# Functional Evaluation and Interpretation of DNA Damage Repair Variants in Prostate Cancer

> **NIH NIH P01** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $409,164

## Abstract

PROJECT SUMMARY/ABSTRACT
Pathogenic variants in DNA damage repair (DDR) pathway genes are prevalent in a subset of men with
metastatic castration-resistant prostate cancer (mCRPC) and occur in both the somatic and germline
genomes. These abnormalities, primarily insertions and deletions resulting in protein truncations, occur in 10–
20% of patients with mCRPC. These variants also occur in lower-grade localized prostate cancers, although
the prevalence of DDR mutations in these tumors and their impact on clinical outcome, survival, and drug
sensitivity are largely unknown. In other projects of the proposed grant, specific mutations in DDR genes will
be identified. The focus of Project 3 will be to prioritize and systematically evaluate these mutations, using a
combination of functional assays, state-of-the-art organoid technology, CRISPR-mediated gene editing, and
analysis of whole genome sequencing. In Aim 1 of Project 3, we will use multiple prostate cancer cell lines to
determine whether specific DDR gene mutations are deleterious or benign variants. We will test the hypothesis
that bona fide pathogenic DDR alleles are associated with a more aggressive tumor phenotype and will
correlate with specific functional DNA repair defects and drug responses. In Aim 2, we will use gene editing to
introduce DDR mutations into the endogenous genetic locus of multiple prostate cancer cell lines to provide a
more physiologic assessment of the specific mutations. In Aim 3, we will analyze the whole-genome
sequences from prostate cancers to identify precise mutational signatures which may result from loss-of-
function mutations in specific DDR genes. Project 3 will have extensive collaborations with the investigators in
Projects 1 and 2 and the Genomics Core as outlined in the attached research plan.

## Key facts

- **NIH application ID:** 10922781
- **Project number:** 5P01CA228696-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** CHARLES L. SAWYERS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $409,164
- **Award type:** 5
- **Project period:** 2019-09-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10922781

## Citation

> US National Institutes of Health, RePORTER application 10922781, Functional Evaluation and Interpretation of DNA Damage Repair Variants in Prostate Cancer (5P01CA228696-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10922781. Licensed CC0.

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