T>G
twelve base substitution
and six
rearrangement
C>A toC>G
C>T T>A andT>C
C>A
C>G
C>T
signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with
0.2
0.2
defective homologous-recombination-based
DNA repair: one with deficient BRCA1
function, another with deficient
Signature
18 across
Signature
BRCA1 or BRCA2 function,
the cause 1
of the third is unknown. This analysis of all classes of
somatic mutation
exons, introns 0.1
and intergenic regions highlights the repertoire of cancer genes and mutational
processes operating, and
0.1
progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
a
The mutational theory of cancer proposes that changes in DNA
sequence, termed0.2
‘driver’ mutations, confer proliferative advantage on a cell, leading to outgrowth
of a neoplastic
clone1. Some
Signature
2
driver mutations are inherited in the germline, but most arise in
0.1
T>A
T>C T>G
somatic cells during the lifetime of the cancer patient, together with
many ‘passenger’ mutations
not implicated in cancer development1.
0.2
Multiple mutational processes, including
endogenous
Signature
17and exogenous mutagen exposures, aberrant DNA editing, replication errors
0.1
1
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. 2East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK.
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund SE-223 81, Sweden. 4Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory,
Los Alamos, NM 87545, New Mexico, USA. 5Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA. 6Department of Human Genetics, University of
Leuven, B-3000 Leuven, Belgium. 7Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam 3015CN,
The Netherlands. 8Radboud University, Department of Molecular Biology, Faculties of Science and Medicine, 6525GA Nijmegen, The Netherlands. 9European Molecular Biology Laboratory,
European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. 10Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital,
The Norwegian Radium Hospital, Oslo 0310, Norway. 11K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo 0310, Norway. 12Department of
Computer Science, University of Oslo, Oslo, Norway. 13Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea. 14Translational Research
Lab, Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon Cedex 08, France. 15Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA. 16The Netherlands
Cancer Institute, 1066 CX Amsterdam, The Netherlands. 17Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000
Brussels, Belgium. 18Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium. 19Dana-Farber Cancer
Institute, Boston, Massachusetts 02215, USA. 20Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. 21Department of Pathology, Asan
Medical Center, College of Medicine, Ulsan University, Ulsan, South Korea. 22Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, South Korea. 23Memorial Sloan
Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA. 24Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson
Cancer Center, 1515 Holcombe Boulevard., Houston, Texas 77030, USA. 25Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, South Korea. 26Institut
National du Cancer, Research Division, Clinical Research Department, 52 avenue Morizet, 92513 Boulogne-Billancourt, France. 27University Hospital of Minjoz, INSERM UMR 1098, Bd Fleming,
Besançon 25000, France. 28Pathology Department, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. 29Oncologie Sénologie, ICM Institut Régional du Cancer, Montpellier, France.
30
The University of Queensland, UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland 4059, Australia. 31Cancer Research Laboratory, Faculty of Medicine, University
of Iceland, 101 Reykjavik, Iceland. 32IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy. 33Department of Pathology, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cédex 08, France.
34
Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium. 35Institut Curie, Department of Pathology and INSERM U934, 26 rue d’Ulm, 75248 Paris Cedex 05, France. 36Cancer
Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. 37Breast Cancer Now Toby Robin’s Research Unit, King’s College London,
London SE1 9RT, UK. 38Breast Cancer Now Toby Robin’s Research Centre, Institute of Cancer Research, London SW3 6JB, UK. 39Department of Clinical Science, University of Bergen, 5020
Bergen, Norway. 40Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway. 41National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore. 42Singapore General
Hospital, Outram Road, 169608, Singapore. 43Equipe Erable, INRIA Grenoble-Rhône-Alpes, 655, Avenue de l’Europe, 38330 Montbonnot-Saint Martin, France. 44Synergie Lyon Cancer, Centre
Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France. 45Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, Texas 77230, USA. 46Department of Radiation Oncology,
Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands. 47Pathology Queensland, The Royal Brisbane and Women’s Hospital, Brisbane,
Queensland 4029, Australia. 48Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, Texas 77030, USA.
