Susceptibilité génétique et cancer bronchique : smoking or not smoking? Hélène Blanché-Koch, Fondation Jean Dausset-CEPH

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1 Susceptibilité génétique et cancer bronchique : smoking or not smoking? Hélène Blanché-Koch, Fondation Jean Dausset-CEPH

2 Data from the Million Woman Study

3 Phase I of National Programme in Cancer Genomics ( ) 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: , 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: , 2009 Breast cancer: Reeves et al. Jama. 304: , 2010; Travis et al. The Lancet. 375: , 2010

4 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 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.

5 Les modifications génétiques Anomalie du nombre de chromosome Mutation (ex: Béta-thalassémie) Changement d un nucléotide Délétion ou insertion Polymorphisme

6 Phénotype / génotype A: Allèle co-dominant B: Allèle co-dominant O: Allèle récessif

7 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

8 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

9 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.

10 Recherche de loci associés à une maladie multifactorielle Etude d association : cas/témoins Etude de liaison : fratries

11 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

12 Log 10 p-value 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 Identification de régions présentant des différences significatives entre cas et témoins cas témoin Confirmation sur des collections plus larges

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16 Lung cancer samples Study Case Controls Countries of Origin Genome-Wide Association Central Europe Eastern European countries Toronto Canada HUNT2/TromsØ Norway CARET USA Total Replication EPIC Western European countries Szczecin Poland CARET USA Liverpool UK Total Overall Total After QC & PCA samples in 1 st phase GWA Hung RJ Nature 452(7187):633-7, 2008

17 The principal common genetic risk factors for lung cancer in Caucasians identified Huang et al Nature 452: , 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= p21 (MHC) P= q25 (CHRNA5 etc.) P=10-20

18 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

19 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

20 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

21 Chromosome 15q25 association region Amino acid change induced by disease-associated variant in CHRNA5 (Asp->Asn)

22 Impact on life-time risk of lung cancer death Example from Poland CC genotype found in about 12% of population

23 Lung cancer GWA scan Huang et al Nature 452: , 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

24 Replication 5p variants in 16 additional lung cancer studies totalling more than 6000 cases and 8000 controls rs rs p=10-11 p=10-11 Two variants with no LD (r 2 =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

25 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

26 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 (rs adh7 P replication =7x10-10, rs adh1b P replication =3x10-10, rs ADH1C P replication =0.001) and the fourth at 12q24 (rs P replication =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) (rs , P replication =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 (rs , 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.

27 Smoking behavior and genetics Oxford- GlaxoSmithkline Tobacco and Genetics (TAG) ENGAGE individuals Smoking initiation, dependency and cessation

28 The TAG consortium, Nature Genet

29 Amos et al Nature Genet : ; Liu et al. Nature Genet ; the TAG Nature Genet ; Thorgeirsson et al. Nature Genet 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

30 Risk of lung cancer in never smokers (Li et al The Lancet, 11: ) 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

31 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) 2 nd 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 rd phase UCLA study (OR = 1.69 in the additive model) All populations Combined p-value 5.94 x 10-6 (OR=1.46)

32 Association of rs with lung cancer in never smokers

33 Expression study 44 SNPs => 36 genes The rs and rs 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

34 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.