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Human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinomas (OPSCC), associated with improved patient outcome, exhibit increased expression of CDKN2A tumor suppressor p16(INK4a), while inactivation of the CDKN2A locus is frequently observed in HPV negative HNSCC. We recently identified a novel region of intragenic DNA hypermethylation within the CDKN2A locus that correlates with RNA expression of two CDKN2A transcripts and improved patient outcome in oropharyngeal and laryngeal SCC. Given the importance of CDKN2A expression in OPSCC, we chose an in vitro model using primary keratinocytes transduced with HPV-16 oncogenes E6 and E7 to study the relationship between CDKN2A methylation and expression. RNA levels for CDKN2A transcripts, p14(ARF) and p16(INK4a), and intragenic CDKN2A methylation were assessed in the primary cells and after transduction with E6 and E7 at two time points. CDKN2A expression increased early post-transduction, while there was a clear delay in intragenic methylation. Methylation eventually increased suggesting that intragenic methylation is not required for transcription at the CDKN2A locus, and that methylation may be a consequence of open and active chromatin.