3
0.2
Signature
0.1 13
0.2
0.1
0.2
0.1
Signature 3
Signature 8
0.2
0.1
0.2
0.1
0.2
0.1
Signature 6
Signature 20
Signature 26
Previously identified
Mutational signatures
in breast cancers
0 0 M O N T H 2 0 1 6 | VO L 0 0 0 | NAT U R E | 1
0.2
0.1
b
Signature 5
The WDR74 promoter showed base substitutions and
0% ind
(q value 4.6 × 10−3) forming a cluster of overlapping mutation
Signatures
1
5 sequence
2 13 6 driver
20 26 mutations
3 8 18 in
17 WDR74
30
(Fig.
2a). Coding
have not b
reported.
No
differences
were
observed
in
WDR74
transcript
le
c
100
80 with WDR74 promoter mutations compared to th
between cancers
Percentage
60
without.
Nevertheless,
the pattern of this non-coding mutation clus
of samples
40
with overlapping
and
different
mutation types, is more compatible w
20
the possibility
of the mutations being drivers.
100,000
Two long10,000
non-coding RNAs, MALAT1 (q value 8.7 × 10−11, as pr
Mutation
12
−2
ouslycount
reported
1,000 ) and NEAT1 (q value 2.1 × 10 ) were enriched w
per sample Transcript
mutations.
levels were not significantly different betw
100
10
mutated and non-mutated
samples. Whether these mutations are d
1
ers or result from local
hypermutability
is unclear.
1
2 13 3
8
5 18 17 6 20 26 30
0.2 Signature 30
0.1
100,000
Previously identified in Novel
other cancer types signatures
Mutational
processes
generating somatic
parti
Figure
3 | Extraction
and contributions
of base mutations
substitutionimprint
signatures
2,2
lar
patterns
of
mutations
on
cancer
genomes,
termed
signatures
in 560 breast cancers. a, Twelve mutation signatures extracted using non25
Applying
a mathematical
approach
extract
negative
matrix
factorization. Each
signature isto
ordered
by mutational
mutation classsig
(C>A/G>T,
C>G/G>C,
C>T/G>A,
T>A/A>T, T>C/A>G,
T>G/A
tures previously
revealed
five base-substitution
signatures
in br
>C),
takingsignatures
immediate1,
flanking
into account.
For each
cancer:
2, 3, 8 sequence
and 13 (refs
2, 24). Using
thisclass,
method
mutations
are
ordered
by
5′
base
(A,
C,
G,
T)
first
before
3′
base
(A,
C,
the 560 cases revealed twelve signatures, including those previou
G, T). b, The spectrum of base substitution signatures within 560 breast
observed and a further seven, of which five have formerly been detec
cancers. Mutation signatures are ordered (and coloured) according to
ARTICLE
doi:10.1038/nature17676
Landscape of somatic mutations in 560
breast cancer whole-genome sequences
Serena Nik-Zainal1,2, Helen Davies1, Johan Staaf3, Manasa Ramakrishna1, Dominik Glodzik1, Xueqing Zou1, Inigo Martincorena1,
Ludmil B. Alexandrov1,4,5, Sancha Martin1, David C. Wedge1, Peter Van Loo1,6, Young Seok Ju1, Marcel Smid7, Arie B. Brinkman8,
Sandro Morganella9, Miriam R. Aure10,11, Ole Christian Lingjærde11,12, Anita Langerød10,11, Markus Ringnér3, Sung-Min Ahn13,
Sandrine Boyault14, Jane E. Brock15, Annegien Broeks16, Adam Butler1, Christine Desmedt17, Luc Dirix18, Serge Dronov1,
Aquila Fatima19, John A. Foekens7, Moritz Gerstung1, Gerrit K. J. Hooijer20, Se Jin Jang21, David R. Jones1, Hyung-Yong Kim22,
Tari A. King23, Savitri Krishnamurthy24, Hee Jin Lee21, Jeong-Yeon Lee25, Yilong Li1, Stuart McLaren1, Andrew Menzies1,
Ville Mustonen1, Sarah O’Meara1, Iris Pauporté26, Xavier Pivot27, Colin A. Purdie28, Keiran Raine1, Kamna Ramakrishnan1,
F. Germán Rodríguez-González7, Gilles Romieu29, Anieta M. Sieuwerts7, Peter T. Simpson30, Rebecca Shepherd1,
Lucy Stebbings1, Olafur A. Stefansson31, Jon Teague1, Stefania Tommasi32, Isabelle Treilleux33, Gert G. Van den Eynden18,34,
Peter Vermeulen18,34, Anne Vincent-Salomon35, Lucy Yates1, Carlos Caldas36, Laura van’t Veer16, Andrew Tutt37,38,
Stian Knappskog39,40, Benita Kiat Tee Tan41,42, Jos Jonkers16, Åke Borg3, Naoto T. Ueno24, Christos Sotiriou17, Alain Viari43,44,
