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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.
Highlights
BRCA1 and BRCA2 tumor suppressor genes play an important role in DNA damage and repair pathways.Germline mutations in these genes are strongly associated with an increased risk of breast and ovarian cancer [1, 2]
15% of the Polish patients diagnosed with ovarian cancer carry germline BRCA1/2 mutation [3,4,5]
Somatic BRCA1 mutations were reported in 5–9% of sporadic ovarian cancer cases, whereas somatic genetic variants of BRCA2 were identified in 3–4% of tumors [11,12,13,14,15]
Summary
BRCA1 and BRCA2 tumor suppressor genes play an important role in DNA damage and repair pathways. Germline mutations in these genes are strongly associated with an increased risk of breast and ovarian cancer [1, 2]. 15% of the Polish patients diagnosed with ovarian cancer carry germline BRCA1/2 mutation [3,4,5]. 20–70% of sporadic ovarian tumors display loss of heterozygosity (LOH) in the BRCA1/2 loci, indicating essential role of these genes in ovarian cancer pathogenesis, somatic mutations of these genes are relatively rare finding [8,9,10]. Somatic BRCA1 mutations were reported in 5–9% of sporadic ovarian cancer cases, whereas somatic genetic variants of BRCA2 were identified in 3–4% of tumors [11,12,13,14,15]
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