A study published in JNCI found two out of 241 variants to be true associations.

When the data from various studies associating DNA repair genes with cancer risk was combined, few of these variants were truly associated with increased cancer risk, according to a team of investigators from the University of Ioannina School of Medicine in Greece. Of the 241 variants studied, they found two that were statistically significant: XRCC1 allele (-77 T>C) and an allele of ERCC2 (codon 751) 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 in a synopsis published online December 30 in the Journal of the National Cancer Institute. “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.”


The scientists identified 241 previously reported associations between gene variants and the risk of cancer and reexamined these associations from 1,087 data sets. Initially 31 of the 241 associations appeared to be statistically significantly associated with cancer risk in the meta-analysis. Only XRCC1 allele (-77 T>C) and an allele of ERCC2 (codon 751), however, remained statistically significant after the researchers adjusted for multiple comparisons.


Thirtyone nominally statistically significant (i.e., 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 less than or equal to 0.0001 and retained P   less than or equal to 0.001 even when the first published studies on the respective associations were excluded.