Abstract 11: APOBEC is a major source of mutations in head and neck squamous cell carcinoma

Background: Cancers arise from an accumulation of somatic mutations. Numerous intrinsic and extrinsic mutagenic sources exist, yet our understanding of which processes are active in a given cancer genome is limited. Specific mutagenic processes have mutational preferences, called signatures. Large-scale analyses of cancer genomes/exomes from The Cancer Genome Atlas (TCGA) have identified 30 unique signatures. APOBEC is a family of cytosine deaminases which function in the immune response to viral infection. A signature for APOBEC3 activity has been identified in a subset of cancers, including head and neck squamous cell carcinoma (HNSCC). The specifics of APOBEC activity in HNSCC remain poorly understood.

Methods: We utilized bioinformatic approaches to explore the role of APOBEC mutations in tumor exomes, transcriptomes and germline exomes from 511 HNSCC patients in TCGA.

Results: 58% of HNSCC are statically enriched for the APOBEC3 signature compared to all other cancers in TCGA. HPV+ HNSCC are statistically enriched for the APOBEC3 signature compared to HPV- samples (p < 0.0013). MutSig was used to test the prevalence of APOBEC3 mutations in known driver genes compared to passengers. While the mean rate of APOBEC3 mutations was similar between MuSig genes and all other genes (19.4% vs 21.9%), PIK3CA demonstrated a 20-fold increase above all other genes. When evaluated by HPV status, 87% of PIK3CA mutations in HPV+ samples were APOBEC3 mutations compared to 55% of mutations in HPV- samples (p <0.025). All APOBEC3 mutations in HPV + samples occurred at two known hotspots, while HPV- mutations were distributed throughout the gene, strongly arguing against a random occurrence in HPV+ samples. Isoform analysis revealed a slight predominance of APOBEC3A mutations compared to other APOBEC3 isoforms. RNA-Seq analysis of 511 transcriptomes showed a weak correlation between APOBEC3 mutation rates and APOBEC3 expression. RNA-Seq Pathway Analysis demonstrated an overrepresentation of immune pathway dysregulation in APOBEC3 mutation rich samples.

Conclusions: APOBEC3 is a major source of mutations in HNSCC. HPV+ HNSCC have the highest enrichment of APOBEC3 mutations. APOBEC3 mutations are strongly overrepresented in PIK3CA at two known hotspots, suggesting these mutations are of functional importance. APOBEC3A is the most likely APOBEC to be active in HPV+ HNSCC; however, expression levels of APOBEC isoforms do not correlate well with APOBEC mutational rates, suggesting a temporal dissonance between enzyme activity and tumor sample harvest. APOBEC3 activity appears to correlate with upregulation of immune signaling pathways, supporting the hypothesis that APOBEC is acting as part of the innate response to viral infection, although its activity in HPV- cancer suggests other mechanisms of upregulation as well.

Citation Format: Daniel L. Faden, Sean Thomas, Jeffrey Myers, Nishant Agrawal, Joseph DeRisi. APOBEC is a major source of mutations in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 11.