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Ref Type Journal Article
PMID (32639993)
Authors Mittempergher L, Piskorz AM, Bosma AJ, Michaut M, Wisman GBA, Kluin RJC, Nieuwland M, Brugman W, van der Ven KJW, Marass F, Morris J, Rosenfeld N, Jimenez-Linan M, de Jong S, van der Zee AGJ, Brenton JD, Bernards R
Title Kinome capture sequencing of high-grade serous ovarian carcinoma reveals novel mutations in the JAK3 gene.
Journal PloS one
Vol 15
Issue 7
Date 2020
URL
Abstract Text 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 was TP53 (97% mutation frequency) followed by BRCA1 (10% mutation frequency). The average mutation frequency of the kinase genes mutated from our panel was 1.5%. 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. For independent validation, we re-sequenced the entire JAK3 coding sequence using tagged amplicon sequencing (TAm-Seq) in 463 HGSOCs resulting in an overall somatic mutation frequency of 1%. TAm-Seq screening of CDK12 in 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 of JAK3 and CDK12 mutations in a large well characterized cohort. Although p.T1022I JAK3 mutations are rare, our functional validation shows that if detected they should be considered as potentially actionable for therapy. The observation of CDK12 mutations 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
JAK3 G888A missense unknown JAK3 G888A lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). G888A results in increased mRNA levels of JAK3, PIM1, PIM2, and PIM3 in a patient sample, but does not support cytokine-independent growth in culture (PMID: 32639993), and therefore, its effect on Jak3 protein function is unknown.
JAK3 K550N missense unknown JAK3 K550N lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). K550N has been identified in the scientific literature (PMID: 32639993), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Aug 2021).
JAK3 K733N missense unknown JAK3 K733N lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). K733N has been identified in the scientific literature (PMID: 32639993), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Aug 2021).
JAK3 L1091P missense no effect - predicted JAK3 L1091P lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). L1091P does not support cytokine-independent growth in culture (PMID: 32639993), and therefore, is predicted to have no effect on Jak3 protein function.
JAK3 P151R missense unknown JAK3 P151R lies within the FERM domain of the Jak3 protein (UniProt.org). P151R has been identified in the scientific literature (PMID: 29681454, PMID: 27151993, PMID: 32639993), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Aug 2021).
JAK3 P307S missense unknown JAK3 P307S lies within the FERM domain of the Jak3 protein (UniProt.org). P307S has been identified in the scientific literature (PMID: 32639993), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Aug 2021).
JAK3 R142C missense unknown JAK3 R142C lies within the FERM domain of the Jak3 protein (UniProt.org). R142C has been identified in the scientific literature (PMID: 32639993), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Aug 2021).
JAK3 T1022I missense gain of function JAK3 T1022I lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). T1022I confers a gain of function on Jak3 as demonstrated by increased phosphorylation of Stat5 and Erk, and cytokine-independent growth in culture (PMID: 32639993).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK3 T1022I Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib) inhibited viability of transformed cells expressing JAK3 T1022I in culture (PMID: 32639993). 32639993