P. Andrew Futreal1,45, Peter J. Campbell1, Paul N. Span46, Steven Van Laere18, Sunil R. Lakhani30,47, Jorunn E. Eyfjord31,
Alastair M. Thompson28,48, Ewan Birney9, Hendrik G. Stunnenberg8, Marc J. van de Vijver20, John W. M. Martens7,
Anne-Lise Børresen-Dale10,11, Andrea L. Richardson15,19, Gu Kong22, Gilles Thomas44 & Michael R. Stratton1
ARTICLE RESEARCH
6
20 26
3
8
18 17 30
inv
trans
trans
Rearrangement
signature 4
0%
60%
0%
60%
0%
Rearrangement
signature 5
60%
0%
60%
60%
>10 Mb
1–10 Mb
0%
10–100 kb
0%
60%
>10 Mb
Rearrangement
signature 6
1–10 kb
0%
1–10 Mb
0.20
100 kb–1 Mb
13
inv
1–10 kb
1–10 Mb
10–100 kb
>10 Mb
100 kb–1 Mb
1–10 kb
1–10 Mb
10–100 kb
>10 Mb
100 kb–1 Mb
1–10 kb
1–10 Mb
10–100 kb
>10 Mb
100 kb–1 Mb
2
0%
Rearrangement
signature 3
100 kb–1 Mb
5
18 17 30
tds
1–10 kb
100 kb–1 Mb
10–100 kb
1–10 Mb
100 kb–1 Mb
>10 Mb
1–10 Mb
1–10 kb
>10 Mb
10–100 kb
Signatures 1
8
tds
0%
1–10 Mb
1–10 kb
>10 Mb
0.20
0.05
0.10
0.15
log
replication
Signatures
1 strand
5 2asymmetry
13 6 20 26 3
0.00
del
10–100 kb
0.00
0.05
0.10
0.15
log replication strand asymmetry
trans
1–10 kb
1–10 Mb
10–100 kb
>10 Mb
100 kb–1 Mb
1–10 kb
1–10 Mb
10–100 kb
>10 Mb
100 kb–1 Mb
1–10 kb
1–10 Mb
10–100 kb
>10 Mb
100 kb–1 Mb
0.00
0.00
0%
APOBEC deaminase
activity
60%
APOBEC deaminase
activity
del
60%
10–100 kb
0.05
Associated with
0.05
mismatch
repair
deficiency
mismatch repair
deficiency
Associated
with
trans
Non-clustered rearrangements
60%
100 kb–1 Mb
0.10
inv
60%
>10 Mb
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund SE-223 81, Sweden. Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory,
Los Alamos, NM 87545, New Mexico, USA. 5Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA. 6Department of Human Genetics, University of
Leuven, B-3000 Leuven, Belgium. 7Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam 3015CN,
The Netherlands. 8Radboud University, Department of Molecular Biology, Faculties of Science and Medicine, 6525GA Nijmegen, The Netherlands. 9European Molecular Biology Laboratory,
Rearrangement
European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. 10Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital,
signature
3
of
The Norwegian Radium Hospital, Oslo 0310, Norway. 11K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo 0310, Norway. 12Department
Computer Science, University of Oslo, Oslo, Norway. 13Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea. 14Translational Research
Lab, Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon Cedex 08, France. 15Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA. 16The Netherlands
Cancer Institute, 1066 CX Amsterdam, The Netherlands. 17Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000
Rearrangement
Cancer
Brussels, Belgium. 18Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium. 19Dana-Farber
4
Asan
Institute, Boston, Massachusetts 02215, USA. 20Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. 21Department of Pathology,signature
Medical Center, College of Medicine, Ulsan University, Ulsan, South Korea. 22Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, South Korea. 23Memorial Sloan
24
Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA. Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson
Cancer Center, 1515 Holcombe Boulevard., Houston, Texas 77030, USA. 25Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, South Korea. 26Institut
National du Cancer, Research Division, Clinical Research Department, 52 avenue Morizet, 92513 Boulogne-Billancourt, France. 27University Hospital of Minjoz, INSERM UMR 1098, Bd Fleming,
Rearrangement
Besançon 25000, France. 28Pathology Department, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. 29Oncologie Sénologie, ICM Institut Régional du Cancer, Montpellier, France.
signature 5
30
