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

BACKGROUND: TP53 mutations are the main drivers of aggressive, high-risk endometrial carcinomas commonly diagnosed in Black individuals. However, TP53 mutations have also been identified in benign, non-cancerous tissues. We sought to understand the TP53 mutational landscape 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 duplex sequencing (∼13,000×) in DNA extracted from histologically normal endometrium collected at autopsy (69 % of cases) or surgery (31 % of cases) from 83 individuals ages 0 to 81 (31 Black and 52 White, median age 35 years) without endometrial cancer. Histologically normal endometrium was also collected from 10 White individuals with endometrial cancer. RESULTS: We identified 266 coding TP53 mutations in the normal endometrium of individuals without endometrial cancer, 57 % of which were pathogenic. The number, pathogenicity, and size of TP53 mutant clones in normal endometrium increased with age. Multivariable models showed no significant association between race or socioeconomic metrics and TP53 mutation frequency in normal endometrium. An exploratory analysis on the histologically normal endometrium of White individuals with endometrial cancer identified the tumor mutations at low levels in the normal biopsy of 5 out of 6 cases. CONCLUSIONS: Our study revealed prevalent TP53 somatic evolution in benign endometrium across human lifespan and no racial differences in this cohort of predominantly younger individuals. Future studies should consider the analysis of larger cohorts with older individuals to detect potential effects of racial disparities on TP53 somatic evolution later in life.