Systematic meta-analyses, field synopsis and global assessment of the evidence of genetic association studies in colorectal cancer.

Zahra Montazeri, Xue Li, Christine Nyiraneza, Xiangyu Ma, Maria Timofeeva, Victoria Svinti, Xiangrui Meng, Yazhou He, Yacong Bo, Samuel Morgan, Sergi Castellví-Bel, Clara Ruiz-Ponte, Ceres Fernández-Rozadilla, Ángel Carracedo, Antoni Castells, Timothy Bishop, Daniel Buchanan, Mark A Jenkins, Temitope O Keku, Annika Lindblom, Fränzel J B van Duijnhoven, Anna Wu, Susan M Farrington, Malcolm G Dunlop, Harry Campbell, Evropi Theodoratou, Wei Zheng, Julian Little

Journal: Gut 2021;69(8):1460-1471

PMID: 31818908

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Abstract

OBJECTIVE

To provide an understanding of the role of common genetic variations in colorectal cancer (CRC) risk, we report an updated field synopsis and comprehensive assessment of evidence to catalogue all genetic markers for CRC (CRCgene2).

DESIGN

We included 869 publications after parallel literature review and extracted data for 1063 polymorphisms in 303 different genes. Meta-analyses were performed for 308 single nucleotide polymorphisms (SNPs) in 158 different genes with at least three independent studies available for analysis. Scottish, Canadian and Spanish data from genome-wide association studies (GWASs) were incorporated for the meta-analyses of 132 SNPs. To assess and classify the credibility of the associations, we applied the Venice criteria and Bayesian False-Discovery Probability (BFDP). Genetic associations classified as 'positive' and 'less-credible positive' were further validated in three large GWAS consortia conducted in populations of European origin.

RESULTS

We initially identified 18 independent variants at 16 loci that were classified as 'positive' polymorphisms for their highly credible associations with CRC risk and 59 variants at 49 loci that were classified as 'less-credible positive' SNPs; 72.2% of the 'positive' SNPs were successfully replicated in three large GWASs and the ones that were not replicated were downgraded to 'less-credible' positive (reducing the 'positive' variants to 14 at 11 loci). For the remaining 231 variants, which were previously reported, our meta-analyses found no evidence to support their associations with CRC risk.

CONCLUSION

The CRCgene2 database provides an updated list of genetic variants related to CRC risk by using harmonised methods to assess their credibility.

Address: School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.; Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, UK.; Department of Epidemiology, College of Preventive Medicine, Third Military Medical University, Chongqing, Chongqing, China.; Colon Cancer Genetics Group, Cancer Research UK Edinburgh Centre and Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, The University of Edinburgh, Edinburgh, UK.; Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Shenzhen, Hong Kong.; Gastroenterology Department, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.; Fundación Pública Galega de Medicina Xenómica, Grupo de Medicina Xenómica, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria de Santiago (IDIS), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain.; Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.; Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.; Genetic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.; Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA.; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Division of Human Nutrition, Wageningen University and Research, Wageningen, The Netherlands.; University of Southern California, Preventative Medicine, Los Angeles, California, USA.; Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, UK [email protected].; Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.; Division of Epidemiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

DOI: 10.1136/gutjnl-2019-319313