Mutational analysis of BRCA1/2 in a group of 134 consecutive ovarian cancer patients. Novel and recurrent BRCA1/2 alterations detected by next generation sequencing

Abstract

The importance of proper mutational analysis of BRCA1/2 in individuals at risk for hereditary breast and ovarian cancer syndrome is widely accepted. Standard genetic screening includes targeted analysis of recurrent, population-specific mutations. The purpose of the study was to establish the frequency of germline BRCA1/2 mutations in a group of 134 unrelated patients with primary ovarian cancer. Next generation sequencing analysis revealed a presence of 20 (14.9 %) mutations, where 65 % (n = 13) were recurrent BRCA1 alterations included in the standard diagnostic panel in northern Poland. However, the remaining seven BRCA1/2 mutations (35 %) would be missed by the standard approach and were detected in unique patients. A substantial proportion (n = 5/12; 41 %) of mutation-positive individuals with complete family history reported no incidence of breast or ovarian cancer in their relatives. This observation, together with the raising perspectives for personalized therapy targeting BRCA1/2 signaling pathways indicates the necessity of comprehensive genetic screening in all ovarian cancer patients. However, due to the limited sensitivity of the standard genetic screening presented in this study (65 %) an application of next generation sequencing in molecular diagnostics of BRCA1/2 genes should be considered.

Detection of somatic BRCA1/2 mutations in ovarian cancer – next‐generation sequencing analysis of 100 cases

“…Among the BRCA1/2 positive cases, the frequency of germline and somatic mutations was 18.6% and 4.1%, respectively. The percentage of identified somatic changes is comparable to previous reports [11][12][13][14][15], whereas the BRCA1/2 germline mutation frequency is higher than the expected frequency in a constitutive ovarian cancer cases (~19% vs. 11-15.3%) [3][4][5][6][7]. However, the explanation of this phenomena could be due to the differences in the studied patient population.…”

“…According to the guidelines of the American Society of Clinical Oncology genetic testing for BRCA1/2 mutations should be performed in each patient with ovarian cancer (1996) [23]. The advantages of this approach were presented in our previous study, where more than one-third of BRCA1/2-positive patients had no family history of breast or ovarian cancer [5]. Unfortunately, in this study, no information about family history of the patients was available.…”

“…Germline mutations in these genes are strongly associated with an increased risk of breast and ovarian cancer [1,2]. Previous studies estimated that approximately 15% of the Polish patients diagnosed with ovarian cancer carry germline BRCA1/2 mutation [3][4][5]. This frequency is comparable to the overall prevalence of BRCA1/2 mutations among ovarian cancer patients worldwide [6,7].…”

Cancer predisposing BARD1 mutations affect exon skipping and are associated with overexpression of specific BARD1 isoforms

“…Moreover, the carrier of c.1690C>T mutation in BARD1 was also diagnosed with mutation c.5266dupC in the BRCA1 gene. The duplication of the cytosine at position c.5266 is the second most frequent BRCA1 mutation all over the world and the most common in Poland (10,11,18). The c.1690C>T mutation in BARD1 was previously described in a family with an aggregation of breast, colon, and uterine cancer and was further identified in four different families with aggregation of breast and ovarian cancer (27,and Ratajska unpublished data).…”

“…Although the actual proportion strongly depends on the studied population and may be much higher, reaching 30% in the Ashkenazi Jews (5)(6)(7)(8). In Poland, the portion of hereditary ovarian cancer due to BRCA1/2 mutation ranges from 13.5 to 14.9% (9)(10)(11).…”