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

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.

Sequence variants of alpha-methylacyl-CoA racemase are associated with prostate cancer risk: a replication study in an ethnically homogeneous population.

BACKGROUND: Examination of variants of the alpha-methylacyl-CoA racemase (AMACR) gene, as genetic contributors to prostate cancer risk, has been of considerable interest given the gene's recently established role as a diagnostic biomarker for prostate cancer. METHODS: The AMACR gene variants, M9V and D175G, were genotyped in a familial dataset comprising 127 cases and in a second sporadic prostate cancer dataset comprising 414 cases and 319 controls. Genotype-disease associations were examined employing the M(QLS) test and unconditional logistic regression. Differences in allele frequencies were examined using the Fisher's exact test. Association between the AMACR haplotypes and prostate cancer risk was also investigated using haplo.score. RESULTS: Significant evidence for association with prostate cancer risk for both the M9V and D175G variants was observed in the Tasmanian prostate cancer dataset. Whilst this association remained significant, it was diminished when relatedness amongst the familial prostate cancer cases was considered. CONCLUSION: This study, performed in a relatively genetically homogenous Tasmanian population, provides further evidence for a significant association between variants within the AMACR gene and prostate cancer risk. Risk was found to be more significantly associated with AMACR gene variants in sporadic compared to familial prostate cancer cases. These findings again highlight that genetic heterogeneity in the study population should be considered when examining genetic risk factors in prostate cancer.