Kinome capture sequencing of high-grade serous ovarian carcinoma reveals novel mutations in theJAK3gene
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2020-07-08
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Journal Article
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Abstract
High-grade serous ovarian carcinoma (HGSOC) remains the deadliest form of epithelial ovarian cancer and despite major efforts little improvement in overall survival has been achieved. Identification of recurring "driver" genetic lesions has the potential to enable design of novel therapies for cancer. Here, we report on a study to find such new therapeutic targets for HGSOC using exome-capture sequencing approach targeting all kinase genes in 127 patient samples. Consistent with previous reports, the most frequently mutated gene wasTP53(97% mutation frequency) followed byBRCA1(10% mutation frequency). The average mutation frequency of the kinase genes mutated from our panel was 1.5%. Intriguingly, afterBRCA1,JAK3was the most frequently mutated gene (4% mutation frequency). We tested the transforming properties of JAK3 mutants using the Ba/F3 cell-basedin vitrofunctional assay and identified a novel gain-of-function mutation in the kinase domain ofJAK3(p.T1022I). Importantly, p.T1022IJAK3mutants displayed higher sensitivity to the JAK3-selective inhibitor Tofacitinib compared to controls. For independent validation, we re-sequenced the entireJAK3coding sequence using tagged amplicon sequencing (TAm-Seq) in 463 HGSOCs resulting in an overall somatic mutation frequency of 1%. TAm-Seq screening ofCDK12in the same population revealed a 7% mutation frequency. Our data confirms that the frequency of mutations in kinase genes in HGSOC is low and provides accurate estimates for the frequency ofJAK3andCDK12mutations in a large well characterized cohort. Although p.T1022IJAK3mutations are rare, our functional validation shows that if detected they should be considered as potentially actionable for therapy. The observation ofCDK12mutations in 7% of HGSOC cases provides a strong rationale for routine somatic testing, although more functional and clinical characterization is required to understand which nonsynonymous mutations alterations are associated with homologous recombination deficiency.
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15 (7)
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PLOS