Variants of numerous DNA repair genes initially appeared to be statistically significantly associated with cancer risk in epidemiological studies. When the data from individual studies are pooled, however, few DNA repair gene variants appear truly associated with increased cancer risk, according to a field synopsis published in the Journal of the National Cancer Institute.

Because DNA damage is associated with cancer development, researchers hypothesized that genes required for DNA repair may influence risk of cancer. Initial reports supported the idea. A comprehensive review of the data has not been available previously.

In the current study, John P. Ioannidis, M.D., of the University of Ioannina School of Medicine in Greece, and colleagues identified 241 previously reported associations between gene variants and the risk of cancer. The team pooled the data from 1,087 data sets and reexamined these associations. 

Initially 31 of the 241 associations appeared to be statistically significantly associated with cancer risk in the meta-analysis. However, only two remained statistically significant after the researchers adjusted for multiple comparisons. An XRCC1 allele (-77 T>C) and an allele of ERCC2 (codon 751) were associated with lung cancer risk.

"The lack of many signals with strong credibility that emerged from our analysis, despite an enormous amount of work in this area over the years, needs careful consideration," the authors write. "The ability of the candidate gene approach to identify genetic risk factors may have been overestimated. Alternatively, the importance of the DNA repair pathway may have been exaggerated. However, there is increasing recognition that genetic risks of cancer conferred by single variants are almost always very modest. This means that even if the DNA repair pathway is essential for carcinogenesis, extremely large-scale evidence would be necessary to establish with high confidence the presence of specific associations."

In an accompanying editorial, Ajay Yesupriya, of the National Office of Public Health Genomics at the Centers for Disease Control and Prevention in Atlanta, and colleagues describe an international collaboration of researchers called the Human Genome Epidemiology Network (HuGENet) that advocates a concerted approach to conducting meta-analyses and systematic reviews of literature on gene-disease association studies. The paper by Ioannidis and colleagues is the first HuGENet Field Synopsis on cancer susceptibility.

"The identification of reliable genetic associations is fundamental to the translation of genomic research findings to clinical and public health applications," the editorialists write. "By synthesizing research findings and assessing cumulative evidence, field synopses can recognize the most credible genetic associations."

Citations:

Article: Vineis et al. A Field Synopsis of Low-Penetrant Variants in DNA Repair Genes and Cancer Susceptibility. J Natl Cancer Inst 2008; 101:24-36.

Editorial: Yesupriya A et al. Building a Knowledge Base on Genetic Variation and Cancer Risk Through Field Synopses. J Natl Cancer Inst 2008; 101:4-5.