Abstract 2288: APOBEC dominant mutational signature defines distinct oral cavity cancer subgroup

Abstract Background: Up to 25% of oral cavity squamous cell carcinoma (OCSCC) cases have no significant exposure to tobacco and alcohol. Compared to the rest of the OCSCC population, these cases tend to be older, more female, and display distinct patterns of oral cavity subsite dominance. The underlying molecular pathophysiology in atypical OCSCC cases remains poorly defined. We hypothesized that analysis of OCSCC genomes using single base substitution (SBS) mutational signatures, which computationally discern patterns associated with discrete mutational processes, would reveal discrete subgroups within the OCSCC population. Methods: We performed an exploratory genomics study using data from The Cancer Genome Atlas (TCGA). Cases included primary oral cavity tumors with whole exome sequencing data. Cases were excluded if oral cavity subsite was not specified or if the tumor had fewer than fifty single bases substitutions. SBS signatures were generated using python packages SigProfilerMatrixGenerator and SigProfilerAssignment with COSMIC SBS Signatures V3.4 as the reference. APOBEC-dominant cases were defined as those where SBS2 and SBS13 accounted for the greatest proportion of mutations relative to the tumor’s total mutational burden. Results: A total of 217 OCSCC cases were included. Of these, 135 (62.2%) showed some degree of ABPOEC-related mutational burden, and in 62 (28.6%) cases APOBEC was the dominant mutational process. APOBEC-dominant cases showed greater SBS mutational burden (median difference 2.65 mutations/MB, Wilcoxon P = 2.22e-09). Compared to the rest of the OCSCC population, APOBEC-dominant cases were older in age (mean difference 4.08 years, 95% CI 0.35 - 7.81, T-test P 0.032), more female (46.8% vs 27.8%, OR 2.28, 95% CI 1.18 - 4.40), and had a significantly lower rate of tobacco use at diagnosis (OR 0.47, 95% CI 0.22 - 0.94). APOBEC mutational burden varied by oral cavity subsite (Kruskal-Wallis P = 1.66e-05), with the majority of hard palate and buccal mucosal tumors being APOBEC-dominant (85.7% and 66.7%, respectively) and floor of mouth tumors showing the lowest rate of APOBEC-dominance (16.1%). APOBEC-dominant cases showed a greater degree of mutations in RAC1, EP300, CASP8, and FAT1 (FDR corrected P <0.05). APOBEC dominant cases showed a trend toward a lower rate of TP53 mutations (OR 0.48, 95% CI 0.23 - 1.01). Conclusions: In TCGA, ABPOEC-dominant OCSCC cases resemble these atypical populations by being enriched for female sex, older age, lower rates of tobacco use, and certain oral cavity subsites. However, APOBEC-dominance was not exclusive to any clinical characteristic, highlighting the potential importance of molecular class labels in understanding population heterogeneity in OCSCC. Further investigation focused on induction of APOBEC in OCSCC is warranted and may elucidate the pathophysiology of oral cavity cancer beyond tobacco and alcohol exposure. Citation Format: Benjamin M. Wahle, Angela L. Mazul, D. Neil Hayes, Jose P. Zevallos, Sidharth V. Puram. APOBEC dominant mutational signature defines distinct oral cavity cancer subgroup [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2288.