Microsatellite instability derivedJAK1frameshift mutations are associated with tumor immune evasion in endometrioid endometrial cancer

// Ellen Stelloo 1, * , Marco A. Versluis 2, * , Hans W. Nijman 2 , Marco de Bruyn 2 , Annechien Plat 2 , Elisabeth M. Osse 1 , Reinhardt H. van Dijk 1 , Remi A. Nout 3 , Carien L. Creutzberg 3 , Geertruida H. de Bock 4 , Vincent T. Smit 1 , Tjalling Bosse 1 , Harry Hollema 5 1 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands 2 Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, The Netherlands 3 Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands 4 Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 5 Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands * These authors have contributed equally to this work Correspondence to: Tjalling Bosse, email: T.Bosse@lumc.nl Keywords: JAK1, microsatellite instability, endometrial cancer, antigen presentation machinery, HLA class I Received: March 07, 2016     Accepted: April 26, 2016     Published: May 17, 2016 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.