Genetic architectures of proximal and distal colorectal cancer are partly distinct

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

doi:10.1136/gutjnl-2020-321534

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Genetic architectures of proximal and distal colorectal cancer are partly distinct

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Genetic architectures of proximal and distal colorectal cancer are partly distinct

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, …

Gut, Vol.70(7), pp.1325-1334

01/07/2021

DOI: https://doi.org/10.1136/gutjnl-2020-321534

PMID: 33632709

Abstract

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.

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Title: Genetic architectures of proximal and distal colorectal cancer are partly distinct
Creators - without role: Jeroen R Huyghe - Fred Hutch Cancer Center
Tabitha A Harrison - Fred Hutch Cancer Center
Stephanie A Bien - Fred Hutch Cancer Center
Heather Hampel - The Ohio State University
Jane C Figueiredo - University of Southern California
Stephanie L Schmit - Cleveland Clinic
David V Conti - University of Southern California
Sai Chen - University of Michigan–Ann Arbor
Conghui Qu - Fred Hutch Cancer Center
Yi Lin - Fred Hutch Cancer Center
Richard Barfield - Fred Hutch Cancer Center
John A Baron - University of North Carolina at Chapel Hill
Amanda J Cross - Imperial College London
Brenda Diergaarde - University of Pittsburgh
David Duggan - Translational Genomics Research Institute
Sophia Harlid - Umeå University
Liher Imaz - Basque Government
Hyun Min Kang - University of Michigan–Ann Arbor
David M Levine - University of Washington
Vittorio Perduca - Centre de recherche en Epidémiologie et Santé des Populations
Aurora Perez-Cornago - University of Oxford
Lori C Sakoda - Fred Hutch Cancer Center
Fredrick R Schumacher - Case Western Reserve University
Martha L Slattery - University of Utah
Amanda E Toland - The Ohio State University
Fränzel J B van Duijnhoven - Wageningen University & Research
Bethany Van Guelpen - Umeå University
Antonio Agudo - Institut Català d'Oncologia
Demetrius Albanes - National Cancer Institute
M Henar Alonso - Institut Català d'Oncologia
Kristin Anderson - University of Minnesota
Coral Arnau-Collell - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
Volker Arndt - German Cancer Research Center
Barbara L Banbury - Fred Hutch Cancer Center
Michael C Bassik - Stanford University
Sonja I Berndt - National Cancer Institute
Stéphane Bézieau - Centre Hospitalier Universitaire de Nantes
D Timothy Bishop - University of Leeds
Juergen Boehm - University of Utah
Heiner Boeing - German Institute of Human Nutrition
Marie-Christine Boutron-Ruault - University of Paris-Saclay
Hermann Brenner - German Cancer Research Center
Stefanie Brezina - Medical University of Vienna
Stephan Buch - TU Dresden
Daniel D Buchanan - Royal Melbourne Hospital
Andrea Burnett-Hartman - Kaiser Permanente
Bette J Caan - Kaiser Permanente
Peter T Campbell - American Cancer Society
Prudence R Carr - German Cancer Research Center
Antoni Castells - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
Sergi Castellví-Bel - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
Andrew T Chan - Brigham and Women's Hospital
Jenny Chang-Claude - German Cancer Research Center
Stephen J Chanock - National Cancer Institute
Keith R Curtis - Fred Hutch Cancer Center
Albert de la Chapelle - The Ohio State University
Douglas F Easton - University of Cambridge
Dallas R English - University of Melbourne
Edith J M Feskens - Wageningen University & Research
Manish Gala - Massachusetts General Hospital
Steven J Gallinger - University of Toronto
W James Gauderman - University of Southern California
Graham G Giles - Cancer Council Victoria
Phyllis J Goodman - Fred Hutch Cancer Center
William M Grady - University of Washington
John S Grove - Cancer Center of Hawaii
