Population-Based Identification of Prostate Cancer
Abstract
Although there is strong evidence for an inherited contribution to prostate cancer (PrCa), there has been very little progress in identification of the genes responsible for PrCa in families. Analysis of multi-generation families with an excess of a disease has been shown to be a powerful approach for identification of the genes responsible. We previously used this approach in Utah to identify several cancer predisposition genes (BRCA1, BRCA2, CDKN2A). We currently have several predisposition gene identification grants funded by the National Cancer Institute that use the same high-risk pedigree study design we propose here, based on sequencing affected cousin pairs for colon cancer, melanoma, and small intestine carcinoid cancers; here we propose extending this approach to PrCa. Previous studies of PrCa pedigrees to identify responsible genes have been limited by: (i) failure to focus on the cases with the most significant clinical outcome (death from PrCa -- lethal PrCa or LPrCa) who are most likely to have a genetic cause, (ii) failure to focus on pedigrees that show a significant excess of PrCa (most studied pedigrees are simply clusters of related cases that have come to clinical attention, rather than truly “high-risk” for PrCa), and (iii) failure to study informative extended pedigrees that include distantly related cases who only share a small portion of their genome and thus provide information on chromosomal location of the causative gene. Using a unique Utah genealogical resource linked to decades of Utah cancer data and death certificate data, we have been able to overcome these limitations and propose a predisposition gene approach that is both complementary to, and more powerful than, any previous efforts. We will generate genetic sequence data for LPrCa cousin pairs in 50 high-risk PrCa pedigrees. Since cousins only share 12% of their genetic material in common, the ~4,000 rare variants that are identified as shared in these cousin pairs will be the best candidate genetic variants to explain the inherited PrCa. Because our resource includes extended high-risk pedigrees with many LPrCa cases, we can identify which of these rare shared genetic variants are also found in the other PrCa cases in the pedigree in which they occur. And finally, we can confirm that each of the candidate variants we identify is associated with increased risk for PrCa in the population. This project is very likely to identify one or more previously unknown PrCa predisposition variant. This knowledge will in the short term allow us to provide better clinical advice to carriers of the predisposition variants; it will allow identification of those at highest risk, and the application of appropriate screening and prevention strategies. Analysis of the predisposition gene(s) identified will immediately expand our understanding of the etiology of PrCa.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810204
Entities
People
- Lisa Albright
Organizations
- United States Army
- University of Utah