Abstract LB416: IncreasedTP53somatic evolution in the fallopian tubes of individuals at high risk of ovarian cancer

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 peritoneum. Recent research in normal tissues and gynecologic liquid biopsies of individuals without HGSC has demonstrated that somatic TP53 mutations accumulate and clonally expand with age, suggesting that TP53 somatic evolution is part of the normal aging process​. To date, however, TP53 somatic evolution in the normal fallopian tube epithelium has not been characterized and it is unknown whether TP53mutations are more abundant in individuals with germline mutations in BRCA1 or BRCA2 (BRCA carriers) who are at a higher risk of developing HGSC​. In this study, we aimed to characterize age-related TP53 somatic mutations in the normal fallopian tube epithelium across the human lifespan and to determine whether the TP53 mutational landscape is altered in BRCA carriers. Our cohort consisted of 46 autopsy cases (age: 0-91 years) from individuals at low-risk of developing ovarian cancer and 48 prophylactic surgery cases (age: 32-69 years) from BRCA carriers. 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 and sequenced for TP53 using ultra-deep duplex sequencing (mean depth: ~12,000x). Pathogenicity was determined using a machine learning algorithm (AlphaMissense) and a well-established predictor of TP53 pathogenicity (Seshat). Preliminary analyses in the normal fallopian tube epithelium collected across human lifespan demonstrated that the mutational profile (e.g. indels, splice, nonsense, missense, and silent mutations) in the aging fallopian tubes mirrored the mutational profile of HGSC. We also observed that the number of unique TP53 mutations and pathogenic clones increased with age, revealing TP53 somatic evolution. Additionally, the number of large TP53 mutant clones (>2 duplex mutant reads) increased exponentially with age, staring at age 30. When comparing the fallopian tubes of BRCA carriers to age-matched normal fallopian tubes, the percentage of pathogenic large clones in BRCA carriers was 22.8% vs. 6.0% in low-risk individuals (Fisher exact test, p < 0.0001), suggesting increased TP53 somatic evolution in the fallopian tubes of BRCA carriers. 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. Preliminary analyses in BRCA carriers indicate that somatic evolution is more prominent in these individuals, which may provide a biological explanation to the increased risk of HGSC and open new venues for better cancer prediction and prevention. Citation Format: CoohleenAnn Coombes, Brendan F. Kohrn, Jeanne U. Fredrickson, Elena Latorre-Esteves, Emma Hazard, Shreya Suresh, Marc R. Radke, Melanie Dillon, Anh P. Vo, Katherine Lai, Ronit Katz, Barbara M. Norquist, Elizabeth M. Swisher, Elizabeth U. Parker, Rosana Risques. IncreasedTP53somatic evolution in the fallopian tubes of individuals at high risk of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB416.