TP53 somatic evolution in the normal endometrium of Black and White individuals

Background: TP53 mutations are the main drivers of aggressive, high-risk endometrialcarcinomas commonly diagnosed in Black individuals. However, TP53 mutations have alsobeen identified in benign, non-cancerous tissues. We sought to understand the TP53 mutationallandscape in benign endometrium throughout the lifespan of Black and White individuals,accounting for structural socioeconomic context.Methods: Ultra-sensitive TP53 mutation detection was performed with high-depth duplexsequencing (~13,000x) in DNA extracted from histologically normal endometrium collected atautopsy (69% of cases) or surgery (31% of cases) from 83 individuals ages 0 to 81 (31 Blackand 52 White, median age 35 years) without endometrial cancer. Histologically normalendometrium was also collected from 10 White individuals with endometrial cancer.Results: We identified 266 coding TP53 mutations in the normal endometrium of individualswithout endometrial cancer, 57% of which were pathogenic. The number, pathogenicity, andsize of TP53 mutant clones in normal endometrium increased with age. Multivariable modelsshowed no significant association between race or socioeconomic metrics and TP53 mutationfrequency in normal endometrium. An exploratory analysis on the histologically normalendometrium of White individuals with endometrial cancer identified the tumor mutations at lowlevels in the normal biopsy of 5 out of 6 cases.Conclusions: Our study revealed prevalent TP53 somatic evolution in benign endometriumacross human lifespan and no racial differences in this cohort of predominantly youngerindividuals. Future studies should consider the analysis of larger cohorts with older individuals todetect potential effects of racial disparities on TP53 somatic evolution later in life.