Department of Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
Minmin Hou , Li Sun , Xiuzhang Yu , Pengyao Du , Chuang Liu , Fanfan Meng , Yaxuan Zhang , Ling Li
Background: BRCA1 and BRCA2 are tumour suppressor genes, involved in the homologous repair of double-stranded DNA breaks, located at 17q21.31 and 13q13.1, respectively. Germline BRCA1/2 mutations are identified in 13-15% of ovarian cancers (OC), while an additional 5-7% of ovarian cancers harbor somatic BRCA1/2 mutations among foreign populations. To determine the landscape of germline and somatic pathogenic BRCA1 and BRCA2 alterations in Chinese patients with ovarian cancer tested by next‐generation sequencing (NGS), with the aim of defining the best strategy to be implemented in future routine testing. Methods: 472 normal-paired samples from Chinese patients with ovarian cancers were analyzed using hybridization capture-based next generation sequencing. Somatic and germline mutations were identified including 500 genes associated with tumor development. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (InDels), copy number alterations (CNA) and gene fusions and rearrangements. Results: Overall, 472 ovarian cancer patients underwent somatic and/or germline NGS analysis, the BRCA1 and BRCA2 genes sequenced in this study covers all targeted coding exons and exon-intron boundaries. Among these patients, 54/472 (11.4%) patients carried BRCA(BRCA1/2) mutations. Inside, there were 43/472 (9.1%) patients occurred somatic BRCA mutations, 62.8% (27/43) of variants were in BRCA1 and 37.2% (16/43) were in BRCA2. Furthermore, 3 cases carried BRCA1 and BRCA2 somatic co-mutation, of which only 1 showed BRCA1/BRCA2 copy number losses. In 54 OC patients who carried BRCA mutations, 10 patients occured copy number alterations, of which 6 patients showed BRCA1 copy number losses, 4 patients showed BRCA2 copy number losses, and 1 patient showed BRCA2 copy number gains. Germline BRCA variant was detected in 18/472 (3.8%) patients, 66.7% (12/18) of variants were in BRCA1 and 33.3% (6/18) were in BRCA2. Of the 12 BRCA1 germline mutations, 11 were pathogenic heterozygous mutations (c.2679_2682del; c.2101_2102del; c.5085_5086insT; c.1660G > T; c.4810C > T; c.1504_1508del; c.1465G > T; c.1480C > T; c.2110_2111del; c.4185+1G > A; c.81-2A > G), one was likely pathogenic heterozygous mutation (c.5216A > G). Of the 6 BRCA2 germline mutations, four were pathogenic heterozygous mutations (c.5722_5723del; c.5291C > G; c.5164_5165del; c.3109C > T), one was likely pathogenic heterozygous mutation (c.869_870del), and one was uncertain significance heterozygous mutation (c.7976+3A > G). Conclusions: This study revealed the molecular features of BRCA1 and BRCA2 in Chinese ovarian cancer patients, which could help to identify therapeutic targets and personalize therapy management, leading to improved patient outcomes as predictive biomarkers or platinum-based therapy.
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