The University of Queensland, UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland 4059, Australia. 31Cancer Research
10 Laboratory, Faculty of Medicine, University
of Iceland, 101 Reykjavik, Iceland. 32IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy. 33Department of Pathology, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cédex 08, France.
34
Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium. 35Institut Curie, Department of Pathology and INSERM U934, 26 rue d’Ulm, 75248 Paris Cedex 05, France. 36Cancer
London,
Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. 37Breast Cancer Now Toby Robin’s Research Unit, King’s CollegeRearrangement
39
London SE1 9RT, UK. 38Breast Cancer Now Toby Robin’s Research Centre, Institute of Cancer Research,
10 London SW3 6JB, UK. Department of Clinical Science, University of Bergen, 5020
signature 6
Bergen, Norway. 40Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway. 41National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore. 42Singapore General
Hospital, Outram Road, 169608, Singapore. 43Equipe Erable, INRIA Grenoble-Rhône-Alpes, 655, Avenue de l’Europe, 38330 Montbonnot-Saint Martin, France. 44Synergie Lyon Cancer, Centre
Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France. 45Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, Texas 77230, USA. 46Department of Radiation Oncology,
Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands. 47Pathology Queensland, The Royal Brisbane and Women’s Hospital, Brisbane,
Queensland 4029, Australia. 48Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, Texas 77030, USA.
Rearrangement
signature 2
1–10 kb
Rearrangement
1
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. 2East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2Associated
9NB, UK.
signature 2 with
Associated with
3
4
0%
1–10 Mb
0.10
tds
60%
100 kb–1 Mb
Rearrangement
somatic cells during the lifetime of the cancer patient, together
with
1
signature
many ‘passenger’ mutations not implicated in cancer development
. 1
Multiple mutational processes, including endogenous and exogenous mutagen exposures, aberrant DNA editing, replication errors
del
60%rearrangements
Clustered
Rearrangement
signature
del 1
inv
0% tds
1–10 kb
The mutational theory of cancer proposes that changes in DNA
sequence, termed ‘driver’ mutations, confer proliferative advan0.15 clone1. Some
tage on a cell, leading to outgrowth of a neoplastic
driver mutations are inherited in the germline, but most arise in
0.15
ARTICLE RESEARCH
Non-clustered rearrangements
Clustered rearrangements
b
10–100 kb
log10 transcription strand asymmetry
log10 transcription strand asymmetry
We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring
clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer
genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have
distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational
signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement
signatures. Three rearrangement signatures, characterized
0.20 duplications or deletions, appear associated with
aby tandem
defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient
BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across
exons, introns and intergenic regions
the repertoire of cancer genes and mutational processes operating,band
0.20
a highlights
progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
Rearrangement size
0 0 M O N T H 2 0 1 6 | VO L 0 0 0 | NAT U R E | 1
Figure 4 | Additional
characteristics of base substitution signatures and
signatures extracted using non-negative matrix factorization. Probability
Rearrangement
size
novel rearrangement signatures in 560 breast cancers. a, Contrasting
of rearrangement
element
on y axis. Rearrangement size on x axis.
