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

Abstract

<b>Objective:</b> 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 somatic <i>TP53</i> variants in <i>BRCA1/2</i> associated high-grade serous ovarian cancer (HGSOC). <b>Methods:</b> The population under study comprised of HGSOCs with pathogenic variants in <i>BRCA1</i> (<i>n</i> = 78) or <i>BRCA2</i> (<i>n</i> = 21). Only chemo-naive and platinum-sensitive patients were included in this study. The case group of the IARC database (<i>n</i> = 1249) with HGSOC not stratified by BRCA status was used as a reference. A custom NGS panel was used for sequencing <i>TP53</i> and mutational hot-spots of other genes, and p53 expression was evaluated by immunohistochemistry for 68 cases of HGSOCs. <b>Results:</b> Somatic <i>TP53</i> variants (95) or inhibition of wild-type p53 expression (3) were observed in 98 cases. The sample with normal p53 had <i>CDKNA1</i> variants. The frequency of truncating variants was significantly higher than in the reference cohort (30.3 vs. 21.0%, <i>p</i> = 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 of <i>TP53</i> mutations. Three specimens had <i>KRAS, BAX, APC</i>, and <i>CTNNB1</i> subclones variants. <b>Conclusion:</b> High frequency of <i>TP53</i> truncating 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.