Daniel L Faden1, Sean Thomas2, Paul G Cantalupo3, Nishant Agrawal4, Jeffrey Myers5, Joseph DeRisi6. 1. Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: DLFaden@gmail.com. 2. Gladstone Institute of Cardiovascular Disease, and Roddenberry Center for Stem Cell Biology and Medicine, Gladstone Institute, San Francisco, CA 94158 USA. 3. Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260 USA. 4. Division of Otolaryngology-Head and Neck Surgery, University of Chicago, Chicago, IL 60637 USA. 5. Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA. 6. Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
Abstract
OBJECTIVES: The mutagenic processes underlying head and neck squamous cell carcinoma (HNSCC) are poorly understood. Pan-cancer mutational signature analyses have identified a signature for APOBEC, a cytosine deaminase, in a subset of cancers, including HNSCC. The role of APOBEC activity in HNSCC remains poorly understood. Therefore, we sought to determine the role of APOBEC in HNSCC pathogenesis. MATERIAL AND METHODS: Utilizing bioinformatic approaches we explored the role of APOBEC mediated mutations in tumor exomes, transcriptomes and germline exomes from 511HNSCC patients in the TCGA. RESULTS: 58% of HNSCC were statistically enriched for the APOBEC signature. APOBEC3A expression had the highest correlation coefficient with APOBEC mutation rate. Gene specific motif analysis revealed a slight predominance of APOBEC3A mutations. Canonical pathway analysis demonstrated immune pathway upregulation in APOBEC mutation rich samples. Overall mutational burden was positively correlated with APOBEC enrichment. CONCLUSIONS: APOBEC mediated mutations are highly prevalent in HNSCC. APOBEC3A is the most likely gene to be active in HPV+ HNSCC. APOBEC activity correlates with upregulation of immune signaling pathways, supporting the hypothesis that APOBEC activity could be activated as part of the innate immune response.
OBJECTIVES: The mutagenic processes underlying head and neck squamous cell carcinoma (HNSCC) are poorly understood. Pan-cancer mutational signature analyses have identified a signature for APOBEC, a cytosine deaminase, in a subset of cancers, including HNSCC. The role of APOBEC activity in HNSCC remains poorly understood. Therefore, we sought to determine the role of APOBEC in HNSCC pathogenesis. MATERIAL AND METHODS: Utilizing bioinformatic approaches we explored the role of APOBEC mediated mutations in tumor exomes, transcriptomes and germline exomes from 511HNSCC patients in the TCGA. RESULTS: 58% of HNSCC were statistically enriched for the APOBEC signature. APOBEC3A expression had the highest correlation coefficient with APOBEC mutation rate. Gene specific motif analysis revealed a slight predominance of APOBEC3A mutations. Canonical pathway analysis demonstrated immune pathway upregulation in APOBEC mutation rich samples. Overall mutational burden was positively correlated with APOBEC enrichment. CONCLUSIONS: APOBEC mediated mutations are highly prevalent in HNSCC. APOBEC3A is the most likely gene to be active in HPV+ HNSCC. APOBEC activity correlates with upregulation of immune signaling pathways, supporting the hypothesis that APOBEC activity could be activated as part of the innate immune response.
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