Abstract PR005: TP53 somatic evolution in healthy fallopian tube across the full spectrum of human lifespan

Abstract

Abstract Introduction: TP53 is the most mutated gene in human cancers but research in recent years has demonstrated that TP53 mutations are also prevalent in healthy tissue. Little is known, however, about how these mutations accumulate with age and how this process might differ between and within individuals. This gap in knowledge is largely due to the difficulty of measuring clonal expansions in normal tissue since mutant clones are typically small and escape the detection of standard sequencing technologies. We previously demonstrated the high sensitivity of duplex sequencing (duplex-seq) to detect low frequency mutations in normal tissue. Here we use duplex-seq to characterize TP53 mutations across the full range of human lifespan in fallopian tube epithelium. Fallopian tube is the site of origin of high-grade serous ovarian carcinoma, a very aggressive cancer type that is almost exclusively driven by TP53 mutations. We hypothesize that TP53 clonal expansions increase in number, size, and pathogenicity during human lifespan, especially in the fimbria, which is the distal part of the tube and the predominant site for cancer formation. Methods: Frozen fallopian tube was collected at autopsy from 84 individuals spanning the full range of human lifespan (from newborn to >90-year-old). For most individuals, collection included a sample from the fallopian tube fimbria (distal part) and ampulla (proximal part). For a subset of patients, both right and left fallopian tubes were sampled. Frozen OCT embedded tissue was sectioned, pathologically examined to determine the presence of fallopian tube epithelium, and macrodissected. TP53 mutations were identified by ultra-deep duplex-seq (12,000x) and were compared between fallopian tube fimbria and ampulla, between right and left tubes, across decades of age, and with cancer mutations reported in the COSMIC database. Results: About 11% of samples have been analyzed, and the full cohort is expected to be completed within the next two months. TP53 mutations were identified in all individuals at an average of 6 mutations per sample (min=0, max=15). The number of mutations significantly increased with age and, in this smaller subset, did not significantly differ between bilateral samples or between fimbria and ampulla. The size of the mutant clones also increased with age. Most mutations were missense, but nonsense, indels, and splice mutations were also detected, especially at older ages. More than half of the mutations were predicted to be pathogenic and coincided with mutations commonly found in ovarian cancer. Conclusions: Ultra-deep sequence has enabled unprecedented resolution to characterize TP53 somatic evolution in normal tissue. TP53 mutant clones accumulate in the fallopian tube with age and are enriched for pathogenic mutations, indicating clonal expansion upon selective advantage. Deep characterization of these mutant clones will inform our knowledge of the normal physiological process of somatic evolution during healthy aging and its potential contribution to cancer formation later in life. Citation Format: Rosana Risques, Coohleen Coombes, Jeanne Fredrickson, Elizabeth U. Parker, Brendan Kohrn, Elena S. Latorre-Esteves, Emma Hazard, Eden M. Milan, Ronit Katz. TP53 somatic evolution in healthy fallopian tube across the full spectrum of human lifespan [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR005.