# The Clinical and Epidemiological Characterization of Pathogenic DNA Damage Repair Pathway Variation in Prostate Cancer

> **NIH NIH P01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $373,961

## Abstract

PROJECT SUMMARY
The natural history of high-risk, localized prostate cancer, accounting for a substantial proportion of the 29,000
prostate cancer–related deaths per year in the U.S., is highly variable: there are patients who are cured with
surgery or radiation, while others develop metastases and succumb to their disease. To date, attempts to
stratify patients within these subsets of high-risk, localized prostate cancer have proven inadequate. There is
particular urgency within the African American population, where risk of lethal disease is highest. There is a
tremendous need for biomarkers that can reliably distinguish the most aggressive forms of disease within high-
risk groups. Specifically, we focus on the DNA damage repair (DDR) pathway, where certain variants appear to
be associated with prostate cancer aggressiveness. In this proposal, we will address two important questions
in the field: 1) Among patients with high-risk, localized prostate cancer, can we identify genetic aberrations in
DDR pathway associated with the most aggressive forms of the disease? 2) Do DDR variants contribute to
increased risk of aggressive prostate cancer among African American men?
In the first aim, we focus on inherited germline variants in the DDR pathway. Using large retrospective and
prospective cohorts of patients with high-risk, localized prostate cancer, we will perform sequencing in DNA
derived from blood samples and examine associations with development of lethal prostate cancer over long-
term follow-up. In our second aim, we will interrogate the somatic genome and matched germline using DNA
derived from radical prostatectomy specimens and corresponding blood samples, and we will study
associations with lethal disease. In the third aim, we will determine the prevalence of germline DDR in a larger
cohort of African American prostate cancer patients and estimate the extent to which DDR mutations contribute
to prostate cancer disparities.
Completion of the experiments outlined in this proposal will provide an unparalleled look at the association
between DDR and lethal forms of prostate cancer. We have the potential to i) discover specific germline and
somatic biomarkers for lethal disease that could be used to determine treatment strategies at the time of
diagnosis, perhaps using strategies such as PARP inhibition or platinum chemotherapy that target the DDR
pathway; ii) discover germline biomarkers that could be developed as screening tools for the most aggressive
forms of prostate cancer; and iii) define the extent to which mutations in in DDR pathway genes may explain
racial disparities in prostate cancer. The genetic loci and target genes comprising this dataset together with the
other projects will stimulate new targets for therapeutic intervention.

## Key facts

- **NIH application ID:** 10003301
- **Project number:** 5P01CA228696-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** KENNETH OFFIT
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $373,961
- **Award type:** 5
- **Project period:** 2019-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003301

## Citation

> US National Institutes of Health, RePORTER application 10003301, The Clinical and Epidemiological Characterization of Pathogenic DNA Damage Repair Pathway Variation in Prostate Cancer (5P01CA228696-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10003301. Licensed CC0.

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