Susceptibilité génétique et cancer bronchique : smoking or not
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Susceptibilité génétique et cancer bronchique : smoking or not smoking ? Hélène Blanché-Koch, Fondation Jean Dausset-CEPH Data from the Million Woman Study Phase I of National Programme in Cancer Genomics (2007-2009) • Lung cancer: Hung et al. Nature 452:633-7, 2008; McKay et al. Nat Genet. 40:1404-6, 2008; Lips et al. Int. J. of Epidemiol, Sept. 2009; Landi et al. Am J Hum Genet 85:679691, 2009. • Head & neck cancers (replication in lung cancer): McKay et al (in press) • Kidney cancer: submitted • Melanoma: Bishop et al. Nat Genet. 41:920-5, 2009 • Glioma: Shete et al. Nat Genet. 41:899-904, 2009 • Breast cancer: Reeves et al. Jama. 304:426-434, 2010; Travis et al. The Lancet. 375:2143-2151, 2010 Un gène • Ensemble des séquences d’ADN (régions régulatrices et codantes) permettant la synthèse, c'est-à-dire la fabrication d’une protéine fonctionnelle donnée. Il est situé à un certain endroit (appelé locus) d'un chromosome. • 20 000 gènes chez l’homme • Environ 5% du génome correspond à des gènes ( « partie codante de l’ADN »). Le reste de l’ADN (région non codante) contient entre autres des régions régulatrices de l’activité des gènes ou des portions d’ADN dont on ne connaît pas encore la fonction. • Chaque gène existe sous deux formes alléliques ou allèles, hérités l’un de la mère et l’autre du père. Les modifications génétiques • Anomalie du nombre de chromosome • Mutation (ex: Béta-thalassémie) – Changement d’un nucléotide – Délétion ou insertion • Polymorphisme Phénotype / génotype A: Allèle co-dominant B: Allèle co-dominant O: Allèle récessif Les maladies génétiques • Maladie causée par une ou plusieurs modifications du génome • Mutation somatique -> cancer, leucémie • Mutation germinale -> maladie génétique héréditaire (myopathie, phénylcétonurie…) • Aberrations chromosomiques • Maladies monogéniques (environ 5000) • Maladies multifactorielles Maladies multifactorielles • Tendance familiale certaine • Transmission au sein des familles non compatible avec une hérédité de type maladie monogénique • Causes génétiques et environnementales qui interagissent entre-elles • Allèles de susceptibilité Deux modèles d’étude des maladies multifactorielles • Polygénique. La susceptibilité à développer la maladie est sous la dépendance d’allèles de nombreux gènes et de facteurs environnementaux dont l’effet individuel est mineur. C’est le cumul d’un certain nombre d’allèles de susceptibilité qui déterminera l’apparition de la maladie (effet seuil). • Mixte. La susceptibilité est sous le contrôle d’un gène majeur, dont l’action est toutefois modulée par plusieurs autres gènes et des facteurs environnementaux. Recherche de loci associés à une maladie multifactorielle • Etude d’association : cas/témoins • Etude de liaison : fratries Hétérogénéité génétique, hétérogénéité de population • Une maladie correspond à plusieurs affections (diabète) • Variations des fréquences alléliques Nord/Sud, Est/Ouest • Faiblesse effet recherché => nécessité statistique robuste, validation indépendante des résultats Detection de variants fréquents associés à un phénotype/maladie 1. cas témoin Criblage du génome sur tous les ADN d’une collection avec 500,000 variants 3. Log 10 p-value 2. Identification de régions présentant des différences significatives entre cas et témoins cas témoin Confirmation sur des collections plus larges Lung cancer samples Study Case Controls Countries of Origin Genome-Wide Association 1 Central Europe 1 841 2 441 6 Eastern European countries Toronto 330 500 Canada HUNT2/TromsØ 403 412 Norway CARET 397 392 USA Total 2 971 3 745 Replication EPIC 1 213 2 591 10 Western European countries Szczecin 908 1 037 Poland CARET2 363 1 128 USA Liverpool 415 817 UK Total 2 899 5 573 Overall Total 5 870 9 318 1 After QC & PCA Hung RJ Nature 452(7187):633-7, 2008 samples in 1st phase GWA The principal common genetic risk factors for lung cancer in Caucasians identified Huang et al Nature 452:633-637, 2008; McKay et al Nat Genet Nov 2008 GWA scan cohort : 2971 Caucasian lung cancer cases & 3746 controls Replication cohort : MHC 2899 Caucasian lung cancer cases & 5,573 controls Genome-wide significant in GWA and replication: 5p15 (TERT region) P=10-11 6p21 (MHC) P=10-8 15q25 (CHRNA5 etc.) P=10-20 The principal common genetic risk factors for lung cancer in Caucasians identified International Meta-analysis •14 collections totaling 13,300 Caucasian lung cancer cases & 19,666 controls • Unpublished results on more than 6,000 cases • Previously described loci at 15q25, 5p15, and 6p21 identified The principal common genetic risk factors for lung cancer in Caucasians identified Huang et al Nature 452:633-7, 2008; McKay et al Nat Genet 40:1404-6, 2008 Associations of chromosome 15q25 markers of nicotinic acetylcholine receptor units Lung cancer Chronic obstructive pulmonary disease Smoking (1 cigarette/day increase) Lung function (forced expiratory volume; VEF1) Mouse models for ACNA5, ACNB4, ACNA3 presently in analysis Chromosome 15q25 association region CHRNA3,CHRNA5,CHRNB4 