The Mutational Landscape of Recurrent vs Non-Recurrent Human Papillomavirus-Associated Oropharyngeal Cancer

Thesis (Master's)--University of Washington, 2017-12Current therapies are effective for a subset of human papillomavirus (HPV)-associated head and neck cancers (HNC), although up to a quarter of these cases fail treatment. Identification of genomic alterations associated with therapeutic response or lack thereof from the outset of treatment would have substantial clinical implications. We hypothesized that HPV-related oropharyngeal squamous cell carcinoma (OPSCC) that recur share similar genomic features to HPV-unrelated HNC, a clinically aggressive phenotype. Data on 57 cases of HPV-related primary OPSCC tumors from three sources, of which 38 did not recur and 19 recurred, were included in the analyses of recurrence. KMT2D, a histone H3 lysine 4 methyltransferase, was the most frequently mutated gene across tumors (16%) and among the recurrent cases (21%). DNA damage response and MAPK genes had the strongest association with recurrence (Multivariable Prevalence Ratio (PR) (95% CI): 1.22 (0.88 – 1.68) and 1.23 (0.89 – 1.70)). Gene mutations and/or copy number aberrations with the strongest association with recurrence in multivariable analyses included CASP8 (PR (95% CI): 3.83 (1.06 – 13.8)), NSD1 (PR (95% CI): 2.34 (0.98 – 5.60)), and PEG3 (PR (95% CI): 3.10 (1.04 – 9.16)). These data suggest that frequently altered genes involved in HPV-unrelated HNC tumorigenesis may play a key role in recurrence in HPV-related OPSCC