Grant Details
Grant Number: |
1R01CA196931-01A1 Interpret this number |
Primary Investigator: |
Haiman, Christopher |
Organization: |
University Of Southern California |
Project Title: |
The Genetic Basis of Aggressive Prostate Cancer: the Role of Rare Variation |
Fiscal Year: |
2016 |
Abstract
DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most common cancer in men with 220,000 new cases and 27,000 deaths estimated this year in the U.S. The vast majority of these deaths occur among the approximately 10-15% of cases diagnosed with aggressive PCa. There are few known risk factors for PCa beyond age, African descent and a family history of PCa, and there are no risk factors that can determine which men will develop aggressive versus non-aggressive disease. Multiple lines of evidence indicate a substantial heritable component of aggressive PCa. Over the past decade, genome-wide association studies (GWAS) have identified over 100 common susceptibility loci that collectively account for 33% of the familial risk of PCa. These loci contribute equally to risk of aggressive and non-aggressive disease which suggests they play a role in the very early stages of PCa tumor evolution. Recent sequencing studies have revealed rare coding variants (well under 1%) in genes such as BRCA1/2 and other DNA repair pathway genes that convey larger risks (3-5 fold) of aggressive PCa relative to non-aggressive disease. These observations suggest that the allelic architecture of aggressive disease may be quite different than overall PCa, and highlight the need for larger efforts focused on rare genetic variation (<1%). This spectrum of variation represents ~80% of all genetic variation in the human genome and is not adequately surveyed through GWAS. In this study, we will apply a multi-staged approach to reveal genes harboring rare variants that are associated with aggressive PCa. Whole-exome sequencing (Aim 1a) of 2,000 aggressive cases and 2,000 non-aggressive cases of European ancestry will be conducted followed by rare variant analysis of single sites and gene burden testing to identify novel susceptibility loci/genes for aggressive disease. We will validate the most significantly associated genes (~500) through targeted sequencing in an additional 7,500 aggressive and 7,500 non-aggressive cases (Aim 1b). Next, we will investigate the clinical predictive utility of the genes/variants identified in 2,300 cases in the STHM3 trial who are undergoing biopsy based on PSA and genetic risk score stratification (Aim 2). Last, we will examine whether the
genes identified in Aim 1 contribute to the greater risk of aggressive PCa in 4,000 men of African ancestry (Aim 3). Through this tiered approach we expect to significantly advance knowledge of aggressive PCa etiology and health disparities as well as guide the development of early detection and prognostic strategies for the subset of men who are most susceptible to this fatal form of disease.
Publications
Germline Sequencing Analysis to Inform Clinical Gene Panel Testing for Aggressive Prostate Cancer.
Authors: Darst B.F.
, Saunders E.
, Dadaev T.
, Sheng X.
, Wan P.
, Pooler L.
, Xia L.Y.
, Chanock S.
, Berndt S.I.
, Wang Y.
, et al.
.
Source: Jama Oncology, 2023-11-01 00:00:00.0; 9(11), p. 1514-1524.
PMID: 37733366
Related Citations
Clonal hematopoiesis and risk of prostate cancer in large samples of European ancestry men.
Authors: Wang A.
, Xu Y.
, Yu Y.
, Nead K.T.
, Kim T.
, Xu K.
, Dadaev T.
, Saunders E.
, Sheng X.
, Wan P.
, et al.
.
Source: Human Molecular Genetics, 2023-01-13 00:00:00.0; 32(3), p. 489-495.
PMID: 36018819
Related Citations
Combined Effect of a Polygenic Risk Score and Rare Genetic Variants on Prostate Cancer Risk.
Authors: Darst B.F.
, Sheng X.
, Eeles R.A.
, Kote-Jarai Z.
, Conti D.V.
, Haiman C.A.
.
Source: European Urology, 2021-05-01 00:00:00.0; , .
EPub date: 2021-05-01 00:00:00.0.
PMID: 33941403
Related Citations
Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.
Authors: Karlsson Q.
, Brook M.N.
, Dadaev T.
, Wakerell S.
, Saunders E.J.
, Muir K.
, Neal D.E.
, Giles G.G.
, MacInnis R.J.
, Thibodeau S.N.
, et al.
.
Source: European Urology Oncology, 2021-01-09 00:00:00.0; , .
EPub date: 2021-01-09 00:00:00.0.
PMID: 33436325
Related Citations
Germline sequencing DNA repair genes in 5,545 men with aggressive and non-aggressive prostate cancer.
Authors: Darst B.F.
, Dadaev T.
, Saunders E.
, Sheng X.
, Wan P.
, Pooler L.
, Xia L.Y.
, Chanock S.
, Berndt S.I.
, Gapstur S.M.
, et al.
.
Source: Journal Of The National Cancer Institute, 2020-08-27 00:00:00.0; , .
EPub date: 2020-08-27 00:00:00.0.
PMID: 32853339
Related Citations
Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease.
Authors: Mijuskovic M.
, Saunders E.J.
, Leongamornlert D.A.
, Wakerell S.
, Whitmore I.
, Dadaev T.
, Cieza-Borrella C.
, Govindasami K.
, Brook M.N.
, Haiman C.A.
, et al.
.
Source: British Journal Of Cancer, 2018 Jul; 119(1), p. 96-104.
EPub date: 2018-06-19 00:00:00.0.
PMID: 29915322
Related Citations