Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
PloS one	15	7	2020	e0235766	PLoS One

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
JAK3	G888A	missense	unknown	JAK3 G888A lies within 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 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, Mar 2024).
JAK3	K733N	missense	unknown	JAK3 K733N lies within 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, Mar 2024).
JAK3	L1091P	missense	no effect - predicted	JAK3 L1091P lies within 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, Mar 2024).
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, May 2024).
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, Mar 2024).
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