Microsatellite instability derived JAK1 frameshift mutations are associated with tumor immune evasion in endometrioid endometrial cancer.

Autor:	Stelloo E; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., Versluis MA; Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, The Netherlands., Nijman HW; Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, The Netherlands., de Bruyn M; Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, The Netherlands., Plat A; Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, The Netherlands., Osse EM; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., van Dijk RH; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., Nout RA; Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands., Creutzberg CL; Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands., de Bock GH; Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Smit VT; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., Bosse T; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., Hollema H; Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2016 Jun 28; Vol. 7 (26), pp. 39885-39893.
DOI:	10.18632/oncotarget.9414
Abstrakt:	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. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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