title: JAK1 truncating mutations in gynecologic cancer define new role of cancer-associated protein tyrosine kinase aberrations.
abstract: Cancer-associated protein tyrosine kinase (PTK) mutations usually are gain-of-function (GOF) mutations that drive tumor growth and metastasis. We have found 50 JAK1 truncating mutations in 36 of 635 gynecologic tumors in the Total Cancer Care® (TCC®) tumor bank. Among cancer cell lines containing JAK1 truncating mutations in the Cancer Cell Line Encyclopedia databank, 68% are gynecologic cancer cells. Within JAK1 the K142, P430, and K860 frame-shift mutations were identified as hot spot mutation sites. Sanger sequencing of cancer cell lines, primary tumors, and matched normal tissues confirmed the JAK1 mutations and showed that these mutations are somatic. JAK1 mediates interferon (IFN)-γ-regulated tumor immune surveillance. Functional assays show that JAK1 deficient cancer cells are defective in IFN-γ-induced LMP2 and TAP1 expression, loss of which inhibits presentation of tumor antigens. These findings identify recurrent JAK1 truncating mutations that could contribute to tumor immune evasion in gynecologic cancers, especially in endometrial cancer.
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ren
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Richard Z
authors.initials: RZ
authors.lastname: Liu
authors.forename: David A
authors.initials: DA
authors.lastname: Fenstermacher
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Wright
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Teer
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D017951:Antigen Presentation / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D005833:Genital Neoplasms, Female / Q000235:genetics* / Q000378:metabolism; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D006680:HLA Antigens; C073119:TAP1 protein, human; C071313:LMP-2 protein; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D053613:Janus Kinase 1; D003546:Cysteine Endopeptidases