Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

Timothy HT Cheng, Deborah Thompson, Jodie Painter, Tracy O’Mara, Maggie Gorman, Lynn Martin, Claire Palles, Angela Jones, Daniel D. Buchanan, Aung Ko Win, John Hopper, Mark Jenkins, Noralane M. Lindor, Polly A. Newcomb, Steve Gallinger, David Conti, Fred Schumacher, Graham Casey, Graham G Giles, Paul Pharoah, Julian Peto, Angela Cox, Anthony Swerdlow, Fergus Couch, Julie M Cunningham, Ellen L Goode, Stacey J Winham, Diether Lambrechts, Peter Fasching, Barbara Burwinkel, Hermann Brenner, Hiltrud Brauch, Jenny Chang-Claude, Helga B. Salvesen, Vessela Kristensen, Hatef Darabi, Jingmei Li, Tao Liu, Annika Lindblom, Per Hall, Magdalena Echeverry de Polanco, Monica Sans, Angel Carracedo, Sergi Castellvi-Bel, Augusto Rojas-Martinez, Samuel Aguiar Jnr, Manuel R. Teixeira, Alison M Dunning, Joe Dennis, Geoffrey Otton, Tony Proietto, Elizabeth Holliday, John Attia, Katie Ashton, Rodney J Scott, Mark McEvoy, Sean C Dowdy, Brooke L Fridley, Henrica MJ Werner, Jone Trovik, Tormund S Njolstad, Emma Tham, Miriam Mints, Ingo Runnebaum, Peter Hillemanns, Thilo Dörk, Frederic Amant, Stefanie Schrauwen, Alexander Hein, Matthias W Beckmann, Arif Ekici, Kamila Czene, Alfons Meindl, Manjeet K Bolla, Kyriaki Michailidou, Jonathan P Tyrer, Qin Wang, Shahana Ahmed, Catherine S Healey, Mitul Shah, Daniela Annibali, Jeroen Depreeuw, Nada A. Al-Tassan, Rebecca Harris, Brian F. Meyer, Nicola Whiffin, Fay J Hosking, Ben Kinnersley, Susan M. Farrington, Maria Timofeeva, Albert Tenesa, Harry Campbell, Robert W. Haile, Shirley Hodgson, Luis Carvajal-Carmona, Jeremy P. Cheadle, Douglas Easton, Malcolm Dunlop, Richard Houlston, Amanda Spurdle, Ian Tomlinson

High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers.