title: Detection of somatic BRCA1/2 mutations in ovarian cancer - next-generation sequencing analysis of 100 cases.
abstract: The overall prevalence of germline BRCA1/2 mutations is estimated between 11% and 15% of all ovarian cancers. Individuals with germline BRCA1/2 alterations treated with the PARP1 inhibitors (iPARP1) tend to respond better than patients with wild-type BRCA1/2. Additionally, also somatic BRCA1/2 alterations induce the sensitivity to iPARP1. Therefore, the detection of both germline and somatic BRCA1/2 mutations is required for effective iPARP1 treatment. The aim of this study was to identify the frequency and spectrum of germline and somatic BRCA1/2 alterations in a group of Polish patients with ovarian serous carcinoma. In total, 100 formalin-fixed paraffin-embedded (FFPE) ovarian serous carcinoma tissues were enrolled to the study. Mutational analysis of BRCA1/2 genes was performed by using next-generation sequencing. The presence of pathogenic variants was confirmed by Sanger sequencing. In addition, to confirm the germline or somatic status of the mutation, the nonneoplastic tissue was analyzed by bidirectional Sanger sequencing. In total, 27 (28% of patient samples) mutations (20 in BRCA1 and 7 in BRCA2) were identified. For 22 of 27 patients, nonneoplastic cells were available and sequencing revealed the somatic character of two BRCA1 (2/16; 12.5%) and two BRCA2 (2/6; 33%) mutations. Notably, we identified six novel frameshift or nonsense BRCA1/2 mutations. The heterogeneity of the detected mutations confirms the necessity of simultaneous analysis of BRCA1/2 genes in all patients diagnosed with serous ovarian carcinoma. Moreover, the use of tumor tissue for mutational analysis allowed the detection of both somatic and germline BRCA1/2 mutations.
authors.affiliation: Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Koczkowska
authors.affiliation: Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Zuk
authors.affiliation: Department of Pathology, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Gorczynski
authors.affiliation: Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ratajska
authors.affiliation: Molecular Oncology and Genetics Department, Innovative Medical Forum, The Franciszek Lukaszczyk Oncology Center, Bydgoszcz, Poland.|Department of Thoracic Surgery and Tumors, Ludwik Rydygier Medical College in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland.
authors.forename: Marzena
authors.initials: M
authors.lastname: Lewandowska
authors.affiliation: Department of Pathology, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Biernat
authors.affiliation: Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Limon
authors.affiliation: Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Wasag
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D014408:Biomarkers, Tumor; D004252:DNA Mutational Analysis; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018740:Genetic Heterogeneity; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor
keywords: BRCA1; BRCA2; PARP inhibitors; next-generation sequencing; ovarian cancer; somatic mutation