Spectrum of TP53 Mutations in BRCA1/2 Associated High-Grade Serous Ovarian Cancer

Objective:Mutations in TP53 lead to loss of function (LOF) or gain of function (GOF) of the corresponding protein p53 and produce a different effect on the tumor. Our goal was to determine the spectrum of somaticTP53variants inBRCA1/2associated high-grade serous ovarian cancer (HGSOC). Methods:The population under study comprised of HGSOCs with pathogenic variants inBRCA1(n= 78) orBRCA2(n= 21). Only chemo-naive and platinum-sensitive patients were included in this study. The case group of the IARC database (n= 1249) with HGSOC not stratified by BRCA status was used as a reference. A custom NGS panel was used for sequencingTP53and mutational hot-spots of other genes, and p53 expression was evaluated by immunohistochemistry for 68 cases of HGSOCs. Results:SomaticTP53variants (95) or inhibition of wild-type p53 expression (3) were observed in 98 cases. The sample with normal p53 hadCDKNA1variants. The frequency of truncating variants was significantly higher than in the reference cohort (30.3 vs. 21.0%,p= 0.01). Most of the samples (41/68) demonstrated low (or absent) expression of p53, and 17 samples overexpressed p53. LOH was typical for TP53 nonsense variants (14/15). In total, 68/95 samples were LOH positive and showed LOH in all tumorous cells, thus indicating the driver effect ofTP53mutations. Three specimens hadKRAS, BAX, APC, andCTNNB1subclones variants. Conclusion:High frequency ofTP53truncating variants, the low expression of mutant p53, and low incidence of oncogene mutations show potential GOF properties of p53 to be poorly represented in BRCA1/2 associated HGSOC.