Nicotinic acetylcholine receptor subunits expressed in multiple cell types Implicated in nicotine dependence Bind to nicotine and potent lung carcinogens Chromosome 15q25 association region Amino acid change induced by disease-associated variant in CHRNA5 (Asp->Asn) Impact on life-time risk of lung cancer death Example from Poland CC genotype found in about 12% of population Lung cancer GWA scan Huang et al Nature 452:633-637, 2008; McKay et al Nat Genet Nov 2008 TERT = reverse transcriptase component of telomerase Markers also associated with idiopathic pulmonary fibrosis Associated with other cancers Replication 5p.15.33 variants in 16 additional lung cancer studies totalling more than 6000 cases and 8000 controls rs2736100 rs402710 p=10-11 p=10-11 • Two variants with no LD (r2 =0.0) have independent effects, • Risk observed in both smokers and never-smokers • Strong heterogeneity by histology with effect restricted to nonsmall cell lung cancer TERT locus in multiple cancers McKay et al Nat Genet Nov 2008; Shete et al Nat Genet Aug 2009 Lung cancer genome scan Glioma genome scan TERT region on chromosome 5p15.33 Identification of 4q21, 4q23 and 12q21 as upper aero-digestive tract cancer susceptibility loci & relationship to lung cancer •Genome-wide association study of 2,091 UADT cases and 8,311 controls followed by replication of 20 variants in an additional 6,545 UADT cases and 7,892 controls. •Five variants presented evidence for significant association in the replication series (one sided p ≤ 0.005). Four were at loci that contain genes involved in alcohol metabolism, three in the alcohol dehydrogenase (ADH) gene cluster on 4q23 (rs1573496-ADH7 Preplication=7x10-10, rs1229984-ADH1B Preplication=3x10-10, rs1042758ADH1C Preplication=0.001) and the fourth at 12q24 (rs4767364 Preplication=4x10-4) located in extended region linkage disequilibrium (LD) containing the aldehyde dehydrogenase 2 (ALDH2) gene. •The fifth replicated variant was at 4q21, located near DNA repair related genes HEL308 and FAM175A (or Abraxas) (rs1494961, Preplication=9x10-6). •The 4q21 variant (not related to a known alcohol metabolism gene) was also associated with lung cancer risk in an independent series of 4186 lung cancer cases and 9472 controls (rs1494961, P=0.002). We have previously shown that the chromosome 15q25 lung cancer susceptibility markers are related to risk of UADT, although not with genome-wide significance. •These results highlight the importance of the genes involved in the metabolism of alcohol in UADT cancer susceptibility, and implicate a novel susceptibility locus as 4q21 in both UADT and lung cancers. Smoking behavior and genetics • Oxford- GlaxoSmithkline • Tobacco and Genetics (TAG) • ENGAGE • 140 000 individuals • Smoking initiation, dependency and cessation The TAG consortium, Nature Genet. 2010 441-447 Amos et al Nature Genet. 2010 5: 366-368; Liu et al. Nature Genet. 2010 436-440; the TAG Nature Genet. 2010 441-447; Thorgeirsson et al. Nature Genet. 2010 448-453 -Brain derived neurotrophic factor (chr 11). Protein involved in neurobiological processes such as social stress and moderating anxiety -Nicotinic acetylcholine receptors. Increase in the level of neurotransmitters including dopamine. - Polymorphisms of cytochrome CYP2A6 (chr 19q13) influences the catabolism of nicotin into inactive metabolites - Non coding RNA at 10q25 - Dopamine β-hydroxylase (chr 9) which catalizes the convertion of dopamine to norepinephrine Risk of lung cancer in never smokers (Li et al. 2010 The Lancet, 11:321-330) • 15% of men, 53% of females develop lung cancer without any history of smoking • Aetiology, clinical characteristics and prognosis different from smokers • GWAS on non smokers (888 cases and 1384 controls) – – – – Mayo (Rochester) 377 matched case-control pairs MDACC (Houston) 328 cases and 407 controls Harvard (Boston) 92 cases and 161 controls UCLA (Los Angeles) 91 cases and 439 controls A four stage study • 1st phase : GWAS on 377 matched cases and controls (Mayo) => 44 top SNPs (Mainly adenocarcinoma and non small cell lung cancer) • 2nd phase MDACC (328 cases and 407 controls) and Harvard (92 cases and 161 controls) => 2 SNPs on chr 13, combined OR = 1.48, p=2.2 x 10-5 • 3rd phase UCLA study (OR = 1.69 in the additive model) • All populations Combined p-value 5.94 x 10-6 (OR=1.46) Association of rs2352028 with lung cancer in never smokers Expression study • 44 SNPs => 36 genes • The rs2352028 and rs2352029 are strongly associated with expression level of GPC5 (p=1.96 x 10-4 and 1.88 x 10-4 ). • Reduced expression of GPC5 in adenocarcinoma tissue (50% lower than in matched normal lung tissue) • GPC5 : member of the glypican gene family, known to regulate signaling pathways important in cell proliferation and division. • Unclear role Normal lung tissue Jean Dausset La médecine prédictive (1985) Pendant des siècles, la médecine s'est préoccupée de soigner. Aujourd'hui, elle s'est donnée comme but ultime de prévenir plutôt que de guérir. Mais, pour prévenir, il faut prédire ainsi est née la médecine prédictive, premier acte de la médecine préventive.
