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00925njm 22002777a 4500 dc Huyghe, Jeroen R. author Harrison, Tabitha A. author Bien, Stephanie A. author Hampel, Heather author Figueiredo, Jane C. author Schmit, Stephanie L. author Conti, David V. author Chen, Sai author Qu, Conghui author Lin, Yi author Barfield, Richard author Peters, Ulrike author Gunter, Marc J. author Banbury, Barbara L. author Chan, Andrew T. author Harlid, Sophia author Imaz, Liher author Sakoda, Lori C. author Kang, Hyun Min author Huang, Wen-yi author Boehm, Juergen author De La Chapelle, Albert author Schumacher, Fredrick R. author Slattery, Martha L. author Gala, Manish author Toland, Amanda E. author Phipps, Amanda I. author Buch, Stephan author Albanes, Demetrius author Alonso Aguado, Maria Henar author Gsur, Andrea author Anderson, Kristin author Rennert, Hedy S. author Gauderman, W. James author Bassik, Michael C. author Berndt, Sonja I. author Hsu, Wan-ling author Bézieau, Stéphane author Haile, Robert W. author Boeing, Heiner author Boutron-Ruault, Marie-Christine author Keku, Temitope O. author Brenner, Hermann author Hudson, Thomas J. author Buchanan, Daniel D. author Burnett Hartman, Andrea author Lejbkowicz, Flavio author Caan, Bette J. author Carr, Prudence R. author Castells Garangou, Antoni author Lindor, Noralane M. author Castellví Bel, Sergi author Chang Claude, Jenny author Chanock, Stephen J. author Moreno, Lorena author Curtis, Keith R. author Easton, Douglas F. author English, Dallas R. author Giles, Graham G. author Feskens, Edith J. M. author Su, Yu-ru author Kooperberg, Charles author Ogino, Shuji author Goodman, Phyllis J. author Grady, William M. author Pharoah, Paul D. P. author Grove, John S. author Cross, Amanda J. author Li, Christopher I. author Hampe, Jochen author Hoffmeister, Michael author Rennert, Gad author Hopper, John L. author Perduca, Vittorio author Platz, Elizabeth A. author Jenab, Mazda author Jenkins, Mark A. author Song, Mingyang author Joshi, Amit D. author Riboli, Elio author Kühn, Tilman author Küry, Sébastien author Ulrich, Cornelia M. author Le Marchand, Loic author Tangen, Catherine M. author Li, Li author Lieb, Wolfgang author Weigl, Korbinian author Lindblom, Annika author Männistö, Satu author Markowitz, Sanford D. author Wu, Anna H. author Milne, Roger L. author Murphy, Neil author Nassir, Rami author Kundaje, Anshul author Offit, Kenneth author Panico, Salvatore author Parfrey, Patrick S. author Potter, John D. author Pearlman, Rachel author Van Guelpen, Bethany author Visvanathan, Kala author Moreno Aguado, Víctor author Prentice, Ross L. author Qi, Lihong author Baron, John A. author Raskin, Leon author Arndt, Volker author Weinstein, Stephanie J. author Schafmayer, Clemens author Schoen, Robert E. author Levine, David M. author Seminara, Daniela author Gallinger, Steven author Diergaarde, Brenda author Thibodeau, Stephen N. author Thomas, Duncan C. author Van Duijnhoven, Fränzel J. B. author Trichopoulou, Antonia author Pérez Cornago, Aurora author Vodicka, Pavel author Vodickova, Ludmila author Arnau Collell, Coral author Vymetalkova, Veronika author Agudo, Antonio author White, Emily author Wolk, Alicja author Bishop, D. Timothy author Woods, Michael O. author Abecasis, Gonçalo R. author Nickerson, Deborah A. author Brezina, Stefanie author Scacheri, Peter C. author Casey, Graham author Gruber, Stephen B. author Campbell, Peter T. author Hsu, Li author Hayes, Richard B. author Newcomb, Polly A. author Duggan, David author 2021-07-22T11:18:39Z 2021-07-22T11:18:39Z 2021-02-25 2021-07-22T11:13:55Z 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. Medicina preventiva Càncer colorectal Genètica Preventive medicine Colorectal cancer Genetics Genetic architectures of proximal and distal colorectal cancer are partly distinct