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