In Silico Analysis Reveals a Shared Immune Signature in CASP8-Mutated Carcinomas with Varying Correlations to Prognosis

Abstract

Background: Sequencing studies across multiple cancers continue to reveal the spectrum of 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 type where about 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 bioinformatics approaches to mine data in The Cancer Genome Atlas, we compared the molecular features and survival of these carcinomas with and without CASP8 mutations. Results:Our in silico analyses showed that HNSCs with CASP8 mutations displayed a prominent signature of genes involved in immune response and inflammation, and were rich in immune cell infiltrates. However, in contrast to Human Papilloma Virus-positive HNSCs, a subtype that exhibits high immune cell infiltration and better overall survival, HNSC patients with mutant-CASP8 tumors did not display any survival advantage. A similar bioinformatic analyses in UCECs revealed that while UCECs with CASP8 mutations also displayed an immune signature, they had better overall survival, in contrast to the HNSC scenario. On further examination, we found that there was significant up-regulation of neutrophils as well as the cytokine, IL33 in mutant-CASP8 HNSCs, both of 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, which is a well-known negative prognosticator in HNSCs, and/or high IL33 levels may be some of the factors affecting survival of mutant-CASP8 cases.3

Identification of key factors shaping integrated levels of ACE2 and TMPRSS2 expression in head and neck squamous cell carcinoma

“…CASP8 is a protease involved in the extrinsic apoptotic pathway and also a negative modulator of programmed cell necrosis [63]. Mutant CASP8 HNSCs had distinctive characteristics of genes associated with inflammation and the immune response and were rich in immune cell infiltration [64]. It has been reported that inactivating mutations of NSD1 define an HNSC intrinsic subtype with significant DNA hypomethylation [65].…”

Bioinformatic Profiling Identifies Prognosis-Related Genes in the Immune Microenvironment of Endometrial Carcinoma

“…Great progresses have been attained in the past few years, making it possible to recognize novel molecular therapeutic targets within the microenvironment of EC [12]. At the same time, several immune-related factors have been identi ed to predict patient prognosis, which emphasizes the signi cance of certain immune status on EC outcomes [13]. Nonetheless, the vast majority of existing studies are pre-clinical basic experiments or have limited available clinical information, while study with a large sample size has not been carried out so far [14].…”