Background: Despite the better prognosis for human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) compared to HPV-negative HNSCC, 10% to 25% of HPV-associated cases recur within 3 years of completing therapy. We sought to compare the mutational profiles of primary tumors among recurrent and non-recurrent HPV-associated HNSCC. We hypothesized that the mutational profile of primary tumors from recurrent cases resembles that of HPV-negative HNSCC.

Methods: Sequencing was performed on DNA extracted from the primary tumors of p16-positive recurrent and non-recurrent HNSCC cases utilizing a high-coverage (>500X), CLIA-certified, 262 multiplexed gene sequencing panel (i.e., UW OncoPlex). Primary tumors from 11 recurrent and 13 non-recurrent cases were included in our sample. Mutational differences between the primary tumors of recurrent and non-recurrent tumors were evaluated.

Results: 88% of patients were male with a mean (standard deviation; SD) age of 60.3 (11) years. Among the recurrent cases, 100% arose from the oropharynx. Among the non-recurrent cases, 77% arose from the oropharynx with the remainder originating from the oral cavity, nasal cavity, and larynx. 83% of patients presented with stage III or higher disease, and the median survival time was 21 months and 19 months among the recurrent and non-recurrent cases, respectively. The mean (SD) number of somatic nucleotide variants per tumor among the recurrent cases was 16.4 (12.2) compared to 4.3 (1.5) among non-recurrent cases (p < 0.05). The ratio of nonsynonymous to synonymous variants among primary tumors of recurrent cases was 2 vs 5 among the non-recurrent cases (p = 0.224). Among primary tumors of recurrent cases, 17% of variants included indels, splice site, and nonsense mutations vs 14% of variants among the non-recurrent cases. The mean (SD) number of tumor suppressor mutations per tumor was 1.2 (1.3) among recurrent cases vs 1.0 (1.0) among non-recurrent cases (p = 0.81). Interestingly, the mean (SD) number of mutations in DNA damage response (DDR) genes among the primary tumors of recurrent cases was 2.7 (2.4) compared to 0.7 (1.2) mutations per tumor among non-recurrent cases (p = 0.07).

Conclusion: We observed a greater mutational burden among the primary tumors of recurrent HPV-associated HNSCC compared to non-recurrent HNSCC. Moreover, among the primary tumors of recurrent cases, there were more mutations in DNA damage response genes coupled and relatively fewer deleterious mutations compared to non-recurrent cases. Dysregulation of DDR genes may select for advantageous mutations via genomic instability. Alternatively, gain of function of DDR genes may promote treatment resistance. Future work aims to further characterize mutational differences between the primary tumors of HPV-associated recurrent and non-recurrent HNSCC and evaluate mechanisms promoting treatment resistance.

Citation Format: Richard A. Harbison, Mark Kubik, Eric Q. Konnick, Seok-Geun Lee, Michael Kao, Michael Mason, Thomas Yu, Chang Xu, Daniel Faden, Colin C. Pritchard, Cristina P. Rodriguez, Chu Chen, Justin Guinney, Umamaheswar Duvvuri, Eduardo Mendez. The mutational landscape of recurrent and nonrecurrent human papillomavirus-associated head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2713. doi:10.1158/1538-7445.AM2017-2713