FHCRC - Whole-Exome Sequencing of Hereditary Prostate Cancer Families

The specific aim of this study is to identify hereditary prostate cancer (HPC) susceptibility genes using a novel study design, whereby whole-exome sequencing will be undertaken on multiple affected relatives from 19 HPC families, in which ≥ 3 affected relatives were diagnosed with clinically aggressive and/or early onset prostate cancer (PC). While whole-exome sequencing of unrelated affected individuals would result in hundreds of candidate disease variants, this family-based, aggressive/early onset phenotype approach will provide an enriched genetic background for discovery and significantly reduce the number of candidate mutations that will require follow-up. Findings from this pilot study will immediately be followed-up to confirm whether candidate mutations found in each family segregate with disease in the remaining unscreened relatives. As part of this pilot study, we aim to: Perform whole-exome sequencing on 80 affected and 11 unaffected relatives from 19 HPC families that have multiple men diagnosed with an aggressive and/or early onset disease phenotype using the Illumina HiSeq platform; and, Analyze sequencing data using BWA, SAMtools and SeattleSeq to prioritize candidate HPC mutations that segregate with aggressive and/or early onset disease in affected relatives. ]]>
FHCRC Study DocumentationWe have identified 19 HPC families, from a larger set of 307 HPC families, in which ≥ 3 affected relatives were diagnosed with clinically aggressive (defined as Gleason score 8-10, regional or distant stage disease, and/or PC-specific death before age 75) and/or early onset disease (diagnosed at or before age 65 years). To increase the probability of detecting mutations that are truly segregating with disease, the majority of affected men chosen for whole-exome sequencing are ≥ second-degree relatives. In addition, where possible an older, unaffected male relative has been chosen as a 'control' from each family.]]>
This study involves a subset of 19 HPC families taken from a larger family-based linkage study of hereditary prostate cancer, the Prostate Cancer Genetic Research Study or PROGRESS. Since 1995, the PROGRESS study has collected baseline and follow-up surveys, clinical data and blood samples for multiple members of 307 HPC families. Two previous genome-wide linkage scans have revealed several putative susceptibility loci in these families but so far, no actual genes or causal mutations/variants have been identified. The 19 families in the current pilot study contain multiple affected men with aggressive and/or early onset prostate cancer. Studying families that include affecteds with an extreme phenotype is expected to reduce some of the heterogeneity that is well recognized in PC. Whole-exome sequencing will be used to enhance detection of the genetic mutations responsible for this more extreme HPC phenotype.]]>