Dataset Information

Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease.

ABSTRACT: Genetic heterogeneity is a difficulty frequently encountered in the search for genes conferring susceptibility to prostate cancer. To circumvent this issue, we selected a large prostate cancer pedigree for genome-wide linkage analysis from a population that is genetically homogeneous. Selected cases and first-degree relatives were genotyped with Affymetrix 10K SNP arrays, identifying a 14 Mb haplotype on chromosome 5 (5p13-q12) inherited identical-by-descent (IBD) by multiple cases. Microsatellite genotyping of additional deceased case samples confirmed that a total of eight cases inherited the common haplotype (P=0.0017). Re-sequencing of eight prioritised candidate genes in the region in six selected individuals identified 15 SNPs segregating with the IBD haplotype, located within the ITGA2 gene. Three of these polymorphisms were selected for genotyping in an independent Tasmanian data set comprising 127 cases with familial prostate cancer, 412 sporadic cases and 319 unaffected controls. Two were associated with prostate cancer risk: rs3212649 (OR=1.67 (1.07-2.6), P=0.0009) and rs1126643 (OR=1.52 (1.01-2.28), P=0.0088). Significant association was observed in both familial and sporadic prostate cancer. Although the functional SNP remains to be identified, considerable circumstantial evidence, provided by in vivo and in vitro studies, supports a role for ITGA2 in tumour development.

SUBMITTER: FitzGerald LM

PROVIDER: S-EPMC2986161 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease.

FitzGerald Liesel M LM Patterson Briony B Thomson Russell R Polanowski Andrea A Quinn Stephen S Brohede Jesper J Thornton Timothy T Challis David D Mackey David A DA Dwyer Terence T Foote Simon S Hannan Garry N GN Stankovich James J McKay James D JD Dickinson Joanne L JL

European journal of human genetics : EJHG 20081001 3

Genetic heterogeneity is a difficulty frequently encountered in the search for genes conferring susceptibility to prostate cancer. To circumvent this issue, we selected a large prostate cancer pedigree for genome-wide linkage analysis from a population that is genetically homogeneous. Selected cases and first-degree relatives were genotyped with Affymetrix 10K SNP arrays, identifying a 14 Mb haplotype on chromosome 5 (5p13-q12) inherited identical-by-descent (IBD) by multiple cases. Microsatelli ...[more]

PMID: 18830231

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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

Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease.

Publications

Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease.

Similar Datasets

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