title: Microsatellite instability derived JAK1 frameshift mutations are associated with tumor immune evasion in endometrioid endometrial cancer.
abstract: JAK1 frameshift mutations may promote cancer cell immune evasion by impeding upregulation of the antigen presentation pathway in microsatellite unstable endometrial cancers (ECs). This study investigated the JAK1 mutation frequency, its functional implication in immune evasion and its prognostic significance in microsatellite unstable EC. Microsatellite instability and three microsatellite repeats within JAK1 were analyzed in 181 ECs. Sixty-two (34%) ECs showed microsatellite instability, of which 22 (35%) had a JAK1 mutation. LMP7, TAP1 and HLA class I protein expression and the presence of CD8-positive T-cells were analyzed in the microsatellite unstable ECs. JAK1 mutant microsatellite unstable ECs showed impaired upregulation of LMP7 (P=0.074) and HLA class I (P<0.001), validated using RNAseq data of the TCGA. TAP1 expression and presence of CD8-positive T-cells were not related to JAK1 mutations. In 198 additional microsatellite unstable ECs, the JAK1 mutation frequency was confirmed but no prognostic significance was found. For, JAK1 wildtype (n=135, 72%) and mutant (n=52, 28%) ECs, 10-year recurrence free rates were 84% and 77% (P=0.301). These observations show that JAK1 mutations are highly frequent in microsatellite unstable EC, not associated with survival, but are associated with impaired upregulation of LMP7 and HLA class I and may therefore facilitate immune escape.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Stelloo
authors.affiliation: Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Versluis
authors.affiliation: Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: de Bruyn
authors.affiliation: Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Annechien
authors.initials: A
authors.lastname: Plat
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Osse
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Reinhardt H
authors.initials: RH
authors.lastname: van Dijk
authors.affiliation: Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Remi A
authors.initials: RA
authors.lastname: Nout
authors.affiliation: Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Carien L
authors.initials: CL
authors.lastname: Creutzberg
authors.affiliation: Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Geertruida H
authors.initials: GH
authors.lastname: de Bock
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Smit
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tjalling
authors.initials: T
authors.lastname: Bosse
authors.affiliation: Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
mesh_terms: D000368:Aged; D017951:Antigen Presentation; D015331:Cohort Studies; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics*; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017423:Sequence Analysis, RNA
chemical_list: D004273:DNA, Neoplasm; D015395:Histocompatibility Antigens Class I; C507904:JAK1 protein, human; D053613:Janus Kinase 1; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex
keywords: HLA class I; JAK1; antigen presentation machinery; endometrial cancer; microsatellite instability