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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01CA089600-10A1
Application #
8503386
Study Section
Special Emphasis Panel (ZRG1-PSE-Q (02))
Program Officer
Seminara, Daniela
Project Start
2000-12-01
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$1,676,727
Indirect Cost
$510,356
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Cooney, Kathleen A (2017) Inherited Predisposition to Prostate Cancer: From Gene Discovery to Clinical Impact. Trans Am Clin Climatol Assoc 128:14-23
Woo, Daniel; Debette, Stephanie; Anderson, Christopher (2017) 20th Workshop of the International Stroke Genetics Consortium, November 3-4, 2016, Milan, Italy: 2016.036 ISGC research priorities. Neurol Genet 3:S12-S18
Winter, Jean M; Gildea, Derek E; Andreas, Jonathan P et al. (2017) Mapping Complex Traits in a Diversity Outbred F1 Mouse Population Identifies Germline Modifiers of Metastasis in Human Prostate Cancer. Cell Syst 4:31-45.e6
Larson, Nicholas B; McDonnell, Shannon K; Fogarty, Zach et al. (2017) Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci. Oncotarget 8:85896-85908
Karyadi, Danielle M; Geybels, Milan S; Karlins, Eric et al. (2017) Whole exome sequencing in 75 high-risk families with validation and replication in independent case-control studies identifies TANGO2, OR5H14, and CHAD as new prostate cancer susceptibility genes. Oncotarget 8:1495-1507
Leapman, Michael S; Cowan, Janet E; Nguyen, Hao G et al. (2017) Active Surveillance in Younger Men With Prostate Cancer. J Clin Oncol 35:1898-1904
Larson, Nicholas B; McDonnell, Shannon; Cannon Albright, Lisa et al. (2017) gsSKAT: Rapid gene set analysis and multiple testing correction for rare-variant association studies using weighted linear kernels. Genet Epidemiol 41:297-308
Luedeke, Manuel; Rinckleb, Antje E; FitzGerald, Liesel M et al. (2016) Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status. Hum Mol Genet 25:5490-5499
Ioannidis, Nilah M; Rothstein, Joseph H; Pejaver, Vikas et al. (2016) REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. Am J Hum Genet 99:877-885
Teerlink, Craig C; Leongamornlert, Daniel; Dadaev, Tokhir et al. (2016) Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24.21. Hum Genet 135:923-38

Showing the most recent 10 out of 70 publications