Abstract B101: Characterizing somatic TP53 mutations in non-cancerous and high-risk fallopian tubes using ultra-deep sequencing

Abstract

Abstract High-grade serous carcinoma (HGSC), the most common and pervasive subtype of ovarian cancer originates in the fallopian tube epithelium from precursor lesions carrying somatic TP53 mutations. These lesions may evolve into carcinomas, eventually spreading to the ovary and peritoneum1,2. Recent research in non-cancerous tissues and gynecologic liquid biopsies of individuals with and without HGSC have demonstrated that somatic TP53 mutations accumulate and clonally expand with age3–9. However, TP53 somatic evolution has not been characterized in the normal fallopian tube epithelium. In addition, it is not known whether TP53 mutations are more abundant in individuals with germline BRCA1/2 mutations (BRCA carriers), who are at a high risk of HGSC10. The goals of this study were to characterize age-related TP53 somatic mutations in non-cancer fallopian tube epithelium across the human lifespan and to determine whether the TP53 mutational landscape is altered in BRCA carriers. Our cohort consisted of 1) autopsy cases, spanning the ages of 0-91 years, from individuals without ovarian cancer (N=46) and 2) prophylactic surgery cases from BRCA carriers and non-carriers (N=26, ongoing analyses). Fallopian tube tissues were collected, frozen, and macrodissected using a 1mm biopsy punch, enriching for the fallopian tube epithelium. DNA was extracted from each sample, the sequenced for TP53 using ultra-deep duplex sequencing (mean depth: ~12,000x). In the normal fallopian tube epithelium collected across human lifespan, we found that the number of unique TP53 mutations and the size of pathogenic clones increased with age, showcasing somatic evolution and clonal expansion of TP53 in non-cancerous fallopian tube epithelium with age. We also found that the number of TP53 mutations in hotspot codons increased with age, suggesting that cancer-like mutations are positively selected as individuals age. We compared the normal fallopian tube TP53 mutations with HGSC TP53 mutations and demonstrated that the types of mutations (e.g. indels, splice, nonsense, missense, and silent mutations) in the aging fallopian tube closely mirrored the mutations types observed in HGSC. Data analysis from BRCA carriers is ongoing, but based on preliminary data, we anticipate a higher burden of pathogenic TP53 mutations, indicating that predisposition to HGSC in BRCA carriers may be related to an excess of TP53 somatic evolution in the fallopian tube. Altogether, our research demonstrates that TP53 somatic evolution is a normal aging phenotype in the fallopian tube, with more and larger pathogenic clones occurring later in life. We expect to determine whether this effect is more prominent in BRCA carriers, which would provide a much needed biological explanation to understand the increased risk of HGSC in these patients, opening new venues for better cancer prediction and prevention. Citation Format: Coleen Ann Coombes, Elizabeth U. Parker, Brendan F. Kohrn, Jeanne Uy Fredrickson, Elena Latorre-Esteves, Emma Hazard, Shreya Suresh, Marc R. Radke, Anh P. Vo, Barbara S. Norquist, Rosana Risques. Characterizing somatic TP53 mutations in non-cancerous and high-risk fallopian tubes using ultra-deep sequencing [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B101.