Sunday, May 11, 2025
5/11/2025
Understanding the role of TP53 mutation in genetic susceptibility to ovarian cancer - 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-resolution picture of the landscape of TP53 mutation in the fallopian tube during normal aging and in women with OC susceptibility, improving our understanding of the pathogenesis of OC and opening new venues for OC prevention and early detection.
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