Abstract A004: TP53 mutational landscape in non-cancerous endometrium during the lifespan of Black and White individuals

Abstract

Abstract Background TP53 somatic mutations accumulate and clonally expand in histologically normal tissues with aging, however, little is known about this process and how it influences cancer development. Within endometrial carcinoma, TP53 mutations tend to be found in aggressive, non-endometrioid histologies associated with poor survival outcomes, more commonly affecting Black women. We seek to understand the TP53 mutational burden in benign endometrium by characterizing mutations acquired throughout a lifespan with the integration of social determinants of health in Black and White women. Methods Endometrial tissue was collected at autopsy or hysterectomy, confirmed with H&E staining, and macrodissected. Ultra-deep duplex sequencing (~10,000x) of isolated DNA was used to sequence TP53somatic mutations with high resolution. Each individual’s TP53 mutation frequency was calculated as the number of unique TP53 variants divided by the total duplex nucleotides sequenced. Mutations were classified as pathogenic if insertion-deletion, splice, or nonsense in addition to all pathogenic substitutions identified by the Seshat TP53 database. Socioeconomic metrics were acquired using zip codes and the 2021 US Census Bureau American Community Survey. Individuals with a history of endometriosis, prior malignancy, or prior chemotherapy were excluded. Results Benign endometrial tissue was collected from 69 individuals (24 Black, 45 White), including 22 aged 0-19 years, 25 aged 20-39 years, 17 aged 40-59 years, and 5 aged over 60 years. 174 TP53 variants were identified. Variant types included 66.7% missense (n=116), 13.2% insertion-deletion (n=23), 12.1% synonymous (n=21), 4.6% nonsense (n=8), and 3.4% splice (n=6). 102 TP53 mutations (58.6%) were pathogenic. TP53 mutation frequency increased linearly with age (Spearman correlation p<0.01). 12.6% of mutations were identified in more than one duplex mutant read (large clone) beginning at age 29 through age 81. The frequency of large TP53 mutant clones increased exponentially with age. In this limited dataset, there was no statistical association between socioeconomic metrics and the mutational burden of Black and White individuals. Conclusions The number and size of TP53 mutant clones in benign endometrium are associated with older age, indicating clonal evolution through life. Most somatic mutations identified were pathogenic substitutions or loss-of-function variants, confirming positive selection of cancer-like mutations. Additional data are needed to determine the role of socioeconomic factors in TP53 genomic burden. Citation Format: Eric Rios-Doria, Elizabeth U. Parker, Brendan F. Kohrn, Elena Latorre-Estevez, Jeanne Fredrickson, Elizabeth M. Swisher, Kemi M. Doll, Rosana Risques. TP53 mutational landscape in non-cancerous endometrium during the lifespan of Black and White individuals [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A004.