Genetic architectures of proximal and distal colorectal cancer are partly distinct

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Jeroen R. Huyghe - , Fred Hutchinson Cancer Research Center (Author)
  • Tabitha A. Harrison - , Fred Hutchinson Cancer Research Center (Author)
  • Stephanie A. Bien - , Fred Hutchinson Cancer Research Center (Author)
  • Heather Hampel - , Ohio State University (Author)
  • Jane C. Figueiredo - , University of Southern California, Cedars-Sinai Medical Center (Author)
  • Stephanie L. Schmit - , Cleveland Clinic Foundation (Author)
  • David V. Conti - , University of Southern California (Author)
  • Sai Chen - , University of Michigan, Ann Arbor (Author)
  • Conghui Qu - , Fred Hutchinson Cancer Research Center (Author)
  • Yi Lin - , Fred Hutchinson Cancer Research Center (Author)
  • Richard Barfield - , Fred Hutchinson Cancer Research Center (Author)
  • John A. Baron - , University of North Carolina at Chapel Hill (Author)
  • Amanda J. Cross - , Imperial College London (Author)
  • Brenda Diergaarde - , University of Pittsburgh (Author)
  • David Duggan - , Translational Genomics Research Institute (Author)
  • Sophia Harlid - , Umeå University (Author)
  • Liher Imaz - , Public Health Division of Gipuzkoa (Author)
  • Hyun Min Kang - , University of Michigan, Ann Arbor (Author)
  • David M. Levine - , University of Washington (Author)
  • Vittorio Perduca - , Universite Paris Descartes 5, Université Paris-Saclay (Author)
  • Aurora Perez-Cornago - , University of Oxford (Author)
  • Lori C. Sakoda - , Fred Hutchinson Cancer Research Center, Kaiser Permanente (Author)
  • Fredrick R. Schumacher - , Case Western Reserve University (Author)
  • Martha L. Slattery - , University of Utah (Author)
  • Amanda E. Toland - , Ohio State University (Author)
  • Fränzel J.B. Van Duijnhoven - , Wageningen University & Research (WUR) (Author)
  • Bethany Van Guelpen - , Umeå University (Author)
  • Antonio Agudo - , University of Barcelona (Author)
  • Demetrius Albanes - , National Cancer Institute (NCI) (Author)
  • M. Henar Alonso - , University of Barcelona, CIBER - Center for Biomedical Research Network (Author)
  • Kristin Anderson - , University of Minnesota System (Author)
  • Coral Arnau-Collell - , University of Barcelona (Author)
  • Volker Arndt - , German Cancer Research Center (DKFZ) (Author)
  • Barbara L. Banbury - , Fred Hutchinson Cancer Research Center (Author)
  • Michael C. Bassik - , Stanford University (Author)
  • Sonja I. Berndt - , National Cancer Institute (NCI) (Author)
  • Stéphane Bézieau - , Université de Nantes (Author)
  • D. Timothy Bishop - , University of Leeds (Author)
  • Juergen Boehm - , University of Utah (Author)
  • Heiner Boeing - , German Institute of Human Nutrition Potsdam-Rehbruecke (Author)
  • Marie Christine Boutron-Ruault - , Université Paris-Saclay, Institut Gustave Roussy (Author)
  • Hermann Brenner - , German Cancer Research Center (DKFZ) (Author)
  • Stefanie Brezina - , Medical University of Vienna (Author)
  • Stephan Buch - , Department of internal Medicine I, Dresden University of Technology (Author)
  • Daniel D. Buchanan - , University of Melbourne, Royal Melbourne Hospital (Author)
  • Andrea Burnett-Hartman - , Kaiser Permanente (Author)
  • Bette J. Caan - , Kaiser Permanente (Author)
  • Peter T. Campbell - , American Cancer Society (Author)
  • Prudence R. Carr - , German Cancer Research Center (DKFZ) (Author)
  • Antoni Castells - , University of Barcelona (Author)
  • Sergi Castellví-Bel - , University of Barcelona (Author)
  • Andrew T. Chan - , Harvard University, Broad Institute of Harvard University and MIT (Author)
  • Jenny Chang-Claude - , German Cancer Research Center (DKFZ), University of Hamburg (Author)
  • Stephen J. Chanock - , National Cancer Institute (NCI) (Author)
  • Keith R. Curtis - , Fred Hutchinson Cancer Research Center (Author)
  • Albert De La Chapelle - , Ohio State University (Author)
  • Douglas F. Easton - , University of Cambridge (Author)
  • Dallas R. English - , University of Melbourne, Cancer Council Victoria (Author)
  • Edith J.M. Feskens - , Wageningen University & Research (WUR) (Author)
  • Manish Gala - , Harvard University (Author)
  • Steven J. Gallinger - , University of Toronto (Author)
  • W. James Gauderman - , University of Southern California (Author)
  • Graham G. Giles - , University of Melbourne, Cancer Council Victoria (Author)
  • Phyllis J. Goodman - , Fred Hutchinson Cancer Research Center (Author)
  • William M. Grady - , Fred Hutchinson Cancer Research Center, University of Washington (Author)
  • John S. Grove - , University of Hawai'i at Mānoa (Author)
  • Andrea Gsur - , Medical University of Vienna (Author)
  • Marc J. Gunter - , International Agency for Research on Cancer (Author)
  • Robert W. Haile - , Cedars-Sinai Medical Center (Author)
  • Jochen Hampe - , Department of internal Medicine I, Dresden University of Technology (Author)
  • Michael Hoffmeister - , German Cancer Research Center (DKFZ) (Author)
  • John L. Hopper - , University of Melbourne, Seoul National University (Author)
  • Li Hsu - , University of Washington (Author)
  • Wen Yi Huang - , National Cancer Institute (NCI) (Author)
