# The Genetic Origin of Hereditary Prostate Cancer

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

Prostate cancer is the most common cancer among Veterans. Nationally, its mortality rate is 76% that of breast
cancer; one in 41 men will die of it. National Comprehensive Cancer Network Guidelines for precision prostate
cancer care have incorporated tumor sequencing for men with advanced-stage prostate cancer, and germline
sequencing of men with a family history of prostate cancer. Its purpose is to discern inherited as well as
somatic drivers to guide precision therapy, though also potentially uncovering familial cancer risks. But the
knowledge base to guide prognostic and therapeutic decision-making in prostate cancer remains very limiting.
Even though prostate cancer has the greatest heritable risk of all common cancers, the causes of nearly 90%
of its inherited forms remain unknown. In contrast to breast and other common cancers, the broad diversity of
hereditary prostate cancer's causes has impeded traditional pedigree-based investigation by linkage. The goal
of this study is to further elucidate diverse causes of hereditary prostate cancer using a novel, alternative
familial case-control study design. We compare independent cases, each with a strong family history of
prostate cancer, to screened controls, each with a negative family history of prostate cancer. Our Aims
capitalize upon dense genetic data to identify cases that share a given disease gene inherited from a common
distant ancestor, even though genealogical relationships among them are not known. We identify disease
genes by discerning excess sharing of ancestral genomic segments among cases, reconstructing haplotypes
harboring mutations with strong risk of prostate cancer, and discerning correlated regional genetic variants and
underlying candidate causal mutations. We introduce a novel algorithm to identify sentinel variants best
detecting the independent risk signals, and forming a clinically predictive model. We further delineate which
genetic loci are responsible for the early age of diagnosis characterizing familial disease, some also impacting
aggressiveness. We employ replication across independent familial case-control study populations to discern
true from false positive observations, and we evaluate additional existing case-control and biobank data sets to
generalize pertinent observations. This study will improve the knowledge base for precision oncology and
familial cancer care of Veterans.

## Key facts

- **NIH application ID:** 10123183
- **Project number:** 1I01CX002155-01A1
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Jeffrey R. Smith
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123183

## Citation

> US National Institutes of Health, RePORTER application 10123183, The Genetic Origin of Hereditary Prostate Cancer (1I01CX002155-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10123183. Licensed CC0.

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