Dataset Information

Genetic variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes are prognostic markers of prostate cancer-specific mortality.

ABSTRACT: BACKGROUND:Prostate cancer is the second leading cause of cancer-related deaths in men, accounting for more than 30,000 deaths annually. The purpose of this study was to test whether variation in selected candidate genes in biological pathways of interest for prostate cancer progression could help distinguish patients at higher risk for fatal prostate cancer. METHODS:In this hypothesis-driven study, we genotyped 937 single nucleotide polymorphisms (SNPs) in 156 candidate genes in a population-based cohort of 1,309 prostate cancer patients. We identified 22 top-ranking SNPs (P ? 0.01, FDR ? 0.70) associated with prostate cancer-specific mortality (PCSM). A subsequent validation study was completed in an independent population-based cohort of 2,875 prostate cancer patients. RESULTS:Five SNPs were validated (P ? 0.05) as being significantly associated with PCSM, one each in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes. Compared with patients with 0 to 2 of the at-risk genotypes those with 4 to 5 at-risk genotypes had a 50% (95% CI, 1.2-1.9) higher risk of PCSM and risk increased with the number of at-risk genotypes carried (P(trend) = 0.001), adjusting for clinicopathologic factors known to influence prognosis. CONCLUSION:Five genetic markers were validated to be associated with lethal prostate cancer. IMPACT:This is the first population-based study to show that germline genetic variants provide prognostic information for prostate cancer-specific survival. The clinical utility of this five-SNP panel to stratify patients at higher risk for adverse outcomes should be evaluated.

SUBMITTER: Lin DW

PROVIDER: S-EPMC3169727 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Genetic variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes are prognostic markers of prostate cancer-specific mortality.

Lin Daniel W DW FitzGerald Liesel M LM Fu Rong R Kwon Erika M EM Zheng Siqun Lilly SL Kolb Suzanne S Wiklund Fredrik F Stattin Pär P Isaacs William B WB Xu Jianfeng J Ostrander Elaine A EA Feng Ziding Z Grönberg Henrik H Stanford Janet L JL

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20110816 9

<h4>Background</h4>Prostate cancer is the second leading cause of cancer-related deaths in men, accounting for more than 30,000 deaths annually. The purpose of this study was to test whether variation in selected candidate genes in biological pathways of interest for prostate cancer progression could help distinguish patients at higher risk for fatal prostate cancer.<h4>Methods</h4>In this hypothesis-driven study, we genotyped 937 single nucleotide polymorphisms (SNPs) in 156 candidate genes in ...[more]

PMID: 21846818

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Project description:The RNASEL gene on chromosome 1q25 was recently identified as a candidate gene for hereditary prostate cancer (PC). To confirm these findings, we screened 326 patients from 163 families with familial PC for potential germline mutations, by use of conformation-sensitive gel electrophoresis, followed by direct sequence analysis. A total of six variants were identified, including one intronic and five exonic changes (three missense and two silent alterations). There were no unequivocal pathogenic changes. To further test for potential associations between genes and increased risk for disease, the three missense polymorphisms (Ile97Leu, Arg462Gln, and Glu541Asp) were genotyped in 438 patients with familial PC and in 510 population-based control subjects. Association testing revealed no significant differences between patients and control subjects for either the Leu97 variant (chi(2) trend test = 1.42; P=.23) or the Asp541 variant (chi2=1.52; P=.22). However, significant differences were detected for the Arg462Gln genotypes (chi2=5.20; P=.02; odds ratio [OR] = 0.54; 95% confidence interval [CI] 0.32-0.91) when the genotype Gln/Gln was compared with Arg/Arg. In subset analyses, associations were also observed in the younger group (age at diagnosis </=64 years) (P=.0008; OR=0.29; 95% CI = 0.13-0.66), in node-negative patients (P=.01; OR=0.48; 95% CI 0.27-0.84), patients with stage T(1)/T(2) disease (P=.008; OR=0.39; 95% CI 0.2-0.75), and patients with low-grade disease (P=.01; OR=0.40; 95% CI 0.20-0.78). To evaluate whether this variant was also associated with sporadic PC, we genotyped an additional 499 patients with sporadic PC. Differences in frequency were not detected between patients with sporadic disease and control subjects. However, the same association was observed between patients with familial disease and patients with sporadic disease for the entire group (chi2=4.82; P=.03), as well as in the subset analyses. These results suggest that polymorphic changes within the RNASEL gene may be associated with increased risk of familial but not sporadic PC.

Dataset Information

Genetic variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes are prognostic markers of prostate cancer-specific mortality.

Publications

Genetic variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes are prognostic markers of prostate cancer-specific mortality.

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