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