Journal of the National Cancer Institute Advance Access originally published online on December 30, 2008
JNCI Journal of the National Cancer Institute 2009 101(1):24-36; doi:10.1093/jnci/djn437
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© The Author 2008. Published by Oxford University Press.
ARTICLES |
A Field Synopsis on Low-Penetrance Variants in DNA Repair Genes and Cancer Susceptibility
Affiliations of authors: Department of Epidemiology and Public Health, Imperial College, London, UK (PV); Institute for Scientific Interchange Foundation, Torino, Italy (MM, SG, AA, FR, ADG, SP, FS, GM); Department of Statistics, Macquarie University, Sydney, Australia (MM); Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece (FKK, JPAI); Biomedical Research Institute, Foundation for Research and Technology-Hellas, Ioannina, Greece (JPAI); Center for Genetic Epidemiology and Modeling, Tufts Medical Center, Tufts University School of Medicine, Boston, MA (JPAI); Department of Genetics, Biology and Biochemistry, University of Torino, Italy (GM)
Correspondence to: John P. A. Ioannidis, MD, Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece (e-mail: jioannid{at}cc.uoi.gr).
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 
.0001 and retained P .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.
| Context and Caveats Prior knowledge Although genetic variation in genes involved in DNA repair may influence susceptibility to cancer and there are many reports of association between individual variants and cancer risk, a comprehensive analysis of genetic association data in this field had not been performed. Study design Meta-analysis of reported associations between individual genetic variants and specific cancers using dominant and recessive models of genetic effects. Contribution An updateable database and an analytic framework for identifying statistically significant associations and assessing their epidemiological strength in terms of amount of evidence, replication consistency, and protection from bias were developed. The analysis suggested that the vast majority of postulated associations between DNA repair alleles and cancer risk have not been replicated sufficiently to give them strong credibility. Implications Possible implications of this work are that larger scale studies would be necessary to establish specific associations of genetic variants in DNA repair and cancer and that the added risk conferred by single variants in DNA repair genes may be small. Limitations Biases in genetic association studies could not be fully assessed in this retrospective analysis; the best approach to modeling the genetic effect of a particular variant was not known. From the Editors
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Manuscript received March 27, 2008; revised September 23, 2008; accepted October 30, 2008.
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