Genetic and behavioral risk factors for prostate cancer in African Americans

PR-1

Background: Prostate cancer (Pca) is a common malignancy that disproportionately affects African American men. Epidemiological studies have suggested that exogenous agents, such as PhIp and MeIQx present in over-cooked meats and/or cigarette smoking, upon activation may contribute to the development of Pca by reacting with genomic DNA to form covalent adducts. Therefore variation in genes responsible for the bioactivation of chemical and dietary carcinogen metabolism and DNA damage repair may modulate Pca risk. In the present study, we examined genetic polymorphisms in the NAT2 gene because of its capacity to activate N-OH-PhIP and N-OH-MeIQx as well as polymorphisms in four NER genes (ERCC-6, ERCC-5, ERCC-4, and ERCC-1) because of their role in repairing DNA damaged caused by chemical adducts. We investigated the association of genetic polymorphisms in NAT2, ERCC-6, ERCC-5, ERCC-4, and ERCC-1, alone and in combination with each other and smoking status, with prostate cancer.
 
 Methods: A total of fourteen single nucleotide polymorphisms (SNPs) in NAT2, ERCC1, XPF/ERCC4, XPG/ERCC5, and CSB/ERCC6 were genotyped in a case-control study of 254 African American prostate cancer cases and 301 age-matched controls from Washington, DC. An association analysis was conducted to determine the role of the SNPs and cigarette smoking in Pca risk. Smoking status, BMI, age and genetic ancestry were included as covariates.
 
 Results: We found that individuals homozygous for the XPG/ERCC5 -72C/T promoter polymorphism had a reduction in risk for Pca (OR= 0.12; P=0.003). A haplotype trend regression test also revealed a protective effect for the haplotype bearing the T allele (P=0.003). In contrast, none of the SNPs typed for NAT2, ERCC1, ERCC4 and ERCC6 showed significant association with risk or aggressiveness. Additional tests for SNP-SNP interactions revealed a significant increased risk for Pca among individuals possessing the minor allele for rs1801280 and rs1799930 of the NAT-2 gene (OR=2.5, P=0.02) and decreased risk for rs1112005 (NAT2) and rs2228529 (ERCC6) (OR=0.22, P=0.01); rs1799930 (NAT2) and rs2020955 (ERCC4) (OR=0.44, P=0.04); rs2228529 (ERCC6) and rs17655 (ERCC5) (OR=0.48, P=0.01); and between rs2227869 (ERCC5) and rs2020955 (OR=0.55, P=0.04).
 
 Conclusions: 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. We also report the presence of an interaction between the two genetic polymorphisms in NAT-2 (rs1801280 and rs1799930) for developing Pca. In addition, we found an absence of an interaction between smoking and the studied polymorphisms. Nominally significant P-values suggest the need for larger sample sizes and exploration of other variants in the genes.