title: A field synopsis on low-penetrance variants in DNA repair genes and cancer susceptibility.
abstract: BACKGROUND
  Several genes encoding for DNA repair molecules implicated in maintaining genomic integrity have been proposed as cancer-susceptibility genes. Although efforts have been made to create synopses for specific fields that summarize the data from genetic association studies, such an overview is not available for genes involved in DNA repair.
  
  
  METHODS
  We have created a regularly updated database of studies addressing associations between DNA repair gene variants (excluding highly penetrant mutations) and different types of cancer. Using 1087 datasets and publicly available data from genome-wide association platforms, meta-analyses using dominant and recessive models were performed on 241 associations between individual variants and specific cancer types that had been tested in two or more independent studies. The epidemiological strength of each association was graded with Venice criteria that assess amount of evidence, replication, and protection from bias. All statistical tests were two-sided.
  
  
  RESULTS
  Thirty-one nominally statistically significant (ie, P < .05 without adjustment for multiple comparisons) associations were recorded for 16 genes in dominant and/or recessive model analyses (BRCA2, CCND1, ERCC1, ERCC2, ERCC4, ERCC5, MGMT, NBN, PARP1, POLI, TP53, XPA, XRCC1, XRCC2, XRCC3, and XRCC4). XRCC1, XRCC2, TP53, and ERCC2 variants were each nominally associated with several types of cancer. Three associations were graded as having "strong" credibility, another four had modest credibility, and 24 had weak credibility based on Venice criteria. Requiring more stringent P values to account for multiplicity of comparisons, only the associations of ERCC2 codon 751 (recessive model) and of XRCC1 -77 T>C (dominant model) with lung cancer had P <or= .0001 and retained P <or= .001 even when the first published studies on the respective associations were excluded.
  
  
  CONCLUSIONS
  We have conducted meta-analyses of 241 associations between variants in DNA repair genes and cancer and have found sparse association signals with strong epidemiological credibility. This synopsis offers a model to survey the current status and gaps in evidence in the field of DNA repair genes and cancer susceptibility, may indicate potential pleiotropic activity of genes and gene pathways, and may offer mechanistic insights in carcinogenesis.
authors.affiliation: Department of Epidemiology and Public Health, Imperial College, London, UK.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.forename: Maurizio
authors.initials: M
authors.lastname: Manuguerra
authors.forename: Fotini K
authors.initials: FK
authors.lastname: Kavvoura
authors.forename: Simonetta
authors.initials: S
authors.lastname: Guarrera
authors.forename: Alessandra
authors.initials: A
authors.lastname: Allione
authors.forename: Fabio
authors.initials: F
authors.lastname: Rosa
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Gregorio
authors.forename: Silvia
authors.initials: S
authors.lastname: Polidoro
authors.forename: Federica
authors.initials: F
authors.lastname: Saletta
authors.forename: John P A
authors.initials: JP
authors.lastname: Ioannidis
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matullo
mesh_terms: D015982:Bias; D004260:DNA Repair / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D016017:Odds Ratio; D019683:Penetrance; D011110:Polymorphism, Genetic; D012189:Retrospective Studies