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

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.

SUBMITTER: Montazeri Z

PROVIDER: S-EPMC7398467 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Montazeri Zahra Z Li Xue X Nyiraneza Christine C Ma Xiangyu X Timofeeva Maria M Svinti Victoria V Meng Xiangrui X He Yazhou Y Bo Yacong Y Morgan Samuel S Castellví-Bel Sergi S Ruiz-Ponte Clara C Fernández-Rozadilla Ceres C Carracedo Ángel Á Castells Antoni A Bishop Timothy T Buchanan Daniel D Jenkins Mark A MA Keku Temitope O TO Lindblom Annika A van Duijnhoven Fränzel J B FJB Wu Anna A Farrington Susan M SM Dunlop Malcolm G MG Campbell Harry H Theodoratou Evropi E Zheng Wei W Little Julian J

Gut 20191209 8

<h4>Objective</h4>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).<h4>Design</h4>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 l ...[more]

PMID: 31818908

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Project description:BackgroundAlthough genetic studies have reported a number of loci associated with cutaneous melanoma (CM) risk, a comprehensive synopsis of genetic association studies published in the field and systematic meta-analysis for all eligible polymorphisms have not been reported.MethodsWe systematically annotated data from all genetic association studies published in the CM field (n = 145), including data from genome-wide association studies (GWAS), and performed random-effects meta-analyses across all eligible polymorphisms on the basis of four or more independent case-control datasets in the main analyses. Supplementary analyses of three available datasets derived from GWAS and GWAS-replication studies were also done. Nominally statistically significant associations between polymorphisms and CM were graded for the strength of epidemiological evidence on the basis of the Human Genome Epidemiology Network Venice criteria. All statistical tests were two-sided.ResultsForty-two polymorphisms across 18 independent loci evaluated in four or more datasets including candidate gene studies and available GWAS data were subjected to meta-analysis. Eight loci were identified in the main meta-analyses as being associated with a risk of CM (P < .05) of which four loci showed a genome-wide statistically significant association (P < 1 × 10(-7)), including 16q24.3 (MC1R), 20q11.22 (MYH7B/PIGU/ASIP), 11q14.3 (TYR), and 5p13.2 (SLC45A2). Grading of the cumulative evidence by the Venice criteria suggested strong epidemiological credibility for all four loci with genome-wide statistical significance and one additional gene at 9p23 (TYRP1). In the supplementary meta-analyses, a locus at 9p21.3 (CDKN2A/MTAP) reached genome-wide statistical significance with CM and had strong epidemiological credibility.ConclusionsTo the best of our knowledge, this is the first comprehensive field synopsis and systematic meta-analysis to identify genes associated with an increased susceptibility to CM.

Dataset Information

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

Publications

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

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