Integrative genomic and functional analysis of human oral squamous cell carcinoma cell lines reveals synergistic effects of FAT1 and CASP8 inactivation

Hayes, Tyler F.; Benaich, Nathan; Goldie, Stephen J.; Sipilä, Kalle; Ames-Draycott, Ashley; Cai, Wenjun; Yin, Guangliang; Watt, Fiona M.

doi:10.1016/j.canlet.2016.09.014

Cited by 42 publications

(45 citation statements)

References 33 publications

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“…As the most compelling novel driver gene for penile cancer, caspase 8 is an apoptosis‐inducing cysteine protease that is activated through the formation of a death‐inducing signaling complex when death receptors are complexed to their specific ligands, such as TRAIL, TNF‐α and Fas. Previous studies showed that CASP8 has been implicated in cancer risk in relation to multiple other cancers, including oral squamous cell carcinoma . In this study, the function of CASP8 has been further confirmed to be closely related to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…The experiment was repeated three times **p < 0.01, ****p < 0.0001. ligands, such as TRAIL, TNF-α and Fas. Previous studies showed that CASP8 has been implicated in cancer risk in relation to multiple other cancers, 33,34 including oral squamous cell carcinoma. 34 In this study, the function of CASP8 has been further confirmed to be closely related to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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Mutational landscape of penile squamous cell carcinoma in a Chinese population

Wang

Chen

et al. 2019

Intl Journal of Cancer

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Penile squamous cell carcinoma (PSCC) is a malignancy that affects the skin and tissues of the penis, but the knowledge of pathogenesis and carcinogenesis is limited. Here, we characterize the PSCC genomic landscape using whole‐exome sequencing. Of the 30 paired blood and tumor samples, we identified recurrent mutations in 11 genes; confirmed previous findings for FAT1 (4/30), HRAS (4/30), NOTCH1 (4/30), TP53 (3/30) and PIK3CA (3/30); and revealed novel candidate driver genes [CASP8 (4/30), SLITRK2 (3/30), FLG (3/30) and TRRAP (3/30)]. Our in vitro experiments suggested CASP8 was involved in mediating TRAIL‐induced apoptosis of penile cancer cell lines. We also observed the frequently altered pathways for potential therapeutic implications: alterations in the Notch (30% of sample altered), RTK–RAS (26.7% altered) and Hippo (23.3% altered) pathways accounted for over 50% of tumors. The frequently altered genes (>10%) in these pathways were proved to be expressed in penile tumors by immunohistochemistry assay. These findings provide new insight into the mutational and pathway landscapes of PSCC and suggest potential novel therapeutic opportunities for this malignancy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mutational landscape of penile squamous cell carcinoma in a Chinese population

Wang

Chen

et al. 2019

Intl Journal of Cancer

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“…We are particularly interested in the heterogeneous group of Head and Neck Squamous cell Carcinomas (HNSCs) as these account for a large number of mortalities each year in the Indian subcontinent (2,3). Multiple exome sequencing studies have revealed the landscape of recurrent somatic mutations in HNSCs and its prevalent subtype of Oral Squamous Cell Carcinomas (OSCCs) (4)(5)(6)(7)(8). While TP53 was the most significant recurrently mutated gene in this cancer type, several other genes such as CASP8, FAT1, and NOTCH1 were also unearthed as significantly recurrently mutated by these large-scale sequencing studies.…”

Section: Introductionmentioning

confidence: 99%

“…Barring TP53, the roles of these genes in oral epithelium homeostasis, and how this is altered owing to their mutation in cancer remain to be fully elucidated (9). In this study, we chose to focus on the CASP8 gene, which is mutated in ~10% of all HNSC cases, and more specifically in 34% of cases with OSCC of the gingiva-buccal sulcus (OSCC-GB), the subtype that accounts for the majority of HNSC cases in the Indian subcontinent (4,7,8). The types of mutations in CASP8 reported in these HNSC cases included loss of function due to frameshift, nonsense mutation or splice mutation as well as missense and deletion mutations.…”

Section: Introductionmentioning

confidence: 99%

Peer Review #2 of "In silico analysis reveals a shared immune signature in CASP8-mutated carcinomas with varying correlations to prognosis (v0.2)"

2019

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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 upregulation 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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“…We are particularly interested in the heterogeneous group of Head and Neck Squamous cell Carcinomas (HNSCs) as these account for a large number of mortalities each year in the Indian subcontinent. Multiple exome sequencing studies have revealed the landscape of recurrent somatic mutations in HNSCs and its prevalent subtype of Oral Squamous Cell Carcinomas (OSCCs) [1][2][3][4][5]. While TP53 was the most significant recurrently mutated gene in this cancer type, several other genes such as CASP8, FAT1, and NOTCH1 were also unearthed as significantly recurrently mutated by these large-scale sequencing studies.…”

Section: Introductionmentioning

confidence: 99%

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

Ghanekar

Sadasivam

2018

Preprint

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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

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Integrative genomic and functional analysis of human oral squamous cell carcinoma cell lines reveals synergistic effects of FAT1 and CASP8 inactivation

Cited by 42 publications

References 33 publications

Mutational landscape of penile squamous cell carcinoma in a Chinese population

Mutational landscape of penile squamous cell carcinoma in a Chinese population

Peer Review #2 of "In silico analysis reveals a shared immune signature in CASP8-mutated carcinomas with varying correlations to prognosis (v0.2)"

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

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