CASP8

Overview

CASP8 (Caspase-8) is a key initiator caspase in the extrinsic apoptosis pathway, activated by death receptor signaling (e.g., FAS/FASL, TRAIL). Somatic mutations in CASP8 impair apoptotic signaling, conferring a survival advantage to tumor cells. CASP8 is among the significantly mutated genes identified in head and neck squamous cell carcinoma (HNSCC) by large-scale whole-exome sequencing.

Alterations observed in the corpus

  • CASP8 mutated in 8% of HNSCC tumors by whole-exome sequencing of 74 tumor-normal pairs; identified by MutSig analysis as a significantly mutated gene associated with apoptosis suppression (Broad Institute cohort, hnsc_broad) PMID:21798893
  • CASP8 mutations identified in breast cancer WES of 100 tumors, implicating apoptotic pathway disruption in breast tumorigenesis PMID:22722201
  • Mutated in 10% (4/40) of oral squamous cell carcinoma (OSCC); nonsense/splice/frameshift mutations consistent with loss-of-function; defines a molecular subtype with fewer CNAs and co-occurring HRAS mutations; CASP8 loss promotes aggressive xenograft phenotype PMID:23619168
  • Mutated in 23.1% of cSCC (differentiation-related); significant driver in cutaneous squamous cell carcinoma PMID:25303977
  • Clustered missense and inactivating mutations in 9% of HNSCC (279-tumor TCGA cohort; 92% of mutations in oral cavity); anti-correlated with 11q13 amplification; co-mutated with HRAS in M-class oral-cavity subset PMID:25631445
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Cancer types (linked)

  • HNSC: CASP8 somatic mutation rate of 8% in whole-exome sequencing cohort (n=74 tumor-normal pairs); functional consequence is suppression of extrinsic apoptosis pathway PMID:21798893

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • CASP8 inactivation may contribute to resistance to apoptosis-inducing therapies including TRAIL-based agents; no specific therapeutic strategies targeting CASP8-mutant HNSCC reported in this study.

Open questions

  • Specific mutation types in CASP8 (missense, truncating, splice) were not detailed in this study; functional consequences of individual mutations remain uncharacterized.

Sources

  • PMID:21798893 — The Mutational Landscape of Head and Neck Squamous Cell Carcinoma (Stransky et al., Science 2011)

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