Dataset Information

Association of HPC2/ELAC2 and RNASEL non-synonymous variants with prostate cancer risk in African American familial and sporadic cases.

ABSTRACT: INTRODUCTION:The RNASEL and HPC2/ELAC2 genes have been implicated in hereditary prostate cancer. Further assessment of the role of these genes in sporadic prostate cancer in African American men (AAM) is warranted. METHODS:Genotyping of HPC2/ELAC2 variants (S217L, A541T), along with RNASEL variants (R462Q and E541D) was completed in 155 African American sporadic and 88 familial prostate cancer cases, and 296 healthy male controls. Logistic regression analysis was performed and odds ratios (OR) were calculated, while correcting for both age and population stratification using admixture informative markers. RESULTS:The HPC2/ELAC2 217L allele was significantly associated with risk of prostate cancer when taking all cases into account (OR = 1.6; 1.0-2.6; P = 0.03). The RNASEL 541D allele was associated with a decrease in risk of prostate cancer in sporadic cases (OR = 0.4; 0.2-0.8; P = 0.01). We did not detect an association between prostate cancer risk and the RNASEL R462Q variant. Results from haplotype analyses of the two RNASEL variants revealed highly significant differences in haplotype allele frequencies between cases and controls suggesting a synergistic effect at the RNASEL locus. One haplotype in particular (462R-541D) is far more frequent in our control population and shows a strong protective effect against prostate cancer (OR = 0.47, P = 8.1 x 10(-9)). CONCLUSIONS:These results suggest that HPC2/ELAC2 and RNASEL may play a role, however minor, in prostate cancer risk among AAM.

SUBMITTER: Robbins CM

PROVIDER: S-EPMC4097307 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Association of HPC2/ELAC2 and RNASEL non-synonymous variants with prostate cancer risk in African American familial and sporadic cases.

Robbins Christiane M CM Hernandez Wenndy W Ahaghotu Chiledum C Bennett James J Hoke Gerald G Mason Terry T Pettaway Curtis A CA Vijayakumar Srinivasan S Weinrich Sally S Furbert-Harris Paulette P Dunston Georgia G Powell Isaac J IJ Carpten John D JD Kittles Rick A RA

The Prostate 20081201 16

<h4>Introduction</h4>The RNASEL and HPC2/ELAC2 genes have been implicated in hereditary prostate cancer. Further assessment of the role of these genes in sporadic prostate cancer in African American men (AAM) is warranted.<h4>Methods</h4>Genotyping of HPC2/ELAC2 variants (S217L, A541T), along with RNASEL variants (R462Q and E541D) was completed in 155 African American sporadic and 88 familial prostate cancer cases, and 296 healthy male controls. Logistic regression analysis was performed and odd ...[more]

PMID: 18767027

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Project description:To investigate the relationship between HPC2/ELAC2 and prostate cancer risk, we performed the following analyses: (1) a linkage study of six markers in and around the HPC2/ELAC2 gene at 17p11 in 159 pedigrees with hereditary prostate cancer (HPC); (2) a mutation-screening analysis of all coding exons of the gene in 93 probands with HPC; (3) family-based and population-based association study of common HPC2/ELAC2 missense variants in 159 probands with HPC, 249 patients with sporadic prostate cancer, and 222 unaffected male control subjects. No evidence for linkage was found in the total sample, nor in any subset of pedigrees based on characteristics that included age at onset, number of affected members, male-to-male disease transmission, or race. Furthermore, only the two previously reported missense changes (Ser217Leu and Ala541Thr) were identified by mutational analysis of all HPC2/ELAC exons in 93 probands with HPC. In association analyses, family-based tests did not reveal excess transmission of the Leu217 and/or Thr541 alleles to affected offspring, and population-based tests failed to reveal any statistically significant difference in the allele frequencies of the two polymorphisms between patients with prostate cancer and control subjects. The results of this study lead us to reject the three alternative hypotheses of (1) a highly penetrant, major prostate cancer-susceptibility gene at 17p11, (2) the allelic variants Leu217 or Thr541 of HPC2/ELAC2 as high-penetrance mutations, and (3) the variants Leu217 or Thr541 as low-penetrance, risk-modifying alleles. However, we did observe a trend of higher Leu217 homozygous carrier rates in patients than in control subjects. Considering the impact of genetic heterogeneity, phenocopies, and incomplete penetrance on the linkage and association studies of prostate cancer and on the power to detect linkage and association in our study sample, our results cannot rule out the possibility of a highly penetrant prostate cancer gene at this locus that only segregates in a small number of pedigrees. Nor can we rule out a prostate cancer-modifier gene that confers a lower-than-reported risk. Additional larger studies are needed to more fully evaluate the role of this gene in prostate cancer risk.

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

Association of HPC2/ELAC2 and RNASEL non-synonymous variants with prostate cancer risk in African American familial and sporadic cases.

Publications

Association of HPC2/ELAC2 and RNASEL non-synonymous variants with prostate cancer risk in African American familial and sporadic cases.

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