Meta-analysis of two ERCC2 (XPD) polymorphisms, Asp312Asn and Lys751Gln, in breast cancer

Abstract

The excision repair cross-complementing group 2 gene (ERCC2) plays a key role in DNA repair. Several polymorphisms in the ERCC2 gene have been described, including the commonly occurring Lys751Gln and Asp312Asn polymorphisms. Studies investigating the association of these polymorphisms with breast cancer risk produced controversial results. To evaluate these associations presented in diverse populations, we have conducted a meta-analysis based on 40 studies from 33 publications in PubMed which included analyses of Lys751Gln (14,545 cases, 15,352 controls) and Asp312Asn polymorphisms (16,254 cases, 14,006 controls). Overall findings of both polymorphisms have implicated null effects (OR = 1.01-1.03) when the analyses were limited to the statistically powerful (≥80%) studies. Although modestly increased statistically significant breast cancer risk was detected in the underpowered studies (≤80%), removal of outliers resulted in null associations. Ethnic stratification showed non-significant and relatively null associations for both polymorphisms with breast cancer risk for the overall Caucasians as well as North American and the European sub-populations. Although statistically increased and decreased risks were observed for the homogenous populations of African-Americans (Lys751Gln, OR 1.25, 95% CI 1.03-1.53, P = 0.03) and Asians (Asp312Asn, ORs: 0.53-0.55, P values: 0.02-0.03), respectively, this may be the result of small sample size. Analyses of the homogeneous adduct studies, with relatively large sample size, exhibited increased risk for Lys751Gln (OR 1.20, 95% CI (1.02-1.41), P = 0.03) and Asp312Asn (OR 1.17 95% CI 1.02-1.34, P = 0.03) under the dominant genetic model. In conclusion, our results suggest null associations of both polymorphisms in the overall and the Caucasian subgroups, although some effects can be suggested for relatively smaller minority studies. Increased risk effect was more visible when the adduct studies are considered, suggesting the role of these polymorphisms in the presence of exposure to DNA damaging agents.

DNA Repair Perspectives in Thyroid and Breast Cancer: The Role of DNA Repair Polymorphisms

“…However, the published results have been contradictory. Recently, one meta-analysis study revealed no association between both polymorphisms and breast cancer risk (Pabalan et al, 2010). We had also reported similar results previously (Silva et al, 2006a).…”

“…These genes are usually involved in the metabolism of environmental carcinogens, in the repair of DNA lesions induced by exogenous and endogenous carcinogens, and in the control of the cell cycle. Individual polymorphic forms in those genes have been associated with individual susceptibility to different types of cancer namely in breast and thyroid cancer (Conde et al, 2009;Gaspar et al, 2004;Pabalan et al, 2010;Peng et al, 2011;Silva et al, 2005;Silva et al, 2006b;Silva et al, 2006a;Silva et al, 2009;Silva et al, 2010;Silva et al, 2007). Several enzymes have evolved for the detoxification of xenobiotic compounds, and their gene expression is induced in response to the presence of numerous compounds (e.g., polycyclic aromatic hydrocarbons found in tobacco smoke).…”

XPD Lys751Gln and Asp312Asn polymorphisms and hepatocellular carcinoma susceptibility: A meta-analysis of 11 case-control studies in an Asian population

“…Numerous meta-analyses have been performed to investigate the association between XPD polymorphism and the risk of different types of cancer, e.g., prostate (30-32), lung (33-35), gastric (8,36), breast (7,37,38), head and neck (39,40) and Gln polymorphism-negative hepatitis B virus infection interaction in the dominant model (Gln/Gln + Lys/Gln vs. Lys/Lys). The squares and horizontal lines correspond to the study-specific OR and 95% CI.…”

“…Several important single nucleotide polymorphisms have been identified in the XPD locus, with high variant frequencies in exon 10 (rs1799793, codon 312 G→A, Asp→Asn) and exon 23 (rs1052559, codon 751 A→C, Lys→Gln) (5). These two polymorphisms have been largely investigated in genetic epidemiological studies, and individuals with these polymorphisms exhibit a higher risk of developing different types of cancer (6)(7)(8).…”

XPD Lys751Gln and Asp312Asn Polymorphisms and Susceptibility to Skin Cancer: A Meta-Analysis of 17 Case-control Studies

“…Among them, Lys751Gln and Asp312Asn polymorphisms were most extensively investigated. The XPD Lys751Gln polymorphism (rs13181) in codon 751 of exon 23, an A to C substitution, results in a Lys to Gln amino acid exchange (Shen et al, 1998;Pabalan et al, 2010). And Asp312Asn polymorphism (rs1799793), a G to A substitution in codon 312 of exon 10, produces Asp to Asn amino acid exchange (Shen et al, 1998;Pabalan et al, 2010).…”