Abstract PR016: Ultra-deep characterization of TP53 somatic evolution in the fallopian tube and its association with ovarian cancer risk

Abstract TP53 mutations drive more than half of human cancers and are commonly found in normal tissues, where they clonally expand with age. Little is known, however, about how these clones influence cancer risk and how the tissue microenvironment might promote their expansion. This gap in knowledge is in part due to the small size of clones, which obscures their detection. Here, we used a multi-omics approach to characterize the TP53 clonal landscape and investigate the tissue microenvironment of the human fallopian tube, which is the site of origin of high-grade serous carcinoma (HGSC), an aggressive subtype of ovarian cancer almost exclusively driven by TP53 mutations. Our goal was to compare age-related TP53 clonal expansions in the fallopian tube with those identified in individuals with BRCA1, BRCA2, BRIP1, PALB2, or RAD51C/D germline mutations (germline mutation carriers) who are at a higher risk of developing HGSC. Human fallopian tube tissues were collected and macrodissected from 67 autopsy cases (average risk group, age: 0-91 years) and 132 prophylactic surgery cases (high-risk group, age: 32-69 years) to assess the TP53 clonal landscape using ultra-deep duplex sequencing (∼12,000x) of the fallopian tube. In addition, we used spatial transcriptomics to study the tissue microenvironment of 47 [RR1] distinct normal fallopian tube areas from 8 individuals (BRCA1: N = 2, BRCA2: N = 4; Non-carriers: N = 2) using the GeoMx Human Whole Transcriptome Atlas probe panel with segmentation separating epithelial and stromal regions of the fallopian tube. Duplex sequencing revealed TP53 mutations in the fallopian tubes of nearly all individuals, with more mutations, increased pathogenicity, and larger clones at older ages. TP53 pathogenic large clones were more abundant in the fallopian tube of germline carriers compared to similar age autopsy cases. Preliminary findings in our transcriptomic study showcased > 6000 transcripts detected across all fallopian tubes of individuals at high-risk of HGSC, though further analyses are underway to determine whether there are differences observed in the epithelial vs. stromal compartments of the fallopian tube. Our results demonstrate prevalent TP53 somatic evolution in the fallopian tube and an excess of pathogenic TP53 clonal expansions in germline carriers, providing a biological explanation for the increased risk of HGSC in these individuals. Citation Format: Coohleen Ann Coombes, Elizabeth U. Parker, Brendan F. Kohrn F. Kohrn, Jeanne Uy. Fredrickson, Shreya Suresh, Elena Latorre-Esteves, Emma Hazard, Melanie R. Dillon, Marc R. Radke, Anh P. Vo, Roseanne J. Gamboa, Katherine Lai, Emily Beirne, Bre A. Mills, Shreeram Akilesh, Ronit Katz, Barbara M. Norquist, Elizabeth M. Swisher, Rosa Ana Risques. Ultra-deep characterization of TP53 somatic evolution in the fallopian tube and its association with ovarian cancer risk [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr PR016.