Multi-modality analysis supports APOBEC as a major source of mutations in head and neck squamous cell carcinoma

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• The specific mutagenic processes driving head and neck squamous cell carcinoma (HNSCC) are not fully understood.
• APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) signatures, linked to cytosine deaminase activity, are observed in some HNSCC cases, but their precise role is unclear.

Purpose of the Study:

• To investigate the role of APOBEC activity in the pathogenesis of head and neck squamous cell carcinoma.
• To determine the prevalence and specific APOBEC gene involvement in HNSCC mutational landscape.

Main Methods:

• Bioinformatic analysis of tumor exomes, transcriptomes, and germline exomes from 511 HNSCC patients.
• Statistical enrichment analysis for APOBEC mutational signatures.
• Gene expression correlation and motif analysis to identify active APOBEC genes.
• Canonical pathway analysis to assess the impact of APOBEC activity on cellular pathways.

Main Results:

• APOBEC signatures were statistically enriched in 58% of HNSCC cases.
• APOBEC3A expression showed the strongest correlation with the APOBEC mutation rate.
• Immune signaling pathways were upregulated in HNSCC samples with high APOBEC enrichment.
• Overall mutational burden positively correlated with APOBEC enrichment.

Conclusions:

• APOBEC-mediated mutations are highly prevalent in HNSCC.
• APOBEC3A is likely the predominant active APOBEC gene in HPV-positive HNSCC.
• APOBEC activity correlates with immune pathway upregulation, potentially indicating activation as part of the innate immune response.