BackgroundSince its discovery almost three decades ago, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway has paved the road for understanding inflammatory and immunity processes related to a wide range of human pathologies including cancer. Several studies have demonstrated the importance of JAK-STAT pathway components in regulating tumor initiation and metastatic progression, yet, the extent of how genetic alterations influence patient outcome is far from being understood.MethodsFocusing on 133 genes involved in JAK-STAT signaling, we investigated genomic, transcriptomic and clinical profiles of over 18,000 patients representing 21 diverse cancer types. We identified a core set of 28 putative gain- or loss-of-function JAK-STAT genes that correlated with survival outcomes using Cox proportional hazards regression and Kaplan-Meier analyses. Differential expression analyses between high- and low-expressing patient groups were performed to evaluate the consequences of JAK-STAT misexpression.ResultsWe found that copy number alterations underpinning transcriptional dysregulation of JAK-STAT pathway genes differ within and between cancer types. Integrated analyses uniting genomic and transcriptomic datasets revealed a core set of JAK-STAT pathway genes that correlated with survival outcomes in brain, renal, lung and endometrial cancers. High JAK-STAT scores were associated with increased mortality rates in brain and renal cancers, but not in lung and endometrial cancers where hyperactive JAK-STAT signaling is a positive prognostic factor. Patients with aberrant JAK-STAT signaling demonstrated pan-cancer molecular features associated with misexpression of genes in other oncogenic pathways (Wnt, MAPK, TGF-β, PPAR and VEGF). Brain and renal tumors with hyperactive JAK-STAT signaling had increased regulatory T cell gene (Treg) expression. A combined model uniting JAK-STAT and Tregs allowed further delineation of risk groups where patients with high JAK-STAT and Treg scores consistently performed the worst.ConclusionProviding a pan-cancer perspective of clinically-relevant JAK-STAT alterations, this study could serve as a framework for future research investigating anti-tumor immunity using combination therapy involving JAK-STAT and immune checkpoint inhibitors.

中文翻译：

---

通过 JAK-STAT 信号成分的临床相关泛癌基因组和转录组改变的免疫逃避策略

背景自从近三十年前被发现以来，Janus 激酶 (JAK) 信号转导和转录激活因子 (STAT) 通路为了解与包括癌症在内的多种人类病理相关的炎症和免疫过程铺平了道路。多项研究已经证明 JAK-STAT 通路成分在调节肿瘤发生和转移进展中的重要性，然而，基因改变如何影响患者结果的程度尚不清楚。方法我们以参与 JAK-STAT 信号传导的 133 个基因为重点，进行了研究代表 21 种不同癌症类型的 18,000 多名患者的基因组、转录组和临床概况。我们使用 Cox 比例风险回归和 Kaplan-Meier 分析确定了一组 28 个假定的功能获得或丧失功能的 JAK-STAT 基因，这些基因与生存结果相关。对高表达和低表达患者组之间的差异表达分析进行评估，以评估 JAK-STAT 错误表达的后果。结果我们发现，支持 JAK-STAT 通路基因转录失调的拷贝数变化在癌症类型内和癌症类型之间存在差异。结合基因组和转录组数据集的综合分析揭示了一组核心 JAK-STAT 通路基因，这些基因与脑癌、肾癌、肺癌和子宫内膜癌的生存结果相关。高 JAK-STAT 评分与脑癌和肾癌死亡率增加相关，但与肺癌和子宫内膜癌无关，而在肺癌和子宫内膜癌中，过度活跃的 JAK-STAT 信号是积极的预后因素。JAK-STAT 信号传导异常的患者表现出与其他致癌途径（Wnt、MAPK、TGF-β、PPAR 和 VEGF）基因错误表达相关的泛癌分子特征。JAK-STAT 信号传导过度活跃的脑和肾肿瘤的调节性 T 细胞基因 (Treg) 表达增加。JAK-STAT 和 Tregs 的组合模型可以进一步划分风险组，其中 JAK-STAT 和 Treg 评分高的患者始终表现最差。 结论 本研究提供了临床相关 JAK-STAT 改变的全癌症视角，可以作为未来研究使用 JAK-STAT 和免疫检查点抑制剂联合疗法研究抗肿瘤免疫的框架。