transcriptional
strand
and replication
strand
del, deletion;
tds, tandem
duplication;
inv, inversion;
trans, translocation.
Figure 4 | Additional
characteristics
of asymmetry
base substitution
signatures
and asymmetry
signatures extracted
using non-negative
matrix
factorization.
Probability
between
twelve in
base
substitution
signatures.
b, Six rearrangement
novel rearrangement
signatures
560 breast
cancers.
a, Contrasting
of rearrangement element on y axis. Rearrangement size on x axis.
transcriptional strand asymmetry and replication strand asymmetry
del, deletion; tds, tandem duplication; inv, inversion; trans, translocation.
between twelve base substitution signatures. b, Six rearrangement
there were nine locations at which recurrence of tandem duplications signatures 4 and 6 (Fig. 4b). Cancers with tandem duplications or deletions
was found across the breast cancers and which often showed multiple, of rearrangement signatures 1, 3 and 5 did not usually demonstrate
there were nine locations
at which
recurrenceinof
tandem duplications
and 6kataegis.
(Fig. 4b).However,
Cancers with
tandem
duplications
deletions of kataegis as
nested tandem
duplications
individual
cases (Extendedsignatures
Data Fig.48).
there
must be
additionalordeterminants
was found acrossThese
the breast
cancers
and which
often
showed
of duplication
rearrangement
signatures
1, 3 and 5 didare
notassociated
usually demonstrate
may be
mutational
hotspots
specific
formultiple,
these tandem
only
2% of rearrangements
with it. A rare (14 out of 1,557
nested tandem duplications
individual
cases (Extended
Data
Fig. 8).
kataegis. However,
there
mustalternative
be additional
determinants
kataegis as with rearrangemutationalin
processes,
although
we cannot
exclude
the possibility
that foci,
0.9%)
form
of kataegis, of
colocalizing
ARTICLE
Received 3 Dec 2015 | Accepted 12 Jun 2016 | Published 13 Jul 2016
DOI: 10.1038/ncomms12222
OPEN
A whole-genome sequence and transcriptome
perspective on HER2-positive breast cancers
Anthony Ferrari1, Anne Vincent-Salomon2, Xavier Pivot3, Anne-Sophie Sertier1, Emilie Thomas1, Laurie Tonon1, Sandrine Boyault4,
Eskeatnaf Mulugeta5, Isabelle Treilleux6, Gaëtan MacGrogan7, Laurent Arnould8, Janice Kielbassa1, Vincent Le Texier1,
Hélène Blanché9, Jean-Franc¸ois Deleuze9, Jocelyne Jacquemier10, Marie-Christine Mathieu11, Frédérique Penault-Llorca12,
Frédéric Bibeau13, Odette Mariani14, Cécile Mannina15, Jean-Yves Pierga16, Olivier Trédan17, Thomas Bachelot17,
Hervé Bonnefoi18, Gilles Romieu19, Pierre Fumoleau8, Suzette Delaloge11, Maria Rios20, Jean-Marc Ferrero21, Carole Tarpin22,
Catherine Bouteille23, Fabien Calvo24, Ivo Glynne Gut25,26, Marta Gut25,26, Sancha Martin27, Serena Nik-Zainal27,28,
NATURE COMMUNICATIONS | DOI: 10.1038/ncomms12222
Michael R. Stratton27, Iris Pauporté29, Pierre Saintigny30,31,32, Daniel Birnbaum33, Alain Viari1,34 & Gilles Thomas1
a
RNA group:
PAM50:
ER/PR:
HER2:
HER2 CNV.:
Ploidy:
B
C
D
LumA
LumB
Her2
Basal
Pos
Neg
NA
3+
2+ / FISH+
Amplified
2
Gained
>2
NA
PAM50
ER
PR
HER2
HER2.CNV
PLOIDY
FGA
[ 75, 100 ]
[ 50, 75 ]
LST
Quartiles
(%):University, Département de
Lyon Cancer, Plateforme de bioinformatique ‘Gilles Thomas’ Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France. 2 Institut
Curie, PSL Research
[ 25, 50 ]
Pathologie, INSERM U934, 26 rue d’Ulm, 75248 Paris, France. 3 Centre Hospitalier Universitaire de Minjoz, UMR INSERM 1098, Boulevard A. Fleming, Besanc¸on 25000, France.
