# Understanding the role of TP53 mutation in genetic susceptibility to ovarian cancer

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $517,103

## Abstract

Project Summary
Understanding the role of TP53 mutation in genetic susceptibility to ovarian cancer
Women with germline mutations in BRCA1 and BRCA2 (BRCA carriers) are at high risk of developing high-grade
serous ovarian cancer (OC) but little is known about the biological mechanisms that underlie this susceptibility.
BRCA-associated OC is believed to originate from TP53 mutant cells in the fallopian tube, where precursor
lesions synchronous to OC and carrying the same TP53-driver mutation have been identified. However, early
precursor lesions overexpressing TP53 but histologically normal (called p53 foci) have been reported in women
without OC, questioning their significance to carcinogenesis. The goal of this grant is to elucidate the role of
TP53 clonal expansions in BRCA-associated carcinogenesis by using ultra-sensitive sequencing to detect TP53
mutations at a resolution never possible before. Using ultra-sensitive TP53 sequencing, we discovered that most
women, with and without OC, carry TP53 mutations in peritoneal fluid and Pap test DNA, but these mutations
are more abundant in women with OC and in BRCA carriers. We also obtained pilot data that indicates that TP53
mutations are frequent in the fallopian tubes of women without cancer, increasing in abundance and
pathogenicity with age. These results are consistent with recent findings of cancer driver mutations in normal
tissues and the notion of cancer as an evolutionary process that takes place through life. Based on these findings,
we hypothesize that TP53 clonal evolution takes place in the fallopian tubes of women in the general population
but this process is enhanced in women with genetic susceptibility to ovarian cancer. As a result, women at high
risk of OC will carry more pathogenic TP53 mutant clones, which we can detect with unprecedented sensitivity
(>4,000 depth) using CRISPR-DS, a novel ultra-sensitive sequencing method developed by our group. In Aim
1, we will sequence TP53 in fallopian tubes collected at autopsy from 82 women at all decades of life from
newborn to centenarian, pioneering the discovery of the natural history of TP53 mutations in this organ and
providing a baseline control for Aim 2. In Aim 2, we will sequence TP53 in fallopian tubes of 235 women that
underwent prophylactic removal of fallopian tubes and ovaries due to susceptibility to OC, including BRCA
carriers and women with mutations in other OC risk genes or without identified germline mutations. We will
perform a comprehensive characterization of mutation traits (type, location, functional impact, pathogenicity) and
we will compare TP53 mutation frequency and traits with those of women in Aim 1, across groups in Aim 2 and
with standard pathological findings of p53 foci. For the same women, in Aim 3, we will sequence peritoneal fluid,
Pap test, and blood DNA collected at surgery to compare TP53 mutations in those samples with those identified
in fallopian tube. These studies will provide a high-resolu...

## Key facts

- **NIH application ID:** 10368074
- **Project number:** 5R01CA259384-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Rosa Ana Risques
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $517,103
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368074

## Citation

> US National Institutes of Health, RePORTER application 10368074, Understanding the role of TP53 mutation in genetic susceptibility to ovarian cancer (5R01CA259384-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10368074. Licensed CC0.

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