Andrea Gsur - Medical University of Vienna
Marc J Gunter - International Agency For Research On Cancer
Robert W Haile - Cedars-Sinai Medical Center
Jochen Hampe - TU Dresden
Michael Hoffmeister - German Cancer Research Center
John L Hopper - University of Melbourne
Wan-Ling Hsu - University of Washington
Wen-Yi Huang - National Cancer Institute
Thomas J Hudson - Ontario Institute for Cancer Research
Mazda Jenab - International Agency For Research On Cancer
Mark A Jenkins - University of Melbourne
Amit D Joshi - Harvard University
Temitope O Keku - University of North Carolina at Chapel Hill
Charles Kooperberg - Fred Hutch Cancer Center
Tilman Kühn - German Cancer Research Center
Sébastien Küry - Centre Hospitalier Universitaire de Nantes
Loic Le Marchand - University of Hawaii System
Flavio Lejbkowicz - Carmel Medical Center
Christopher I Li - Fred Hutch Cancer Center
Li Li - University of Virginia
Wolfgang Lieb - Kiel University
Annika Lindblom - Karolinska Institutet
Noralane M Lindor - Mayo Clinic in Arizona
Satu Männistö - Finnish Institute for Health and Welfare
Sanford D Markowitz - University Hospitals of Cleveland
Roger L Milne - Cancer Council Victoria
Lorena Moreno - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
Neil Murphy - International Agency For Research On Cancer
Rami Nassir - Umm al-Qura University
Kenneth Offit - Memorial Sloan Kettering Cancer Center
Shuji Ogino - Dana-Farber Cancer Institute
Salvatore Panico - University of Naples Federico II
Patrick S Parfrey - Memorial University of Newfoundland
Rachel Pearlman - The Ohio State University
Paul D P Pharoah - University of Cambridge
Amanda I Phipps - University of Washington
Elizabeth A Platz - Johns Hopkins University
John D Potter - Hutchinson
Ross L Prentice - Hutchinson
Lihong Qi - University of California, Davis
Leon Raskin - Vanderbilt University School of Medicine
Gad Rennert - Technion – Israel Institute of Technology
Hedy S Rennert - Technion – Israel Institute of Technology
Elio Riboli - Imperial College London
Clemens Schafmayer - Department of General Surgery, University Hospital Rostock, Rostock, Germany
Robert E Schoen - University of Pittsburgh Medical Center
Daniela Seminara - Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, USA
Mingyang Song - Harvard University
Yu-Ru Su - Hutchinson
Catherine M Tangen - SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
Stephen N Thibodeau - Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, MayoClinic, Rochester, Minnesota, USA
Duncan C Thomas - Department of Preventive Medicine and USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
Antonia Trichopoulou - National and Kapodistrian University of Athens
Cornelia M Ulrich - University of Utah
Kala Visvanathan - Johns Hopkins University
Pavel Vodicka - Charles University
Ludmila Vodickova - Charles University
Veronika Vymetalkova - Charles University
Korbinian Weigl - Heidelberg
Stephanie J Weinstein - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
Emily White - Hutchinson
Alicja Wolk - Karolinska Institutet
Michael O Woods - Memorial University of Newfoundland
Anna H Wu - Department of Preventive Medicine and USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
Goncalo R Abecasis - University of Michigan–Ann Arbor
Deborah A Nickerson - University of Washington
Peter C Scacheri - Case Western Reserve University
Anshul Kundaje - Stanford University
Graham Casey - University of Virginia
Stephen B Gruber - City Of Hope National Medical Center
Li Hsu - University of Washington
Victor Moreno - Universitat de Barcelona
Richard B Hayes - Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, New York, USA
Polly A Newcomb - University of Washington
Ulrike Peters - University of Washington
Publication Details: Gut, Vol.70(7), pp.1325-1334
Identifiers: 9931514108331
Academic Unit: Umm Al Qura University
Language: English
Resource Type: Journal article