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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.

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