Prostate cancer (PC) diagnoses in the U.S. in 2012 are estimated to account for 29% (241,740) of all newly diagnosed cancers in men and 9% (28,170) of male cancer deaths. The heterogeneity of PC aggressiveness and the inability to accurately identify men destined to suffer and die from the disease cause a significant public health problem of possible over-diagnosis and over-treatment of patients with indolent PC. Several studies have implicated a genetic etiology for PC, and multiple genome-wide association studies have identified several risk alleles for PC that account for a small proportion of genetic risk. However, less than 30% of the heritability of PC has been defined, and it is likel that a proportion of the undefined risk is due to rare susceptibility alleles. The genetic causes o PC aggressiveness represent one of the most important questions in PC research today. With the new generation of DNA sequencing technology, the potential application of applying sequencing information to patient care is emerging for screening decisions and identification of molecular pathways involved in the development and progression of PC. Better markers to identify aggressive PC could have a substantial effect on patient care. Overall, we hypothesize that rare risk alleles can be identified by utilizing next-generation sequencing technologies to perform whole-exome sequencing in highly enriched familial cases of PC. The International Consortium for Prostate Cancer Genetics (ICPCG) is in the unique position of having identified and sampled the most informative high-risk PC pedigrees known throughout the world. Sequencing PC cases from those high-risk pedigrees with the most evidence for a genetic contribution is a new approach that has significant power to identify rare predisposition genes/variants explaining PC in these pedigrees. To define these rare risk alleles, we have several objectives for this grant proposal. First, we will identify candidate PC susceptibility genes from whole-exome sequencing data derived from 763 familial cases (from 458 independent families) and prioritize those genes with variants that are most damaging (e.g., nonsense, frame-shift, splice site variants and selected other variants), co-segregate with PC within the tested families, and are rare in the general population (Aim 1). Second, we will further analyze the top 1000 candidate genes identified in Aim 1 by re-sequencing the coding regions in an independent set of 500 hereditary PC cases and 500 controls, looking specifically for genes with multiple damaging variants and variants that are found to be significantly more frequent among our cases compared to control data (Aim 2). Third, we will identify the most likely PC susceptibility loci by end-to-end re-sequencing of the top 100 genes identified in Aim 2 in an independent set of 1000 hereditary PC cases and 1000 controls (Aim 3). Our long-term goal is to identify genes associated with increased PC risk and aggressiveness that may be used to better screen men for PC and reduce the significant morbidity and mortality associated with this disease.
Prostate cancer is highly curable if diagnosed when still localized. Current screening procedures are not highly specific, however, causing many men to undergo unnecessary biopsies and treatment that often results in debilitating side effects. Defining the genes involved in prostate cancer risk and aggressiveness will help improve screening of men at high risk for developing clinically significant prostate cancer, will increase our understanding of the disease, and may identify much-needed approaches to prevent the substantial suffering and death from this malignancy.
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