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Original research
Systematic meta-analyses, field synopsis and global assessment of the evidence of genetic association studies in colorectal cancer
  1. Zahra Montazeri1,
  2. Xue Li2,
  3. Christine Nyiraneza1,
  4. Xiangyu Ma3,
  5. Maria Timofeeva4,
  6. Victoria Svinti4,
  7. Xiangrui Meng2,
  8. Yazhou He2,
  9. Yacong Bo5,
  10. Samuel Morgan1,
  11. Sergi Castellví-Bel6,
  12. Clara Ruiz-Ponte7,
  13. Ceres Fernández-Rozadilla7,
  14. Ángel Carracedo7,
  15. Antoni Castells6,
  16. Timothy Bishop8,
  17. Daniel Buchanan9,10,11,
  18. Mark A Jenkins9,
  19. Temitope O Keku12,
  20. Annika Lindblom13,14,
  21. Fränzel J B van Duijnhoven15,
  22. Anna Wu16,
  23. Susan M Farrington4,
  24. Malcolm G Dunlop4,
  25. Harry Campbell2,
  26. Evropi Theodoratou2,17,
  27. Wei Zheng18,
  28. Julian Little1
  1. 1 School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
  2. 2 Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, UK
  3. 3 Department of Epidemiology, College of Preventive Medicine, Third Military Medical University, Chongqing, Chongqing, China
  4. 4 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
  5. 5 Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Shenzhen, Hong Kong
  6. 6 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
  7. 7 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
  8. 8 Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
  9. 9 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
  10. 10 Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
  11. 11 Genetic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
  12. 12 Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA
  13. 13 Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
  14. 14 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  15. 15 Division of Human Nutrition, Wageningen University and Research, Wageningen, The Netherlands
  16. 16 University of Southern California, Preventative Medicine, Los Angeles, California, USA
  17. 17 Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK
  18. 18 Division of Epidemiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  1. Correspondence to Dr Evropi Theodoratou, School of Molecular, Genetic and Population Health Sciences, University of Edinburgh, Edinburgh, Lothian, UK; e.theodoratou{at}ed.ac.uk

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.

  • colorectal cancer
https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/gutjnl-2019-319313

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    Footnotes

    • ZM and XL are joint first authors.

    • Twitter @ccgg_edinburgh

    • Contributors JL, WZ, ET and HC conceived the study; JL, WZ, ET, HC, ZM and XL designed it; ZM, XL, ET, JL and HC wrote the article with input from other authors; ZM, XL, CN, MT and VS undertook data manipulations and statistical analysis; ZM, XL, CN, XMa, XMeng, YH and YB undertook the literature review and coordinated and/or undertook related abstraction, handling and curation of the data; SM, SC-B, CR-P, CF-R, ACarracedo, ACastells, DB, MAJ, TOK, AL, FJBvD, AW, SMF and MGD provided access to GWAS data. HC, ET, WZ and JL are joint corresponding authors.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.