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An immunoevasive strategy through clinically-relevant pan-cancer genomic and transcriptomic alterations of JAK-STAT signaling components.

ABSTRACT: 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.

SUBMITTER: Chang WH

PROVIDER: S-EPMC6829980 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell leukemia. Recent studies detected genomic aberrations affecting JAK and STAT genes in T-PLL. Due to the limited number of primary patient samples available, genomic analyses of the JAK/STAT pathway have been performed in rather small cohorts. Therefore, we conducted-via a primary-data based pipeline-a meta-analysis that re-evaluated the genomic landscape of T-PLL. It included all available data sets with sequence information on JAK or STAT gene loci in 275 T-PLL. We eliminated overlapping cases and determined a cumulative rate of 62.1% of cases with mutated JAK or STAT genes. Most frequently, JAK1 (6.3%), JAK3 (36.4%), and STAT5B (18.8%) carried somatic single-nucleotide variants (SNVs), with missense mutations in the SH2 or pseudokinase domains as most prevalent. Importantly, these lesions were predominantly subclonal. We did not detect any strong association between mutations of a JAK or STAT gene with clinical characteristics. Irrespective of the presence of gain-of-function (GOF) SNVs, basal phosphorylation of STAT5B was elevated in all analyzed T-PLL. Fittingly, a significant proportion of genes encoding for potential negative regulators of STAT5B showed genomic losses (in 71.4% of T-PLL in total, in 68.4% of T-PLL without any JAK or STAT mutations). They included DUSP4, CD45, TCPTP, SHP1, SOCS1, SOCS3, and HDAC9. Overall, considering such losses of negative regulators and the GOF mutations in JAK and STAT genes, a total of 89.8% of T-PLL revealed a genomic aberration potentially explaining enhanced STAT5B activity. In essence, we present a comprehensive meta-analysis on the highly prevalent genomic lesions that affect genes encoding JAK/STAT signaling components. This provides an overview of possible modes of activation of this pathway in a large cohort of T-PLL. In light of new advances in JAK/STAT inhibitor development, we also outline translational contexts for harnessing active JAK/STAT signaling, which has emerged as a 'secondary' hallmark of T-PLL.

Project description:BackgroundMost seasonally circulating enteroviruses result in asymptomatic or mildly symptomatic infections. In rare cases, however, infection with some subtypes can result in paralysis or death. Of the 300 subtypes known, only poliovirus is reportable, limiting our understanding of the distribution of other enteroviruses that can cause clinical disease.ObjectiveThe overarching objectives of this study were to: 1) describe the distribution of enteroviruses in Arizona during the late summer and fall of 2022, the time of year when they are thought to be most abundant, and 2) demonstrate the utility of viral pan-assay approaches for semi-agnostic discovery that can be followed up by more targeted assays and phylogenomics.MethodsThis study utilizes pooled nasal samples collected from school-aged children and long-term care facility residents, and wastewater from multiple locations in Arizona during July-October of 2022. We used PCR to amplify and sequence a region common to all enteroviruses, followed by species-level bioinformatic characterization using the QIIME 2 platform. For Enterovirus-D68 (EV-D68), detection was carried out using RT-qPCR, followed by confirmation using near-complete whole EV-D68 genome sequencing using a newly designed tiled amplicon approach.ResultsIn the late summer and early fall of 2022, multiple enterovirus species were identified in Arizona wastewater, with Coxsackievirus A6, EV-D68, and Coxsackievirus A19 composing 86% of the characterized reads sequenced. While EV-D68 was not identified in pooled human nasal samples, and the only reported acute flaccid myelitis case in Arizona did not test positive for the virus, an in-depth analysis of EV-D68 in wastewater revealed that the virus was circulating from August through mid-October. A phylogenetic analysis on this relatively limited dataset revealed just a few importations into the state, with a single clade indicating local circulation.SignificanceThis study further supports the utility of wastewater-based epidemiology to identify potential public health threats. Our further investigations into EV-D68 shows how these data might help inform healthcare diagnoses for children presenting with concerning neurological symptoms.

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An immunoevasive strategy through clinically-relevant pan-cancer genomic and transcriptomic alterations of JAK-STAT signaling components.

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