Polymorphisms in DNA Repair Gene XRCC 1 and Skin Cancer Risk : A Meta-analysis

Published data on the association between polymorphisms of the X-ray repair cross-complementing group 1 (XRCC1) gene and skin cancer risk are inconsistent. Hence, we conducted a meta-analysis of three frequently occurring XRCC1 polymorphisms and risk of skin cancer to obtain the most reliable estimate of the association. Odds ratios (ORs) with 95% confidence intervals (CIs) were extracted from a total of 10 eligible studies describing 4,801 cases and 4,960 controls for the Arg399Gln (G>A) polymorphism, 1,026 cases and 1,089 controls for the Arg194Trp (C>T) polymorphism, and 1,392 cases and 1,476 controls for the Arg280His (G>A) polymorphism. The distributions of genotypes in the controls were consistent with Hardy-Weinberg equilibrium. The Arg399Gln and Arg194Trp polymorphisms were not correlated with skin cancer risk when all studies were pooled into the metaanalysis under three genetic models. No significant association was observed in stratified analyses of Arg399Gln and Arg194Trp polymorphisms by tumor type, race, or control source. In contrast, the Arg280His polymorphism was associated with an approximate 3.5-fold increase in skin cancer risk in homozygote codominant and recessive models. DNA repair is essential for maintaining genomic stability and the prevention of cancer. However, polymorphisms in DNA repair genes may result in individual differences in DNA repair activity and mutation rates (1), and these differences could be used to predict susceptibility to certain types of cancer, including skin cancer (2). X-Ray repair cross-complementing group 1 (XRCC1) is a protein involved in repairing DNA damaged by ionizing radiation, alkylating agents, and oxidative stress. As an important component of base excision repair (BER) (3), XRCC1 interacts with a DNA repair protein complex consisting of poly (ADP-ribose) polymerase (PARP), DNA ligase III, and DNA polymerase β (4-6). Several single nucleotide polymorphisms (SNPs) in the XRCC1 gene, located at chromosome 19q13.2, have been reported for amino acid differences between arginine and glutamine at codon 399 (Arg399Gln, G to A base change), arginine and tryptophan at codon 194 (Arg194Trp, C to T base change), and arginine and histidine at codon 280 (Arg280His, G to A base change). If any of these XRCC1 polymorphisms contribute to impaired DNA repair, it would be expected to heighten the risk of developing skin cancer. Previous reviews and meta-analyses have discussed the association between XRCC1 polymorphisms and the risk of developing cancer (7-10), but not skin cancer specifically. In these studies, the XRCC1 399Gln/Gln variant was associated with increased risk of tobacco-related cancer in light smokers but with lower risk among heavy smokers (10); the 194Trp allele showed a protective effect in various tumor types (810); and 280His was a risk factor in a number of cancer types (9). Although several epidemiological studies have explored the relationship between XRCC1 polymorphisms and the development of melanoma, basal cell carcinoma, and squamous cell carcinoma, these studies have reached inconsistent conclusions on whether any XRCC1 genetic variant could serve as a biomarker for skin cancer, with some studies showing an association (11-15) and others failing to show any clear association (16-23). A quantitative overview of these epidemiological data would help to resolve these discrepant findings. Although the pathobiology of different skin cancer types might be dissimilar, all three types of skin cancer share common genetic risk factors (24), which makes analysis of polymorphisms of XRCC1 feasible. In this study, we performed a meta-analysis focusing on the association 3945 Correspondence to: Arkadiusz Dudek, MD, Ph.D., Division of Hematology, Oncology and Transplantation, University of Minnesota, 420 Delaware Street SE, MMC 480, Minneapolis, MN 55455, U.S.A. Tel: +16126240123, Fax: +16126256919, e-mail: dudek002@umn.edu