Kinome capture sequencing of high-grade serous ovarian carcinoma reveals novel mutations in theJAK3gene
| Autor: | Wim Brugman, Marja Nieuwland, Magali Michaut, Nitzan Rosenfeld, Mercedes Jimenez-Linan, Ate G.J. van der Zee, Astrid Bosma, Roelof J.C. Kluin, René Bernards, Steven de Jong, James D. Brenton, Kevin J. W. van der Ven, Lorenza Mittempergher, Anna M. Piskorz, Francesco Marass, G. Bea A. Wisman, James Morris |
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| Přispěvatelé: | Targeted Gynaecologic Oncology (TARGON), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Mittempergher, Lorenza [0000-0003-3425-3965], Marass, Francesco [0000-0002-8993-7320], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Epidemiology medicine.disease_cause Cohort Studies Database and Informatics Methods 0302 clinical medicine Mutation frequency Frameshift Mutation Ovarian Neoplasms education.field_of_study Mutation Multidisciplinary BRCA1 Protein Cancer Risk Factors High-Throughput Nucleotide Sequencing Nonsense Mutation CANCER Ovarian Cancer Oncology 030220 oncology & carcinogenesis Medicine Female JAK3 Research Article EXPRESSION GENES Science Population Nonsense mutation Genetic Causes of Cancer BEVACIZUMAB Biology Frameshift mutation 03 medical and health sciences Germline mutation medicine Genetics Point Mutation Humans education Medicine and health sciences REPAIR Biology and life sciences Point mutation Cancers and Neoplasms Janus Kinase 3 DNA Cystadenocarcinoma Serous Research and analysis methods 030104 developmental biology Biological Databases Medical Risk Factors Case-Control Studies Mutation Databases Cancer research Somatic Mutation Tumor Suppressor Protein p53 CDK12 Gynecological Tumors Protein Kinases GENOMIC INSTABILITY |
| Zdroj: | PLoS ONE, 15 (7) PLoS ONE, Vol 15, Iss 7, p e0235766 (2020) PLoS ONE PLoS ONE, 15(7):0235766. PUBLIC LIBRARY SCIENCE |
| ISSN: | 1932-6203 |
| Popis: | 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. PLoS ONE, 15 (7) ISSN:1932-6203 |
| Databáze: | OpenAIRE |
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