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

ObjectiveAn 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.DesignTo 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.ResultsWe 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.ConclusionGenetic 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.