Genetic Predisposition to Prostate Cancer: The Contribution of the HPCX locus and TGFB1 gene

Abstract

There is a significant genetic component to prostate cancer (PrCa) risk. Multiple epidemiologic and linkage studies suggest X-linked heritability. Located at chromosome Xq27-28, HPCX has been identified as a PrCa susceptibility locus in multiple independent studies. We hypothesized that HPCX harbors common variants of modest effect size predisposing to risk of PrCa. This dissertation details a comprehensive large-scale haplotype-based investigation within HPCX to test this hypothesis complemented by two prior independent studies. These two complementary studies were designed to test novel methods and to assess the power of our newly ascertained PrCa study population for use in the HPCX investigation. First, we successfully develop our haplotype-based study design using a proven study population investigating a candidate gene of known significance with an undefined causal variant; the study population was the Shanghai Breast Cancer Study, and the breast cancer associated gene was the rate-limiting enzyme of steroid biosynthesis, CYP11A1. Second, through confirmation of a known risk variant on chromosome 8q24, we assess the power of our new PrCa study population, uniquely comprised of cases with a family history of PrCa who were age-matched to controls with no family history of PrCa. Furthermore, in this study we investigate a locus at chromosome 19q12-13 associated with PrCa aggressiveness. This locus harbors transforming growth factor-ƒÒ1 (TGFB1), an ideal candidate gene. We test the hypothesis that the common T29C functional polymorphism within TGFB1 impacts PrCa risk and aggressiveness and report an association specific to indolent disease, the first of its type. Finally, we comprehensively investigate a 352 kb candidate interval within HPCX for association with risk of PrCa in a large-scale genetic association study. We perform de novo SNP discovery and assay non-unique genomic regions disregarded by current high-throughput platforms. We find one variant significantly associated with risk of PrCa in two independent populations, obtained by dividing our PrCa study population into discrete training and test sets. The work presented in this thesis represents part of a worldwide effort to uncover elusive variants predisposing to PrCa risk.