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In silico analysis reveals a shared immune signature in CASP8-mutated carcinomas with varying correlations to prognosis

BACKGROUND: Sequencing studies across multiple cancers continue to reveal mutations and genes involved in the pathobiology of these cancers. Exome sequencing of oral cancers, a subset of Head and Neck Squamous cell Carcinomas (HNSCs) common among tobacco-chewing populations, revealed that ∼34% of th...

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Autores principales: Ghanekar, Yashoda, Sadasivam, Subhashini
Formato: Online Artículo Texto
Lenguaje:English
Publicado: PeerJ Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375258/
https://www.ncbi.nlm.nih.gov/pubmed/30775178
http://dx.doi.org/10.7717/peerj.6402
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author Ghanekar, Yashoda
Sadasivam, Subhashini
author_facet Ghanekar, Yashoda
Sadasivam, Subhashini
author_sort Ghanekar, Yashoda
collection PubMed
description BACKGROUND: Sequencing studies across multiple cancers continue to reveal mutations and genes involved in the pathobiology of these cancers. Exome sequencing of oral cancers, a subset of Head and Neck Squamous cell Carcinomas (HNSCs) common among tobacco-chewing populations, revealed that ∼34% of the affected patients harbor mutations in the CASP8 gene. Uterine Corpus Endometrial Carcinoma (UCEC) is another cancer where ∼10% cases harbor CASP8 mutations. Caspase-8, the protease encoded by CASP8 gene, plays a dual role in programmed cell death, which in turn has an important role in tumor cell death and drug resistance. CASP8 is a protease required for the extrinsic pathway of apoptosis and is also a negative regulator of necroptosis. Using multiple tools such as differential gene expression, gene set enrichment, gene ontology, in silico immune cell estimates, and survival analyses to mine data in The Cancer Genome Atlas, we compared the molecular features and survival of these carcinomas with and without CASP8 mutations. RESULTS: Differential gene expression followed by gene set enrichment analysis showed that HNSCs with CASP8 mutations displayed a prominent signature of genes involved in immune response and inflammation. Analysis of abundance estimates of immune cells in these tumors further revealed that mutant-CASP8 HNSCs were rich in immune cell infiltrates. However, in contrast to Human Papilloma Virus-positive HNSCs that also exhibit high immune cell infiltration, which in turn is correlated with better overall survival, HNSC patients with mutant-CASP8 tumors did not display any survival advantage. Similar analyses of UCECs revealed that while UCECs with CASP8 mutations also displayed an immune signature, they had better overall survival, in contrast to the HNSC scenario. There was also a significant up-regulation of neutrophils (p-value = 0.0001638) as well as high levels of IL33 mRNA (p-value = 7.63747E−08) in mutant-CASP8 HNSCs, which were not observed in mutant-CASP8 UCECs. CONCLUSIONS: These results suggested that carcinomas with mutant CASP8 have broadly similar immune signatures albeit with different effects on survival. We hypothesize that subtle tissue-dependent differences could influence survival by modifying the micro-environment of mutant-CASP8 carcinomas. High neutrophil numbers, a well-known negative prognosticator in HNSCs, and/or high IL33 levels may be some of the factors affecting survival of mutant-CASP8 cases.
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spelling pubmed-63752582019-02-15 In silico analysis reveals a shared immune signature in CASP8-mutated carcinomas with varying correlations to prognosis Ghanekar, Yashoda Sadasivam, Subhashini PeerJ Bioinformatics BACKGROUND: Sequencing studies across multiple cancers continue to reveal mutations and genes involved in the pathobiology of these cancers. Exome sequencing of oral cancers, a subset of Head and Neck Squamous cell Carcinomas (HNSCs) common among tobacco-chewing populations, revealed that ∼34% of the affected patients harbor mutations in the CASP8 gene. Uterine Corpus Endometrial Carcinoma (UCEC) is another cancer where ∼10% cases harbor CASP8 mutations. Caspase-8, the protease encoded by CASP8 gene, plays a dual role in programmed cell death, which in turn has an important role in tumor cell death and drug resistance. CASP8 is a protease required for the extrinsic pathway of apoptosis and is also a negative regulator of necroptosis. Using multiple tools such as differential gene expression, gene set enrichment, gene ontology, in silico immune cell estimates, and survival analyses to mine data in The Cancer Genome Atlas, we compared the molecular features and survival of these carcinomas with and without CASP8 mutations. RESULTS: Differential gene expression followed by gene set enrichment analysis showed that HNSCs with CASP8 mutations displayed a prominent signature of genes involved in immune response and inflammation. Analysis of abundance estimates of immune cells in these tumors further revealed that mutant-CASP8 HNSCs were rich in immune cell infiltrates. However, in contrast to Human Papilloma Virus-positive HNSCs that also exhibit high immune cell infiltration, which in turn is correlated with better overall survival, HNSC patients with mutant-CASP8 tumors did not display any survival advantage. Similar analyses of UCECs revealed that while UCECs with CASP8 mutations also displayed an immune signature, they had better overall survival, in contrast to the HNSC scenario. There was also a significant up-regulation of neutrophils (p-value = 0.0001638) as well as high levels of IL33 mRNA (p-value = 7.63747E−08) in mutant-CASP8 HNSCs, which were not observed in mutant-CASP8 UCECs. CONCLUSIONS: These results suggested that carcinomas with mutant CASP8 have broadly similar immune signatures albeit with different effects on survival. We hypothesize that subtle tissue-dependent differences could influence survival by modifying the micro-environment of mutant-CASP8 carcinomas. High neutrophil numbers, a well-known negative prognosticator in HNSCs, and/or high IL33 levels may be some of the factors affecting survival of mutant-CASP8 cases. PeerJ Inc. 2019-02-11 /pmc/articles/PMC6375258/ /pubmed/30775178 http://dx.doi.org/10.7717/peerj.6402 Text en ©2019 Ghanekar and Sadasivam http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.
spellingShingle Bioinformatics
Ghanekar, Yashoda
Sadasivam, Subhashini
In silico analysis reveals a shared immune signature in CASP8-mutated carcinomas with varying correlations to prognosis
title In silico analysis reveals a shared immune signature in CASP8-mutated carcinomas with varying correlations to prognosis
title_full In silico analysis reveals a shared immune signature in CASP8-mutated carcinomas with varying correlations to prognosis
title_fullStr In silico analysis reveals a shared immune signature in CASP8-mutated carcinomas with varying correlations to prognosis
title_full_unstemmed In silico analysis reveals a shared immune signature in CASP8-mutated carcinomas with varying correlations to prognosis
title_short In silico analysis reveals a shared immune signature in CASP8-mutated carcinomas with varying correlations to prognosis
title_sort in silico analysis reveals a shared immune signature in casp8-mutated carcinomas with varying correlations to prognosis
topic Bioinformatics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375258/
https://www.ncbi.nlm.nih.gov/pubmed/30775178
http://dx.doi.org/10.7717/peerj.6402
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