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

Yashoda Ghanekar,Subhashini Sadasivam

doi:10.7717/peerj.6402

Abstract

BackgroundSequencing 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.ResultsDifferential 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.ConclusionsThese 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.

Highlights

Exome sequencing, RNA-sequencing, and copy number variation analysis of different cancers have revealed a cornucopia of disease-relevant mutations and altered pathways (Cancer Genome Atlas Research Network et al, 2013b)
Since all the Head and Neck Squamous cell Carcinomas (HNSCs) cases carrying CASP8 mutations were HPV-negative, and were from specific sites within the oral cavity, HNSCs carrying wild-type-CASP8 that were HPV-negative and from these same sites were selected as controls for all subsequent analyses
In contrast to HNSCs, Caspase-8 pathway can be explored to identify potential drug targets in Uterine Corpus Endometrial Carcinoma (UCEC). In this in silico study, we explore the implications of CASP8 mutations that have been identified across carcinomas through large-scale genomic studies

Summary

Introduction

RNA-sequencing, and copy number variation analysis of different cancers have revealed a cornucopia of disease-relevant mutations and altered pathways (Cancer Genome Atlas Research Network et al, 2013b). 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. CASP8 is a protease required for the extrinsic pathway of apoptosis and is 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. These results suggested that carcinomas with mutant CASP8 have broadly similar immune signatures albeit with different effects on survival. 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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