Understanding Ovarian Cancer Risk: Pathogenic TP53 mutation burden in peritoneal fluid is associated with BRCA germline mutation status

Abstract

Individuals with germline BRCA1 and BRCA2 mutations (BRCA carriers) have an increased risk of developing high-grade serous ovarian cancer (HGSOC), the most common and deadliest subtype of ovarian cancer. While HGSOC is initiated by TP53 mutations, these mutations are also now recognized as a common feature of normal human aging. We hypothesize that BRCA carriers harbor increased TP53 mutation burden, underlying their predisposition to HGSOC. We used high-fidelity, high-depth duplex sequencing to analyze mutations in TP53 in Paps and peritoneal fluid of 25 BRCA1 carriers, 21 BRCA2 carriers, and 11 BRCA non-carriers. Mutations were annotated and compared across groups, sample types, and with the TP53 UMD HGSOC database. TP53 coding and pathogenic mutation burden were associated with age in Paps and peritoneal fluid of all individuals. BRCA1 carriers older than 45 years old had a significantly higher pathogenic mutation burden than BRCA2 carriers and controls of the same age in peritoneal fluid, but not in Paps, Peritoneal fluid from BRCA1 carriers older than 45 years old had the most significant enrichment of hotspot TP53 mutations with 36.2% of all mutations identified in hotspot codons compared to 7.7% expected by chance (p = 5x10-8). 2.6% (6 out of 230) of peritoneal fluid TP53 variants were also found in Paps but not in blood. BRCA1 carriers harbor an excess of TP53 pathogenic mutations in peritoneal fluid after age 45, coinciding with the age of increased HGSOC risk. Paps have no resolution to detect differences in TP53 mutation burden due to germline status.