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.
Highlights
About 30% of endometrial cancers, predominantly of endometrioid histology, can be molecularly characterized by microsatellite instability (MSI)
The functional implication of JAK1 in tumor immune evasion was analyzed by expression analysis of TAP1, LMP7, HLA class I and presence of CD8positive T-cells in the MSI endometrial cancers (Table 2)
JAK1 mutations were associated with impaired upregulation of antigen presenting machinery proteins LMP7 and HLA class I
Summary
About 30% of endometrial cancers, predominantly of endometrioid histology, can be molecularly characterized by microsatellite instability (MSI). MSI is a hypermutable phenotype caused by the loss of DNA mismatch repair (MMR) activity mostly due to sporadic MLH1 promoter hypermethylation [1]. Tumors that exhibit this phenotype have numerous insertions and deletions in coding microsatellites causing frameshift mutations and loss of protein function. The coding microsatellite-containing genes frequently affected by MSI are believed to be involved in progression of MSI tumors [2] Some target genes, such as BAX, are altered in diverse MSI tumor types (e.g. colorectal- and ovarian cancer), whereas others, such as JAK1, have a very restricted occurrence in MSI endometrial cancers [3,4,5,6]. MSI endometrial cancers show a remarkably high number of JAK1 frameshift mutations that may have clinical implications [4, 5]
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