Molecular profiles of BRCA1‐associated ovarian cancer treated by platinum‐based therapy: Analysis of primary, residual and relapsed tumors

Abstract

Our study aimed to analyze the evolution of molecular portraits of BRCA1-driven ovarian cancer (OC) during treatment. BRCA1 loss-of-heterozygosity status (LOH) and exome profiles were investigated in serial OC samples from 13 patients, which included primary tumors (n = 11) obtained before neoadjuvant therapy (NACT) or at primary debulking surgery, residual post-NACT cancer tissues (n = 13) and tumor relapses (16 samples from 13 patients). Loss of the wild-type BRCA1 allele was detected in 11/11 (100%) primary tumors, 6/13 (46%) residual post-NACT OC samples and 15/16 (94%) OC relapses. Full tumor triplets were available for four patients undergoing NACT; whereas primary carcinomas from these patients demonstrated BRCA1 LOH, the retention of the wild-type allele was detected in all four post-NACT residual tumors. These four women provided to the study 5 recurrent OC samples; 4 out of 5 tumor relapses had BRCA1 LOH thus resembling BRCA1 status observed in primary but not residual OC tissues. TP53 mutation was detected in 12 out of 13 patients and was retained across all serial samples. OC relapses tended to acquire additional intragenic mutations in genes involved in cell migration, adhesion and cell junction assembly. BRCA1-driven OCs demonstrate the plasticity of BRCA1 status during the treatment course. NACT results in rapid selection of pre-existing BRCA1-proficient cells. However, BRCA1 proficiency appears to be disadvantageous in the absence of platinum exposure, as tumor relapses usually re-acquire BRCA1 LOH during therapy holidays.Additional Supporting Information may be found in the online version of this article.

The G199X and V157fs mutations in the TP53 gene promote malignancy in serous ovarian cancer: an analysis using whole-exome sequencing

“…Prior evidence suggested that theTP53 R273H, R248Q, R175H, and R248W point mutations were the four most frequent mutations (or "hotspots") in many cancers, including bladder, lung, liver, breast, larynx, and skin cancers (13). In ovarian cancer, TP53 mutations includingp.E298X, p.R248Q, p.Y163C, c.997delG, and c.833delC have been reported (14,15). Other studies have shown that approximately 75% of TP53 mutations were of the missense type.…”

Gastric Cancer in <b><i>BRCA1</i></b> Germline Mutation Carriers: Results of Endoscopic Screening and Molecular Analysis of Tumor Tissues

“…BRCA1 somatic loss-of-heterozygosity (LOH) was analyzed in atrophic or tumor samples by digital-droplet PCR as described in Preobrazhenskaya et al [11]. High-grade gastric dysplasia and gastric carcinoma observed in the same BRCA1 mutation carrier were investigated by whole-exome sequencing (WES) using the methodology described in Sokolenko et al [12]. We also added to molecular profiling analysis 4 archival gastric cancers, which were identified in BRCA1/2 heterozygotes; 2 of these cases were taken from the study by Moiseyenko et al [3], while the remaining 2 carcinomas were identified upon routine BRCA1/2 diagnostic testing.…”

“…org/gatk/documentation/tooldocs/3.8-0/org_broadinstitute_ gatk_tools_walkers_cancer_m2_MuTect2.php) [13]. Chromosomal instability (CIN), which is a hallmark of the BRCAness phenotype and is manifested by multiple copy number variations spread across the genome, was determined according to the procedure described in Sokolenko et al [12]. The examples of NGSbased analysis of the copy number variations are given in online supplementary Figure S1.…”

Frequency and molecular characteristics of PALB2‐associated cancers in Russian patients

“…All selected mutations were reviewed in the Golden Helix genome browser 30 . The level of chromosomal instability was evaluated as described previously 31 …”