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Loss of function JAK1 mutations occur at high frequency in cancers with microsatellite instability and are suggestive of immune evasion. | LitMetric

AI Article Synopsis

  • - Immune evasion is a key feature of cancer, and higher mutation burdens in tumors can trigger stronger immune responses; researchers studied the JAK family of kinases to investigate mutations linked to immune evasion in these tumors.
  • - A comprehensive analysis of 61,704 solid tumors revealed that recurrent frameshift mutations in JAK1 were prevalent in high mutation burden and microsatellite unstable tumors, particularly in types like endometrial and colorectal cancers.
  • - The study concluded that JAK1 mutations reduce interferon response and anti-tumor immune activities, suggesting that JAK1 loss of function plays a role in helping tumors escape immune detection across various cancer types.

Article Abstract

Immune evasion is a well-recognized hallmark of cancer and recent studies with immunotherapy agents have suggested that tumors with increased numbers of neoantigens elicit greater immune responses. We hypothesized that the immune system presents a common selective pressure on high mutation burden tumors and therefore immune evasion mutations would be enriched in high mutation burden tumors. The JAK family of kinases is required for the signaling of a host of immune modulators in tumor, stromal, and immune cells. Therefore, we analyzed alterations in this family for the hypothesized signature of an immune evasion mutation. Here, we searched a database of 61,704 unique solid tumors for alterations in the JAK family kinases (JAK1/2/3, TYK2). We used The Cancer Genome Atlas and Cancer Cell Line Encyclopedia data to confirm and extend our findings by analyzing gene expression patterns. Recurrent frameshift mutations in JAK1 were associated with high mutation burden and microsatellite instability. These mutations occurred in multiple tumor types including endometrial, colorectal, stomach, and prostate carcinomas. Analyzing gene expression signatures in endometrial and stomach adenocarcinomas revealed that tumors with a JAK1 frameshift exhibited reduced expression of interferon response signatures and multiple anti-tumor immune signatures. Importantly, endometrial cancer cell lines exhibited similar gene expression changes that were expected to be tumor cell intrinsic (e.g. interferon response) but not those expected to be tumor cell extrinsic (e.g. NK cells). From these data, we derive two primary conclusions: 1) JAK1 frameshifts are loss of function alterations that represent a potential pan-cancer adaptation to immune responses against tumors with microsatellite instability; 2) The mechanism by which JAK1 loss of function contributes to tumor immune evasion is likely associated with loss of the JAK1-mediated interferon response.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679612PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176181PLOS

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