4 Plateforme de génomique des cancers, Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France. 5 Institut Curie, UMR 3215 CNRS, Génétique et biologie du développement, Epigénèse et
[ 0 , 25 ]
développement des mammifères, U934 Inserm, 26 rue d’Ulm, 75248 Paris, France. 6 Centre Léon Bérard, Département de Pathologie, 28 rue Laënnec, 69008 Lyon, France. 7 Département
de Biopathologie, Unité Inserm U916, Institut Bergonié, 229 cours de l’Argonne, 33076 Bordeaux, France. 8 Centre Georges-Franc¸ois Leclerc et CRB Ferdinand Cabanne, 1 rue du Professeur
Marion, Inserm U866-UBFC, 21000 Dijon, France. 9 Centre d’Etude du Polymorphisme Humain (CEPH), Fondation Jean Dausset, 27 rue Juliette Dodu, 75010 Paris, France. 10 Institut PaoliCalmettes, Département de Pathologie, 232 Boulevard de Sainte-Marguerite, 13009 Marseille, France. 11 Institut Gustave Roussy, Comité de Pathologie Mammaire, 114 rue Edouard Vaillant,
94805 Villejuif, France. 12 Centre Jean Perrin, Département de Biopathologie, EA 4677 ERTICa, Université d’Auvergne, 58 rue Montalembert, 63000 Clermont-Ferrand, France. 13 Institut
Régional du Cancer de Montpellier (ICM), Département de Pathologie, 208 Avenue des Apothicaires, 34298 Montpellier, France. 14 Institut Curie, PSL Research University, Service de
Pathologie, Centre de Ressources Biologiques, BRIF BB-0033-00048, 26 rue d’Ulm, 75248 Paris, France. 15 Département de Pathologie, Institut Bergonié, 229 cours de l’Argonne, CS 61283,
33076 Bordeaux, France. 16 Institut Curie, PSL Research University, Département d’Oncologie Médicale, Université Paris Descartes, 26 rue d’Ulm, 75248 Paris, France. 17 Centre Léon Bérard,
Département de Cancérologie Médicale, 28 rue Laënnec, 69008 Lyon, France. 18 Department of Medical Oncology, Institut Bergonié Unicancer, University of Bordeaux, INSERM U916,
CIC1401, 229 cours de l’Argonne, CS 61283, 33076 Bordeaux, France. 19 Institut Régional du Cancer de Montpellier (ICM), Oncologie Sénologie, 208 Avenue des Apothicaires, 34298
Montpellier, France. 20 Centre Alexis Vautrin, Département d’Oncologie Médicale, 6 Avenue de Bourgogne, 54511 Vandoeuvre Les Nancy, France. 21 Centre Antoine Lacassagne,
Département d’Oncologie Médicale, 33 Avenue de Valombrose, 06189 Nice, France. 22 Institut Paoli-Calmettes, Département d’Oncologie Médicale, 232Missense
Boulevard de mutation
Sainte-Marguerite,
13009 Marseille, France. 23 Clinique Mutualiste de Bellevue, Chirurgie Gynécologique et Mammaire, 3 rue le Verrier, 42100 Saint-Etienne, France. 24 Institut Gustave Roussy, Cancer Core
26 Universitat Pompeu Fabra,
Europe, 39 rue Camille Desmoulins, Villejuif 94805, France. 25 CNAG-CRG, Centre for Genomic Regulation (CRG), C/Baldiri Reixac 4, 08028 Barcelona, Spain.
