DNA Repair Gene XRCC1 and XPD Polymorphisms and Risk of Prostate Cancer

Abstract

The X-ray repair cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XPD) genes are involved in base excision repair and nucleotide excision repair of DNA repair pathways, respectively. A growing body of evidence suggests that XRCC1 and XPD are important in environmentally induced cancers, and polymorphisms in both genes have been identified. To determine whether the XRCC1 (codon Arg399Gln) and XPD (codon Asp312Asn and codon Lys751Gln) polymorphisms are associated with prostate cancer susceptibility, we genotyped these polymorphisms in a primarily Caucasian sample of 506 sibships (n ‫؍‬ 1,117) ascertained through a brother with prostate cancer. Sibships were analyzed with a Cox proportional hazards model with age at prostate cancer diagnosis as the outcome. Of the three polymorphisms investigated, only the XPD codon 312 Asn/Asn genotype had an odds ratio (OR) significantly different from one (OR, 1.61; 95% CI, 1.03-2.53). Analyses stratified by the clinical characteristics of affected brothers in the sibship did not reveal any significant heterogeneity in risk. In exploring two-way gene interactions, we found a markedly elevated risk for the combination of the XPD codon 312 Asn/Asn and XRCC1 codon 399 Gln/Gln genotypes (OR, 4.81; 95% CI, 1.66 -13.97). In summary, our results suggest that the XPD codon 312 Asn allele may exert a modest positive effect on prostate cancer risk when two copies of the allele are present, and this effect is enhanced by the XRCC codon 399 Gln allele in its recessive state.

Polymorphisms in Nucleotide Excision Repair Genes, Polycyclic Aromatic Hydrocarbon-DNA Adducts, and Breast Cancer Risk

“…We found that the association between breast cancer risk and XPD Asp 312 Asn genotype was more pronounced among those with increasing PAH-DNA adduct levels. Several studies have supported an association between the XPD Asp 312 Asn variant allele and increased risk for lung cancer (29), upper aerodigestive tract cancers (46), and prostate cancer (31). However, other studies have not supported a higher risk for the Asp 312 Asn variant allele of the XPD gene for lung cancer (44), skin cancer (30), and esophageal cancer (47).…”

“…The five single nucleotide polymorphisms (SNP) included ERCC1 (3 ¶-untranslated region 8092C/A, rs3212986), XPA (5 ¶-untranslated region À4A/G at position À4 from the ATG start codon, rs1800975), XPD (Asp-to-Asn substitution in codon 312 of exon 10, rs1799793), XPF (Arg-toGln substitution in codon 415 of exon 8, rs1800067), and XPG (Asp-to-His substitution in codon 1104 of exon 15, rs17655). Evidence from recent reports suggests that these genetic polymorphisms alter DNA repair capacity and contribute to cancer susceptibility (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). We hypothesized that those with suboptimal DNA repair, as characterized by genotype, would have a greater breast cancer risk due to increased PAH-DNA adduct levels.…”

NAT2 and NER genetic variants and sporadic prostate cancer susceptibility in African Americans

“…Studies concerning NER genes and prostate cancer risk have been performed mainly in European descent populations with varying results. 1,2,28,29 However, few studies have focused on NER gene variation and prostate cancer risk in a large number of African Americans.…”

XRCC1 Arg399Gln and Arg194Trp polymorphisms in prostate cancer risk: a meta-analysis

“…The XRCC1 Arg399Gln polymorphism was shown to be correlated with DNA repair activity and associated with susceptibility to various cancers, including PCa. 18,21 The presence of the Gln/Gln genotype of XRCC1 has been shown to be associated with tumor-suppressor gene TP53 mutations, 45 elevated levels of sister chromatid exchanges 15 and higher level of DNA adducts. 14 Thus, it may alter PCa susceptibility, especially in Asian population.…”

“…16 So far, many studies have focused on the associations between PCa risk and DNA repair pathway gene polymorphisms. However, the results of these studies [6][7][8][17][18][19][20][21][22][23][24][25] are conflicting and inconclusive. Therefore, it is highly necessary to perform a quantitative and systematic study with rigorous methods.…”