Kinome capture sequencing of high-grade serous ovarian carcinoma reveals novel mutations in the JAK3 gene

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. Consistent with previous reports, in our patient set the most frequently mutated gene was TP53 (97% mutation frequency) followed by BRCA1 (10% mutation frequency). Intriguingly, after BRCA1, JAK3 was the most frequently mutated gene (4% mutation frequency). We tested the transforming properties of JAK3 mutants using the Ba/F3 cell-based in vitro functional assay and identified a novel gain-of-function mutation in the kinase domain of JAK3 (p.T1022I). Importantly, p.T1022I JAK3 mutants displayed higher sensitivity to the JAK3-selective inhibitor Tofacitinib compared to controls. In light of this, we re-sequenced the entire JAK3 coding sequence using TAm-Seq in 463 HGSOCs resulting in an overall somatic mutation frequency of 1%. Such a mutation frequency, although lower than expected, translates to large number of potential HGSOC patients worldwide that could benefit from a novel targeted-treatment.Additionally, TAm-Seq screening of CDK12 gene revealed a 7% mutation frequency with the mutations being-loss-of-function. Our findings support the putative tumor suppressor role of CDK12 and underscore its potential clinical utility as biomarker for PARP inhibitor therapy in HGSOC.