Truncating
mutation
Plac¸a de la Mercè, 10, 08002 Barcelona, Spain. 27 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. 28 East Anglian Medical Genetics Service, Cambridge University
Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK. 29 Institut National du Cancer, Département de Recherche Clinique, 52 Avenue Morizet, 92513 Boulogne-Billancourt, France.
Amplification
30 INSERM U1052-CNRS 5286, Cancer Research Center of Lyon, F-69008 Lyon, France. 31 Université de Lyon, F-69622 Lyon, France. 32 Centre Léon Bérard,
28 rue Laënnec, 69008 Lyon,
France. 33 Département d’Oncologie Moléculaire, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, INSERM, CNRS, Aix-Marseille Université, 232 boulevard de
Sainte-Marguerite, 13009 Marseille, France. 34 Equipe Erable, INRIA Grenoble-Rhône-Alpes, 655 Avenue de l’Europe, 38330 Montbonnot-Saint Martin,Homozygous
France. Correspondence
and
deletion
requests for materials should be addressed to A.F. (email: [email protected]) or to A.V. (email: [email protected]).
1 Synergie
b
NATURE COMMUNICATIONS | 7:12222 | DOI: 10.1038/ncomms12222 | www.nature.com/naturecommunications
RNA
A
1
pLum
mLum
0 10 20 30 40 50
SV17
TP53
PIK3CA
KMT2C
JAK2
KMT2D
MAP2K4
GATA3
CDH1
NF1
ERBB2
CDK12
PPM1D
RPS6KB1
TOP2A
CCND1
KAT7
BCAS3
MYC
ZNF703
RAD21
ZNF217
FGFR1
MCL1
MDM4
HMGA2
MDM2
GNAS
PI001
PI046
PI049
PI053
PI059
PI073
PI078
PI085
PI088
PI089
PI099
PI017
PI020
PI038
PI061
PI074
PI084
PI093
PI036
PI042
PI005
PI003
PI009
PI014
PI015
PI019
PI023
PI027
PI044
PI048
PI051
PI055
PI062
PI079
PI068
PI013
PI052
PI069
PI045
PI012
PI011
PI071
PI006
PI098
PI002
PI024
PI056
PI064
PI096
PI097
PI091
PI035
PI063
PI076
PI010
PI041
PI057
PI066
PI082
PI090
PI094
PI022
PI034
PI092
HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for
which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying
diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease
heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of
64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression
data, with distinctive genomic features in terms of somatic mutations, copy-number changes or
structural variations. The results suggest that, despite being clinically defined by a specific gene
amplification, HER2-positive tumours melt into the whole luminal–basal breast cancer spectrum
rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show
that several cases of amplifications are compatible with a breakage–fusion–bridge mechanism.
ARTICLE
ERBB2 amplifica-on mechanism Anthony Ferrari, Anne Vincent-­‐Salomon, Xavier Pivot et al Nature comm 2016
PI078
!
!
19
18
17
16
Breakage-­‐Fusion-­‐Bridge 15
14
13
12
12
tumoral copy number
12
11
10
9
8
8
7
6
5
4
3
2
2
1
0
?
3.60e+07
3.65e+07
3.70e+07
>
3.75e+07
3.80e+07
< >
3.85e+07
3.90e+07
position
PI034
!!
!
25
24
23
22
21
20
18
19
18
16
17
from MaroZa et al. Breast Cancer Research 2012 tumoral copy number
16
14
15
14
14
12
13
12
10
11
10
8
9
8
7
6
5
4
2
3
2
1
0
?
