AUTHOR=Boyarskikh Ulyana A. , Gulyaeva L. F. , Avdalyan A. M. , Kechin A. A. , Khrapov E. A. , Lazareva D. G. , Kushlinskii N. E. , Melkonyan A. , Arakelyan A. , Filipenko Maxim Leonidovich 

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

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.01103

DOI=10.3389/fonc.2020.01103

ISSN=2234-943X

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