DNA repair enzyme genotypes and their toxicologically relevant phenotypes

A comprehensive review of studies of polymorphisms in DNA repair genes and associations with cancer risk was undertaken by Goode et al. [1]. In that study the authors concluded that published data were consistent with associations between: (a) the 8-oxoguanine-DNA glycosylase
(hOGG1) Ser326Cys variant genotype and increased risk of various types of cancer; (b) the X-ray repair cross-complementing group 1 (XRCC1) Arg194Trp variant genotype and reduced risk of various types of cancer; and (c) the BRCA2 Asn372His variant genotype and increased risk of breast cancer. Suggestive results were seen for polymorphisms in other genes; however, small sample sizes may have contributed to false-positive or false-negative findings [1]. These conclusions were largely confirmed by a recent meta-analysis of associations between genes involved in the base excision repair pathway and cancer risk [2]. This study focused on three key genes: hOGG1, apurinic/apyrimidinic endonuclease gene (APE1/APEX1), and XRCC1. They found increased lung cancer risk among subjects carrying the hOGG1 Cys326Cys genotype.
In addition they found a protective effect of the XRCC1 194Trp allele for tobacco-related cancers.
The XRCC1 Gln399Gln genotype was associated with increased risk of tobacco-related cancers among light smokers suggesting effect modification by tobacco smoking [2].
In this review we have analysed the link between genetic polymorphisms in the various
DNA repair genes and cancer. The choice of genes depended on the relative importance
of the gene to a given DNA repair pathway. Therefore for the base excision repair (BER), we have looked at polymorphisms in hOGG1 and XRCC1 genes; for the nucleotide excision repair pathway we have examined the link between polymorphisms in excision repair cross-complementing
group 2 (XPD) gene and cancer; for the DNA double strand break repair, we looked at the influence of X-ray repair cross complementing group 3 (XRCC3) gene polymorphisms on cancer outcome. The relevant articles were identified through a PubMed search of literature published between January 1999 and April 2006. The searches were limited to articles published
in English, and keywords gene, polymorphism, and cancer risk were used.