Polymorphisms of DNA repair genes: ADPRT, XRCC1, and XPD and cancer risk in genetic epidemiology

Abstract

Many studies have suggested that adenosine diphosphate ribosyl transferase (ADPRT), X-ray repair cross-complementing 1 (XRCC1), and xeroderma pigmentosum complementary group D (XPD) are three major DNA base excision repair (BER) genes and that they act interactively in stimulating and executing BER processes. Polymorphisms of these genes may influence the rate of gene transcription, the stability of the messenger RNA, or the quantity and activity of the resulting protein. Thus, the susceptibility or severity of several disorders is influenced by possession of specific alleles of polymorphic genes. So, it is plausible that variations and mutations in these genes affect DNA repair capacity in normal populations, and thus facilitate cancer development in normal or exposed individuals. To promote translation of scientific findings for potential clinical application of DNA repair function, we have searched publications relevant to molecular epidemiology studies of associations between single-nucleotide polymorphisms (SNPs) in the genes, and several frequent human cancer. We have focused on five particular polymorphisms as our starting point: the T-->C polymorphism (Val762Ala) in exon 17 of ADPRT, the novel transition at the promoter region (-77T-->C) of XRCC1, two common nonsynonymous polymorphisms (Arg194Trp and Arg399Gln), and the C-->A silent polymorphism (Arg156Arg) in exon 6 of XPD. We review here the case-control studies examining whether these polymorphisms are correlated with reduced DNA repair efficiency, their influence on the development of different solid tumors, and their possible interactions with other genetic factors and environmental exposures.