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Published on: September 9, 2021
An immunoevasive strategy through clinically-relevant pan-cancer genomic and transcriptomic alterations of JAK-STAT
Wai Hoong Chang1, Alvina G Lai2
1Institute of Health Informatics, University College London, 222 Euston Road, London, NW1 2DA, UK.
Background:
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 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.
Methods:
Focusing 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.
Results:
We 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.
Conclusion:
Providing 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.
Insights
Genetic alterations in the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway impact cancer patient outcomes. This study identifies key JAK-STAT genes linked to survival across 21 cancer types, offering insights into targeted therapies.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is crucial for inflammatory and immunity processes, with implications in various human pathologies including cancer.
- While JAK-STAT pathway components are known to regulate tumor initiation and metastasis, the precise impact of genetic alterations on patient outcomes remains incompletely understood.
Purpose of the Study:
- To investigate the correlation between genetic alterations in JAK-STAT signaling pathway genes and patient survival across diverse cancer types.
- To identify a core set of JAK-STAT genes whose gain or loss of function influences clinical outcomes.
Main Methods:
- Genomic, transcriptomic, and clinical data from over 18,000 patients across 21 cancer types were analyzed, focusing on 133 JAK-STAT signaling genes.
- Cox proportional hazards regression and Kaplan-Meier analyses were employed to identify JAK-STAT genes associated with survival.
- Differential expression analyses were conducted to assess the consequences of JAK-STAT pathway misexpression.
Main Results:
- A core set of 28 JAK-STAT genes correlated with survival outcomes in specific cancers like brain, renal, lung, and endometrial types.
- High JAK-STAT scores indicated increased mortality in brain and renal cancers, but served as a positive prognostic factor in lung and endometrial cancers.
- Aberrant JAK-STAT signaling was linked to molecular features of other oncogenic pathways and increased regulatory T cell (Treg) expression in brain and renal tumors, with a combined JAK-STAT and Treg score predicting poor outcomes.
Conclusions:
- This pan-cancer analysis provides a comprehensive view of clinically relevant JAK-STAT alterations and their impact on patient survival.
- The findings suggest a framework for future research on anti-tumor immunity, potentially involving combination therapies with JAK-STAT inhibitors and immune checkpoint inhibitors.
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