JAK1 truncating mutations in gynecologic cancer define new role of cancer-associated protein tyrosine kinase aberrations

Ren, Yuan; Zhang, Yonghong; Liu, Richard Z.; Fenstermacher, David; Wright, Kenneth L.; Teer, Jamie K.; Wu, Jie

doi:10.1038/srep03042

Cited by 55 publications

(69 citation statements)

References 29 publications

(42 reference statements)

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“…showed that JAK1 inhibition is associated with cell cycle arrest and apoptosis in colorectal cancer [25]. No effect on cell viability upon IFNγ was found in JAK1 mutant gynecological cell lines [10]. In conclusion, we confirmed the remarkably high frequency of JAK1 mutations and associations with impaired upregulation of antigen presenting machinery components in MSI endometrial cancers, which suggest a functional role for JAK1 in an intriguing tissue-specific manner.…”

Section: Discussionsupporting

confidence: 73%

“…Both studies also showed that JAK1 frameshift mutations in MSI tumors are tissue specific and significantly less important in colorectal cancers as compared with endometrial cancers. Similarly, Ren et al identified JAK1 frameshift mutations mainly in gynecological cancers, primarily in endometrial and cervical cancer, when sequencing more than 3,000 tumors from various human tissues [10]. Altogether, the occurrence of JAK1 mutation specifically in endometrial cancer is suggestive of a positive selection for this mutation in endometrial cancer.…”

Section: Discussionmentioning

confidence: 98%

“…An in vitro study with one endometrial cancer and two ovarian cancer cell lines harboring JAK1 frameshift mutations demonstrated that JAK1 mutations impede STAT1 posphorylation and upregulation of antigen presenting machinery components LMP2 and TAP1 [10]. Kim et al have shown that JAK1 mutations were associated with hampered JAK/STAT signaling and lymphocyte activation [4].…”

Section: Discussionmentioning

confidence: 99%

“…Ren et al have shown that JAK1 mutant gynecological cancer cell lines were defective in interferon gamma (IFNγ) induced STAT1 tyrosine phosphorylation and thereby impede upregulation of antigen processing machinery components such as LMP2 and TAP1 [10]. Impaired antigen processing and presentation due to hindered expression of LMP and/or TAP proteins are associated with lack of HLA class I upregulation and resistance to cytotoxic T-cell mediated lysis [11, 12].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…Gab1 was immunoprecipitated using Gab1 mouse antibody. Immunoblotting was performed as described previously [6, 30-32]. …”

Section: Methodsmentioning

confidence: 99%

Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma

et al. 2015

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Epidermal growth factor receptor (EGFR) mutants drive lung tumorigenesis and are targeted for therapy. However, resistance to EGFR inhibitors has been observed, in which the mutant EGFR remains active. Thus, it is important to uncover mediators of EGFR mutant-driven lung tumors to develop new treatment strategies. The protein tyrosine phosphatase (PTP) Shp2 mediates EGF signaling. Nevertheless, it is unclear if Shp2 is activated by oncogenic EGFR mutants in lung carcinoma or if inhibiting the Shp2 PTP activity can suppress EGFR mutant-induced lung adenocarcinoma. Here, we generated transgenic mice containing a doxycycline (Dox)-inducible PTP-defective Shp2 mutant (tetO-Shp2CSDA). Using the rat Clara cell secretory protein (CCSP)-rtTA-directed transgene expression in the type II lung pneumocytes of transgenic mice, we found that the Gab1-Shp2 pathway was activated by EGFRL858R in the lungs of transgenic mice. Consistently, the Gab1-Shp2 pathway was activated in human lung adenocarcinoma cells containing mutant EGFR. Importantly, Shp2CSDA inhibited EGFRL858R-induced lung adenocarcinoma in transgenic animals. Analysis of lung tissues showed that Shp2CSDA suppressed Gab1 tyrosine phosphorylation and Gab1-Shp2 association, suggesting that Shp2 modulates a positive feedback loop to regulate its own activity. These results show that inhibition of the Shp2 PTP activity impairs mutant EGFR signaling and suppresses EGFRL858R-driven lung adenocarcinoma.

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Discordant prognosis of mismatch repair deficiency in colorectal and endometrial cancer reflects variation in antitumour immune response and immune escape

Glaire

Ryan

Ijsselsteijn

et al. 2022

The Journal of Pathology

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Defective DNA mismatch repair (dMMR) causes elevated tumour mutational burden (TMB) and microsatellite instability (MSI) in multiple cancer types. dMMR/MSI colorectal cancers (CRCs) have enhanced T‐cell infiltrate and favourable outcome; however, this association has not been reliably detected in other tumour types, including endometrial cancer (EC). We sought to confirm this and explore the underpinning mechanisms. We first meta‐analysed CRC and EC trials that have examined the prognostic value of dMMR/MSI and confirmed that dMMR/MSI predicts better prognosis in CRC, but not EC, with statistically significant variation between cancers (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.54–0.73 versus HR = 1.15, 95% CI = 0.72–1.58; PINT = 0.02). Next, we studied intratumoural immune infiltrate in CRCs and ECs of defined MMR status and found that while dMMR was associated with increased density of tumour‐infiltrating CD3+ and CD8+ T‐cells in both cancer types, the increases were substantially greater in CRC and significant only in this group (PINT = 4.3e‐04 and 7.3e‐03, respectively). Analysis of CRC and EC from the independent Cancer Genome Atlas (TCGA) series revealed similar variation and significant interactions in proportions of tumour‐infiltrating lymphocytes, CD8+, CD4+, NK cells and immune checkpoint expression, confirming a more vigorous immune response to dMMR/MSI in CRC than EC. Agnostic analysis identified the IFNγ pathway activity as strongly upregulated by dMMR/MSI in CRC, but downregulated in EC by frequent JAK1 mutations, the impact of which on IFNγ response was confirmed by functional analyses. Collectively, our results confirm the discordant prognosis of dMMR/MSI in CRC and EC and suggest that this relates to differences in intratumoural immune infiltrate and tumour genome. Our study underscores the need for tissue‐specific analysis of cancer biomarkers and may help inform immunotherapy use. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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JAK1 truncating mutations in gynecologic cancer define new role of cancer-associated protein tyrosine kinase aberrations

Cited by 55 publications

References 29 publications

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

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

Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma

Discordant prognosis of mismatch repair deficiency in colorectal and endometrial cancer reflects variation in antitumour immune response and immune escape

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