Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

Authors:
Stephanie L Schmit Christopher K Edlund Fredrick R Schumacher Jian Gong Tabitha A Harrison Jeroen R Huyghe Chenxu Qu Marilena Melas David J Van Den Berg Hansong Wang Stephanie Tring Sarah J Plummer Demetrius Albanes M Henar Alonso Christopher I Amos Kristen Anton Aaron K Aragaki Volker Arndt Elizabeth L Barry Sonja I Berndt Stéphane Bezieau Stephanie Bien Amanda Bloomer Juergen Boehm Marie-Christine Boutron-Ruault Hermann Brenner Stefanie Brezina Daniel D Buchanan Katja Butterbach Bette J Caan Peter T Campbell Christopher S Carlson Jose E Castelao Andrew T Chan Jenny Chang-Claude Stephen J Chanock Iona Cheng Ya-Wen Cheng Lee Soo Chin James M Church Timothy Church Gerhard A Coetzee Michelle Cotterchio Marcia Cruz Correa Keith R Curtis David Duggan Douglas F Easton Dallas English Edith J M Feskens Rocky Fischer Liesel M FitzGerald Barbara K Fortini Lars G Fritsche Charles S Fuchs Manuela Gago-Dominguez Manish Gala Steven J Gallinger W James Gauderman Graham G Giles Edward L Giovannucci Stephanie M Gogarten Clicerio Gonzalez-Villalpando Elena M Gonzalez-Villalpando William M Grady Joel K Greenson Andrea Gsur Marc Gunter Christopher A Haiman Jochen Hampe Sophia Harlid John F Harju Richard B Hayes Philipp Hofer Michael Hoffmeister John L Hopper Shu-Chen Huang Jose Maria Huerta Thomas J Hudson David J Hunter Gregory E Idos Motoki Iwasaki Rebecca D Jackson Eric J Jacobs Sun Ha Jee Mark A Jenkins Wei-Hua Jia Shuo Jiao Amit D Joshi Laurence N Kolonel Suminori Kono Charles Kooperberg Vittorio Krogh Tilman Kuehn Sébastien Küry Andrea LaCroix Cecelia A Laurie Flavio Lejbkowicz Mathieu Lemire Heinz-Josef Lenz David Levine Christopher I Li Li Li Wolfgang Lieb Yi Lin Noralane M Lindor Yun-Ru Liu Fotios Loupakis Yingchang Lu Frank Luh Jing Ma Christoph Mancao Frank J Manion Sanford D Markowitz Vicente Martin Koichi Matsuda Keitaro Matsuo Kevin J McDonnell Caroline E McNeil Roger Milne Antonio J Molina Bhramar Mukherjee Neil Murphy Polly A Newcomb Kenneth Offit Hanane Omichessan Domenico Palli Jesus P Paredes Cotoré Julyann Pérez-Mayoral Paul D Pharoah John D Potter Conghui Qu Leon Raskin Gad Rennert Hedy S Rennert Bridget M Riggs Clemens Schafmayer Robert E Schoen Thomas A Sellers Daniela Seminara Gianluca Severi Wei Shi David Shibata Xiao-Ou Shu Erin M Siegel Martha L Slattery Melissa Southey Zsofia K Stadler Mariana C Stern Sebastian Stintzing Darin Taverna Stephen N Thibodeau Duncan C Thomas Antonia Trichopoulou Shoichiro Tsugane Cornelia M Ulrich Franzel J B van Duijnhoven Bethany van Guelpan Joseph Vijai Jarmo Virtamo Stephanie J Weinstein Emily White Aung Ko Win Alicja Wolk Michael Woods Anna H Wu Kana Wu Yong-Bing Xiang Yun Yen Brent W Zanke Yi-Xin Zeng Ben Zhang Niha Zubair Sun-Seog Kweon Jane C Figueiredo Wei Zheng Loic Le Marchand Annika Lindblom Victor Moreno Ulrike Peters Graham Casey Li Hsu David V Conti Stephen B Gruber

J Natl Cancer Inst 2019 Feb;111(2):146-157

Department of Preventive Medicine, USC Norris Comprehensive Cancer Center.

Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.

Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.

Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.

Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

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http://dx.doi.org/10.1093/jnci/djy099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555904PMC
February 2019
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Inheritance of colorectal cancer
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Drug Discov Today Dis Mech. 2007

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