Abstract
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.
Highlights
Since 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
Our study identifies a core set of candidate JAK-STAT drivers that correlated with tumor progression and that predict overall survival outcomes in brain, renal, lung and endometrial cancers converging on similar downstream oncogenic pathways
The following is a list of cancer cohorts and corresponding The Cancer Genome Atlas (TCGA) abbreviations in parentheses: bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), glioma (GBMLGG), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), pan-kidney cohort (KIPAN), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), pancreatic adenocarcinoma (PAAD), sarcoma (SARC), stomach adenocarcinoma (STAD), stomach and esophageal carcinoma (STES) and uterine corpus endometrial carcinoma (UCEC)
Summary
Since 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 JAKSTAT pathway components in regulating tumor initiation and metastatic progression, yet, the extent of how genetic alterations influence patient outcome is far from being understood. In their quest to survive and prosper, tumor cells are armored with a unique ability to manipulate the host’s immune system and promote pro-inflammatory pathways. Inflammation can both initiate and stimulate cancer progression, and in turn, tumor cells can create an inflammatory microenvironment to sustain their growth further (Mantovani et al, 2008; Trinchieri, 2012). In cancers associated with chronic inflammation such as liver and colorectal cancers (Grivennikov et al, 2009; Park et al, 2010), STAT3 activation by growth factors or interleukins suppresses T cell activation and promotes the recruitment of anti-immunity factors such as myeloid-derived suppressor cells and regulatory T cells (Poschke et al, 2010; Tartour et al, 2011)
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