A Case-control Study On The Associatin Between Single Nucleotide Polymorphism (SNP) Of ERCC2/XPD And HOGG1 And Prostate Cancer Susceptibility

Prostate cancer (PCa) is among the most common malignant tumors in Western males, ranking second only to lung cancer in cancer mortality. PCa incidence in Asian men is significantly lower, however, the incidence of PCa in China has increased significantly in recent years.The etiology of prostate cancer is largely unknown. It is a multi-factorial disease, where both genetic and environmental factors contribute to disease incidence. In addition, several risk factors have been shown, ethnicity, family history and age have been associated with the increased risk. The exponential increase in risk of prostate cancer associated with aging may reflect the accumulation of DNA damage as a result of a series of processes including oxidative stress, inflammation or environmental carcinogens or a decrease in DNA damage-repair response capacity. DNA repair is essential to an individual's ability to respond to damage caused by environmental carcinogens. DNA repair mechanisms are important pathways in removal of oxidative DNA compounds or DNA adducts from damaged genomic sites. The key DNA repair pathways that are often associated with cancer risk include:Base excision repair removes simple base modifications, including single-strand breaks, oxidative DNA damage, and alkylation and nonbulky adducts. Nucleotide excision repair removes larger lesions, which often result from environmental damage, including UV radiation and external carcinogens. Mismatch Repair is thought to involve MLH1, MSH2, PMS2, and MSH6 in damage recognition, followed by excision, polymerization, and ligation. And double-strand-break repair(DDSBR) consists of two pathways, Homologous recombination and nonhomologous end-joining. Among of these four pathways, NER and BER are more common and more important.In this study, we investigated polymorphisms of the XPD and hOGG1 genes. Excision repair cross-complementing rodent repair deficiency, complementation group 2 (ERCC2)/Xeroderma pigmentosum complementary group D (XPD), a gene involved in NER and basal transcription, may influence individual DNA repair capacity, particularly of bulky adducts. Several epidemiologic studies have evaluated the potential role of ERCC2 Arg156Arg polymorphism.(rs238406) on cancer, but the results have been conflicting across studies.Human homolog of the 8-oxoguanine glycosylase 1 (hOGGl) is a protein involved in the BER pathway, which repairs one of the most mutagenic lesions among base modifications,8-hydroxyguanine (8-oxoG). Many epidemiological studies have investigated the association between the Ser326Cys polymorphism(rs1052133) in the hOGGl gene and the risk for different types of cancers, significant risk increases were observed for the hOGG1 326 polymorphism in the risk for esophageal cancer, lung cancer, colon cancer and so on.Song FJ, et al. analyze the trend of the incidence of prostate cancer in urban Tianjin area of china between 1981 and 2004 so as to provide scientific rationales for the prevention and control of prostate cancer. They got the conclusion that despite a low incidence of prostate cancer in Tianjin, it is increasing at a fast rate. This prompted us to search for an association between prostate cancer occurrence and progression and variants of the ERCC2/XPD and hOGG1 genes in the southeastern Chinese population. We investigated codon 156 (the Argl56Arg) polymorphism in XPD and codon 326 (the Ser326Cys) polymorphism in hOGG1.DNA repair genes play a key role in maintaining genomic stability and integrity. DNA repair gene polymorphisms, such as those of hOGG1 and ERCC2/XPD, contribute to carcinogenesis.In this study, we investigated the correlation between prostate cancer risk and hOGG1, ERCC2/XPD genetic variants.The study subjects were consisted of 100 cases with newly diagnosed PCa and 100 cancer-free male controls recruited from the The the First Affiliated Hospital, School of Medicine, Zhejiang University, between May 2009 and June 2010. We collected 3ml peripheral vein blood each person, extract peripheral blood genome DNA, then genotyped two polymorphisms using the polymerase chain reaction'restriction fragment length polymorphism(PCR-RFLP) method. At last we use statistics method to find the relationship between the two genes and prostate cancer.Results showed significant association of XPD156 homozygous mutant(AA) (OR =3.80; 95%CI=1.19-12.18; P=0.017), heterozygous (AC) (OR=2.48; 95%CI= 1.02-6.35; P=0.033) and combined mutant (AA+AC) (OR=2.76; 95%CI=1.18-6.84; P=0.011) genotypes with predisposition to high-risk prostate cancer. In the stratified analysis, increase risk of high-risk prostate cancer was also associated with the mutant genotypes of hOGG1 326 homozygous mutant(GG) (OR=2.93; 95%CI=1-8.74; P= 0.033). We also found that the A allele of XPD Arg156Arg and the G allele of hOGG1 Ser326Cys is associated with increased risk of prostate cancer (OR=1.86 and 1.62; 95%CI=1.13-3.06, and 1-2.67, respectively).The findings of our study do suggest that ERCC2/XPD Arg156Arg polymorphism and hOGG1 Ser326Cys polymorphism contribute to high-risk prostate cancer susceptibility in a Chinese population.