  • Thomas J. Hudson - , Ontario Institute for Cancer Research (Author)
  • Mazda Jenab - , International Agency for Research on Cancer (Author)
  • Mark A. Jenkins - , University of Melbourne (Author)
  • Amit D. Joshi - , Harvard University (Author)
  • Temitope O. Keku - , University of North Carolina at Chapel Hill (Author)
  • Charles Kooperberg - , Fred Hutchinson Cancer Research Center (Author)
  • Tilman Kühn - , German Cancer Research Center (DKFZ) (Author)
  • Sébastien Küry - , Université de Nantes (Author)
  • Loic Le Marchand - , University of Hawai'i at Mānoa (Author)
  • Flavio Lejbkowicz - , Carmel Medical Center, Clalit Health Services (Author)
  • Christopher I. Li - , Fred Hutchinson Cancer Research Center (Author)
  • Li Li - , University of Virginia (Author)
  • Wolfgang Lieb - , Kiel University (Author)
  • Annika Lindblom - , Karolinska Institutet (Author)
  • Noralane M. Lindor - , Mayo Clinic Rochester, MN (Author)
  • Satu Männistö - , National Institute for Health and Welfare (Author)
  • Sanford D. Markowitz - , Case Western Reserve University (Author)
  • Roger L. Milne - , University of Melbourne, Cancer Council Victoria (Author)
  • Lorena Moreno - , University of Barcelona (Author)
  • Neil Murphy - , International Agency for Research on Cancer (Author)
  • Rami Nassir - , Umm Al-Qura University (Author)
  • Kenneth Offit - , Memorial Sloan-Kettering Cancer Center, Cornell University (Author)
  • Shuji Ogino - , Broad Institute of Harvard University and MIT, Harvard University, Dana-Farber Cancer Institute (Author)
  • Salvatore Panico - , University of Naples Federico II (Author)
  • Patrick S. Parfrey - , Memorial University of Newfoundland (Author)
  • Rachel Pearlman - , Ohio State University (Author)
  • Paul D.P. Pharoah - , University of Cambridge (Author)
  • Amanda I. Phipps - , Fred Hutchinson Cancer Research Center, University of Washington (Author)
  • Elizabeth A. Platz - , Johns Hopkins University (Author)
  • John D. Potter - , Fred Hutchinson Cancer Research Center (Author)
  • Ross L. Prentice - , Fred Hutchinson Cancer Research Center (Author)
  • Lihong Qi - , University of California at Davis (Author)
  • Leon Raskin - , Vanderbilt University (Author)
  • Gad Rennert - , Carmel Medical Center, Clalit Health Services, Technion-Israel Institute of Technology (Author)
  • Hedy S. Rennert - , Carmel Medical Center, Clalit Health Services, Technion-Israel Institute of Technology (Author)
  • Elio Riboli - , Imperial College London (Author)
  • Clemens Schafmayer - , University of Rostock (Author)
  • Robert E. Schoen - , University of Pittsburgh (Author)
  • Daniela Seminara - , National Cancer Institute (NCI) (Author)
  • Mingyang Song - , Harvard University (Author)
  • Yu Ru Su - , Fred Hutchinson Cancer Research Center (Author)
  • Catherine M. Tangen - , Fred Hutchinson Cancer Research Center (Author)
  • Stephen N. Thibodeau - , Mayo Clinic Rochester, MN (Author)
  • Duncan C. Thomas - , University of Southern California (Author)
  • Antonia Trichopoulou - , Helenic Health Foundation, National and Kapodistrian University of Athens (Author)
  • Cornelia M. Ulrich - , University of Utah (Author)
  • Kala Visvanathan - , Johns Hopkins University (Author)
  • Pavel Vodicka - , Czech Academy of Sciences, Charles University (Author)
  • Ludmila Vodickova - , Czech Academy of Sciences, Charles University (Author)
  • Veronika Vymetalkova - , Czech Academy of Sciences, Charles University (Author)
  • Korbinian Weigl - , German Cancer Research Center (DKFZ), Heidelberg University  (Author)
  • Stephanie J. Weinstein - , National Cancer Institute (NCI) (Author)
  • Emily White - , Fred Hutchinson Cancer Research Center (Author)
  • Alicja Wolk - , Karolinska Institutet (Author)
  • Michael O. Woods - , Memorial University of Newfoundland (Author)
  • Anna H. Wu - , University of Southern California (Author)
  • Goncalo R. Abecasis - , University of Michigan, Ann Arbor (Author)
  • Deborah A. Nickerson - , University of Washington (Author)
  • Peter C. Scacheri - , Case Western Reserve University (Author)
  • Anshul Kundaje - , Stanford University (Author)
  • Graham Casey - , University of Virginia (Author)
  • Stephen B. Gruber - , University of Southern California, City of Hope National Medical Centers (Author)
  • Li Hsu - , Fred Hutchinson Cancer Research Center, University of Washington (Author)
  • Victor Moreno - , University of Barcelona, CIBER - Center for Biomedical Research Network (Author)
  • Richard B. Hayes - , New York University (Author)
  • Polly A. Newcomb - , Fred Hutchinson Cancer Research Center, University of Washington (Author)
  • Ulrike Peters - , Fred Hutchinson Cancer Research Center, University of Washington (Author)

Abstract

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.

Details

Original languageEnglish
Pages (from-to)1325-1334
Number of pages10
JournalGut
Volume70
Issue number7
Publication statusPublished - 1 Jul 2021
Peer-reviewedYes

External IDs

Scopus 85101809425
PubMed 33632709
ORCID /0000-0003-2928-015X/work/146166322

Keywords

Sustainable Development Goals

Keywords

  • cancer genetics, cancer susceptibility, colon carcinogenesis, colorectal cancer, genetic polymorphisms