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Title: Genetic architectures of proximal and distal colorectal cancer are partly distinct.
Authors: Huyghe JR,  Harrison TA,  Bien SA,  Hampel H,  Figueiredo JC,  Schmit SL,  Conti DV,  Chen S,  Qu C,  Lin Y,  Barfield R,  Baron JA,  Cross AJ,  Diergaarde B,  Duggan D,  Harlid S,  Imaz L,  Kang HM,  Levine DM,  Perduca V,  Perez-Cornago A,  Sakoda LC,  Schumacher FR,  Slattery ML,  Toland AE,  van Duijnhoven FJB,  Van Guelpen B,  Agudo A,  Albanes D,  Alonso MH,  Anderson K,  Arnau-Collell C,  Arndt V,  Banbury BL,  Bassik MC,  Berndt SI,  Bézieau S,  Bishop DT,  Boehm J,  Boeing H,  Boutron-Ruault MC,  Brenner H,  Brezina S,  Buch S,  Buchanan DD,  Burnett-Hartman A,  Caan BJ,  Campbell PT,  Carr PR,  Castells A,  Castellví-Bel S,  Chan AT,  Chang-Claude J,  Chanock SJ,  Curtis KR,  de la Chapelle A,  Easton DF,  English DR,  Feskens EJM,  Gala M,  Gallinger SJ,  Gauderman WJ,  Giles GG,  Goodman PJ,  Grady WM,  Grove JS,  Gsur A,  Gunter MJ,  Haile RW,  Hampe J,  Hoffmeister M,  Hopper JL,  Hsu WL,  Huang WY,  Hudson TJ,  Jenab M,  Jenkins MA,  Joshi AD,  Keku TO,  Kooperberg C,  Kühn T,  Küry S,  Le Marchand L,  Lejbkowicz F,  Li CI,  Li L,  Lieb W,  Lindblom A,  Lindor NM,  Männistö S,  Markowitz SD,  Milne RL,  Moreno L,  Murphy N,  Nassir R,  Offit K,  Ogino S,  Panico S,  Parfrey PS,  Pearlman R,  Pharoah PDP,  Phipps AI,  Platz EA,  Potter JD,  Prentice RL,  Qi L,  Raskin L,  Rennert G,  Rennert HS,  Riboli E,  Schafmayer C,  Schoen RE,  Seminara D,  Song M,  Su YR,  Tangen CM,  Thibodeau SN,  Thomas DC,  Trichopoulou A,  Ulrich CM,  Visvanathan K,  Vodicka P,  Vodickova L,  Vymetalkova V,  Weigl K,  Weinstein SJ,  White E,  Wolk A,  Woods MO,  Wu AH,  Abecasis GR,  Nickerson DA,  Scacheri PC,  Kundaje A,  Casey G,  Gruber SB,  Hsu L,  Moreno V,  Hayes RB,  Newcomb PA,  Peters U
Journal: Gut
Date: 2021 Feb 25
Branches: CGR, MEB, OD, OEEB
PubMed ID: 33632709
PMC ID: not available
Abstract: OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.