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

Abstract

Prostate cancer is a common malignancy that disproportionately affects African-American men. Environmental factors and variation in genes responsible for chemical and dietary carcinogen metabolism and DNA damage repair may modulate risk. Fourteen single nucleotide polymorphisms in NAT2 and four NER genes (ERCC1, XPF/ERCC4, XPG/ERCC5 and CSB/ERCC6) were genotyped in a case-control study of 254 African-American prostate cancer cases and 301 healthy controls from Washington, DC. Smoking status, BMI, age and genetic ancestry were included as covariates in the association analyses. We found that individuals homozygous for the XPG/ERCC5 À72C/T promoter polymorphism had a significant reduction in risk, for prostate cancer (OR ¼ 0.12; 95% CI ¼ 0.03-0.48). A haplotype trend regression test also revealed a protective effect for the haplotype bearing the T allele (P ¼ 0.003). In silica analyses suggest a functional implication for the promoter variant since it deletes a GCF transcriptional factor-binding site responsible for the downregulation of transcription. The protective effect of the promoter SNP on risk for prostate cancer was independent of smoking. In contrast, none of the SNPs typed for NAT2, ERCC1, ERCC4 and ERCC6 showed significant association with risk. Additional tests for genotype interactions were not significant. We note that there may be other factors, such as dietary exposures, which may modulate prostate cancer risk in combination with genetic variation within the NAT2 and NER genes. Our results, in combination with previous observations of LOH for ERCC5 in prostate tumors, provide further evidence for a role of XPG/ERCC5 in the etiology of prostate cancer.

Role of DNA Repair-related Gene Polymorphisms in Susceptibility to Risk of Prostate Cancer

“…Our finding is consistent with those of several other studies in Indian population, American population and African Americans (Hyytinen et al, 1999;Hooker et al, 2008;Berhane et al, 2012). However, the significance of XPG rs2296147 polymorphisms in the development of prostate cancer in Chinese population is unclear.…”

“…Berhane et al reported that polymorphism XPG rs2296147contributes to cancer risk susceptibility and can affect the development of prostate cancer in a Indian population, with a adjusted OR of 2.53 . Hyytinen et al (1999) reported that the polymorphism XPG Asp1104His plays an important role in the development of prostate cancer, while Hooker et al conducted a population-based study in United State reported no significant correlation between XPG polymorphisms and risk of prostate tumors (Hooker et al, 2008). Since these studies were conducted in different populations, it is difficult to make direct comparisons between them.…”

“…Another experimental study indicated that chronic exposure to arsenic causes DNA damage and increased cell survival that may ultimately result in neoplastic transformation of human prostate epithelial cells (Singh et al, 2011). Only a recent study conducted in African-American men reported that the CSB polymorphism have no effect on the risk of prostate cancer (Hooker et al, 2008). The inconsistency of these studies may be explained by differences in genetic origin, population background, source of controls, and sample size, or by chance.…”

“…Previous studies have examined the association between DNA repaired gene polymorphisms and risk of prostate cancer in various populations Hooker et al, 2008;Berhane et al, 2012;Liao et al, 2012;Sobti et al, 2012). However, these results are inconsistent.…”

The DNA Repair Gene ERCC6 rs1917799 Polymorphism is Associated with Gastric Cancer Risk in Chinese

“…Subsequently, disruption of this gene was related to the development of age-related macular degeneration (Tuo et al, 2006). Quite recently, genetic variations of ERCC6 have been linked to the susceptibility to various cancers, including lung cancer (Lin et al, 2008;Ma et al, 2009), breast cancer (Mechanic et al, 2006;Rajaraman et al, 2008), prostate cancer (Hooker et al, 2008), bladder cancer (Chen et al, 2007;Chang et al, 2009) and colorectal cancer Huang et al, 2006). However, the relation of ERCC6 polymorphism with gastric cancer risk is still unclear, which deserves to be further clarified.…”