# DNA repair gene mutations and prostate cancer

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2022 · $683,795

## Abstract

Prostate cancer (PCa) is one of the most heritable human cancers, with inherited risk estimates of up to 60%;
however, the underlying inherited genetic architecture is still largely unexplained. Our unique access to a
collection of 446 blood specimens from 211 PCa families has enabled an innovative family-based approach to
identifying novel disease-susceptibility loci. To date, we have collected targeted sequencing data from a panel
of 48 “cancer risk genes” using samples from all of the PCa families, and whole-exome sequencing (WES) data
using samples from a subset of the PCa families. We identified 45 familial loss-of-function and missense
mutations in 32 DNA damage response and repair genes. Most of these gene products are known to participate
in homology-directed DNA repair (HDR), an error-free type of DNA double-strand break (DSB) repair. DSBs can
result from androgen receptor (AR)-induced transcriptional stress and increase cancer risk in androgen-
responsive tissues, such as the prostate. In response to androgen stimulation, both TOP2B topoisomerase and
LINE-1 endonuclease are recruited to active transcription sites and induce DSBs. Accumulated evidence
suggests that loss of HDR will promote other error-prone repair pathways, such as alternative non-homologous
end joining, causing mutation accumulation and genomic instability. The mutations we have identified are all
germline mutations, representing potential causal genetic factors. We therefore hypothesize that functional
deficiency in the HDR pathway, due to loss-of-function and missense mutations in HDR genes, contributes to
genomic instability and PCa. We have designed the following three specific aims to test our central hypothesis:
1) To determine the functional defects in DNA damage response and HDR caused by PCa-associated HDR
gene mutations; 2) To define the roles of nucleases EXO5 and EXD2 and helicases HFM1 and FANCM in
resecting DNA ends at AR-induced, TOP2B-linked DSBs for HDR in prostate cells; 3) To assess the biological
significance of AR signaling and the HDR pathway in PCa tumorigenesis. Our strong research team includes Dr.
Binghui Shen (contact PI, City of Hope [COH]) and Dr. Xiaochun Yu (mPI; COH), both experts in the fields of
DNA damage repair and cancer genetics, and recognized PCa biologists Dr. Zijie Sun (mPI; COH) and Dr. Ming-
Fong Lin (co-I; University of Nebraska Medical Center). We will test the role of HDR gene mutations as risk
factors for PCa and define the underlying molecular mechanism(s) linking HDR gene mutations to illegitimate
DNA repair and PCa development. Completion of the proposed work will significantly advance our understanding
of the role of HDR in cancer, especially PCa. We will use an innovative approach to identify novel PCa-associated
HDR defects based on familial inheritance and evaluation of both loss-of-function and missense mutations.
These insights will impact the field by increasing the availability of biomarkers for early diagnosis ...

## Key facts

- **NIH application ID:** 10307594
- **Project number:** 5R01CA233664-03
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** BINGHUI SHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $683,795
- **Award type:** 5
- **Project period:** 2019-12-02 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10307594

## Citation

> US National Institutes of Health, RePORTER application 10307594, DNA repair gene mutations and prostate cancer (5R01CA233664-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10307594. Licensed CC0.

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