TY - JOUR

T1 - Spectrum of TP53 Mutations in BRCA1/2 Associated High-Grade Serous Ovarian Cancer

AU - Boyarskikh, Ulyana A.

AU - Gulyaeva, L. F.

AU - Avdalyan, A. M.

AU - Kechin, A. A.

AU - Khrapov, E. A.

AU - Lazareva, D. G.

AU - Kushlinskii, N. E.

AU - Melkonyan, A.

AU - Arakelyan, A.

AU - Filipenko, Maxim Leonidovich

N1 - Copyright © 2020 Boyarskikh, Gulyaeva, Avdalyan, Kechin, Khrapov, Lazareva, Kushlinskii, Melkonyan, Arakelyan and Filipenko.

PY - 2020/7/16

Y1 - 2020/7/16

N2 - 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 somatic TP53 variants in BRCA1/2 associated high-grade serous ovarian cancer (HGSOC). Methods: The population under study comprised of HGSOCs with pathogenic variants in BRCA1 (n = 78) or BRCA2 (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 sequencing TP53 and mutational hot-spots of other genes, and p53 expression was evaluated by immunohistochemistry for 68 cases of HGSOCs. Results: Somatic TP53 variants (95) or inhibition of wild-type p53 expression (3) were observed in 98 cases. The sample with normal p53 had CDKNA1 variants. 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 of TP53 mutations. Three specimens had KRAS, BAX, APC, and CTNNB1 subclones variants. Conclusion: High frequency of TP53 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.

AB - 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 somatic TP53 variants in BRCA1/2 associated high-grade serous ovarian cancer (HGSOC). Methods: The population under study comprised of HGSOCs with pathogenic variants in BRCA1 (n = 78) or BRCA2 (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 sequencing TP53 and mutational hot-spots of other genes, and p53 expression was evaluated by immunohistochemistry for 68 cases of HGSOCs. Results: Somatic TP53 variants (95) or inhibition of wild-type p53 expression (3) were observed in 98 cases. The sample with normal p53 had CDKNA1 variants. 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 of TP53 mutations. Three specimens had KRAS, BAX, APC, and CTNNB1 subclones variants. Conclusion: High frequency of TP53 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.

KW - BRCA1/2 carriers

KW - gain of function

KW - loss of function

KW - ovarian cancer

KW - p53 expression

KW - TP53 somatic mutations

KW - APOPTOSIS

KW - INSTABILITY

KW - SUBTYPES

KW - PATTERNS

KW - BRCA1

KW - TP53 MUTATIONS

KW - MUTANT P53

KW - RESISTANCE

KW - CARCINOMA

KW - TUMORIGENESIS

KW - GAIN

KW - 2 carriers

UR - http://www.scopus.com/inward/record.url?scp=85088820479&partnerID=8YFLogxK

U2 - 10.3389/fonc.2020.01103

DO - 10.3389/fonc.2020.01103

M3 - Article

C2 - 32766142

AN - SCOPUS:85088820479

VL - 10

JO - Frontiers in Oncology

JF - Frontiers in Oncology

SN - 2234-943X

M1 - 1103

ER -