3.4e+07
3.6e+07
<
< ?
>
< >
3.8e+07
position
>
4.0e+07
4.2e+07
HER-­‐posi-ve breast cancer heterogeneity: a whole genome sequence and transcriptome perspec-ve Anthony Ferrari, Anne Vincent-­‐Salomon, Xavier Pivot et al Nature comm 2016
100
80
60
40
q24.3
q25.1
q25.2
q25.3
q24.3
q25.2
q25.1
q25.2
q25.3
q25.3
q24.2
q24.1
q23.3
q23.2
q23.1
q22
q21.33
q21.32
q21.31
q21.1
q21.2
q12
q11.2
q11.1
p11.1
p11.2
p12
p13.1
0
p13.2
0
p13.3
20
20
40
60
80
100
ERBB2 100
100
CDK12 KAT7 TOP2A 60
60
PPM1D SPOP BCAS3 40
40
20
q24.2
q25.1
q24.1
q23.1
q22
q23.2
q21.33
q22
q21.33
q21.32
q21.31
q21.32
q21.1
q21.2
q12
q21.31
q11.2
q21.2
q11.1
p11.1
q21.1
p11.2
q12
p12
q11.2
p13.1
0
p13.2
0
q23.3
q23.1
q24.1
q23.2
q24.2
q24.3
q23.3
DDX5 20
20
p13.1
p13.3
p11.2
q11.1
frequency
80
80
RPS6KB1 amplifications
HER-­‐posi-ve breast cancer heterogeneity: a whole genome sequence and transcriptome perspec-ve Anthony Ferrari, Anne Vincent-­‐Salomon, Xavier Pivot et al Nature comm 2016
106 kb 100
0
IKZF3
GRB7
MIEN1
ERBB2
PGAP3
TCAP
PNMT
20
STARD3
40
PPP1R1B
60
NEUROD2
80
RNA
HER-­‐posi-ve breast cancer heterogeneity: a whole genome sequence and transcriptome perspec-ve PAM50
ER
PR
Anthony Ferrari, Anne Vincent-­‐Salomon, Xavier Pivot et al HER2
Nature comm 2016
HER2.CNV
PLOIDY
FGA
LST
pLum
0
10
20
30
40
50
10
20
30
40
50
PAM50
SV17
0
RNA
mLum
ER
TP53
PIK3CA
PR
KMT2C
HER2
JAK2
KMT2D
HER2.CNV
MAP2K4
GATA3
PLOIDY
CDH1
FGA
NF1
Truncating mutation!
Amplification!
Homozygous deletion!
ERBB2
LST
CDK12
pLum
PPM1D
RPS6KB1
mLum
TOP2A
SV17
CCND1
KAT7
TP53
BCAS3
PIK3CA
MYC
KMT2C
ZNF703
JAK2
RAD21
KMT2D
ZNF217
MAP2K4
FGFR1
GATA3
MCL1
CDH1
MDM4
NF1
HMGA2
ERBB2
MDM2
CDK12
GNAS
PPM1D
RPS6KB1
TOP2A
CCND1
KAT7
BCAS3
MYC
ZNF703
RAD21
ZNF217
FGFR1
PI001
PI046
PI049
PI053
PI059
PI073
PI078
PI085
PI088
PI089
PI099
PI017
PI020
PI038
PI061
PI074
PI084
PI093
PI036
PI042
PI005
PI003
PI009
PI014
PI015
PI019
PI023
PI027
PI044
PI048
PI051
PI055
PI062
PI079
PI068
PI013
PI052
PI069
PI045
PI012
PI011
PI071
PI006
PI098
PI002
PI024
PI056
PI064
PI096
PI097
PI091
PI035
PI063
PI076
PI010
PI041
PI057
PI066
PI082
PI090
PI094
PI022
PI034
PI092
Missense mutation!
SIGNAL study : GWAS findings No associaGons between SNPs and HER2 status X Pivot et al Nature Journal Breast Cancer 2017