XPD Common Variants and their Association with Melanoma and Breast Cancer Risk

Abstract

There are suggestions in the literature that common variants in the XPD gene may be associated with an altered risk of melanoma and breast cancer. To establish if the XPD common variants Asp312Asn and Lys751Gln are associated with an increased melanoma or breast cancer risk we performed an association study based on genotyping 426 unselected patients with malignant melanoma (MM) and 1830 consecutive breast cancer cases and compared the results to 1262 geographically matched newborns, 621 adults from the region of Szczecin (unselected for age and cancer family history), 421 healthy adults age- and sex-matched with the melanoma cases and 511 healthy controls matched with the breast cancer patients from the region of Szczecin. Additionally we examined the prevalence of three additional XPD variants, Gly156Gly, Leu485Pro and Arg112His amongst the 421 unselected melanoma patients. All of the variants when evaluated singularly were found not to be associated either with melanoma or breast cancer risk in younger or older patients. A modest association was observed with breast cancer risk when the Lys751Gln_CC/Asp312Asn_AA genotype (OR=1.5, p<0.05) segregated together. Individuals harboring the Lys751Gln_CC/Gly156Gly_CC genotype were significantly over-represented among late-onset melanoma cases (OR=1.7, p<0.05). The results of analyses of linkage disequilibrium and haplotype frequency support the thesis that a combination of at least two SNPs (Lys751Gln_CC/Gly156Gly_CC or Lys751Gln_CC/Asp312Asn_AA) inherited as a haplotype was associated with disease. These two pairs of SNPs could therefore be regarded as a single hereditary unit that would have a very small probability of being disrupted by recombination. Additional studies are required to determine whether these particular changes can be associated with an increased risk of other malignancies at different sites of origin.

The Polymorphism of DNA Repair Gene ERCC2/XPD Arg156Arg and Susceptibility to Breast Cancer in a Chinese Population

“…Justernhoven et al (2004) observed that ERCC2 Lys751Gln CC (OR = 3.69, 95% CI = 1.76-7.74) was one risk genotype for breast cancer, and ERCC2 Asp312Asn G/Lys751Gln C was the most potent riskconferring haplotype for breast cancer (OR = 3.49, 95% CI = 2.30-5.28) in a German population. Debniak et al (2006) demonstrated a modest association with breast cancer risk when the ERCC2 Lys751Gln CC/Asp312Asn AA genotype (OR = 1.5, P \ 0.05) segregated together in a Poland population. In a Finnish Caucasian population, Mestsola et al (2005) reported a significant increase in breast cancer risk among women who had ever smoked if they carried the ERCC2 Lys751Gln Gln/Gln genotype (OR = 2.52, 95% CI = 1.27-5.03, P = 0.011), compared with women who smoked but did not carry these genotypes.…”

DNA Repair Gene XPD Polymorphisms and Cancer Risk: A Meta-analysis Based on 56 Case-Control Studies

“…Additionally, the power of statistical analysis can be substantially increased by assuming linked loci. However, only 23% of the reviewed studies identified different potent risk-conferring haplotypes (9,(28)(29)(30) and explored the role of these haplotypes on cancer susceptibility. The sample size for each haplotype is too small for meta-analysis.…”

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

“…After screening the titles and abstracts, only 20 potentially eligible articles were identified for further detailed evaluation. After full-text assessment of these articles, we included a total of 15 articles (Dybdahl et al, 1999;Winsey et al, 2000;Vogel et al, 2001;Yin et al, 2003;Baccarelli et al, 2004;Lovatt et al, 2005;Festa et al, 2005;Han et al, 2005;Thirumaran et al, 2006;Li et al, 2006;Millikan et al, 2006;Debniak et al, 2006;Povey et al, 2007;Kertat et al, 2008;Paszkowska-Szczur et al, 2013) in this meta analysis, including 9 studies for cutaneous melanoma (Winsey et al, 2000;Baccarelli et al, 2004;Han et al, 2005;Li et al, 2006;Millikan et al, 2006;Debniak et al, 2006;Povey et al, 2007;Kertat et al, 2008;Paszkowska-Szczur et al, 2013), 7 studies for basal cell carcinoma (Dybdahl et al, 1999;Vogel et al, 2001;Yin et al, 2003;Lovatt et al, 2005;Festa et al, 2005;Han et al, 2005;Thirumaran et al, 2006) and 1 for squamous cell carcinoma (Han et al, 2005). All articles were written in English.…”