Background: Head and neck cancers account for 5% of all cancer related deaths and present with complex molecular pathology and clinical features owing to their functional anatomical location. The molecular etiology of head and neck squamous cancer (HNSC) has gained extensive attention recently revealing key mutations, viral infection, and an emerging landscape of varying disease sub-types. While perineural invasion has long been associated with poor outcome in HNSC, the association of neurogenesis-related genes with cancer progression has only recently come into focus in HNSC. Using prospectively acquired patient samples and TCGA HNSC mutational analyses we further characterized the sequelae of molecular changes in neurogenesis-related genes and propose that these genes play a significant role in HNSC development.
Methods: All clinical specimens were collected under approval by Institutional Review Board. Prospectively collected samples were analyzed for HPV DNA by linear arrays (InnoLipa) and q-PCR for E7-RNA. Gene expression arrays were conducted to determine differences in HPV activity and neuronal associated gene ontologies (Agilent). Gene expression profiles were compared in oral HPV+ and HPV- cultured oral keratinocytes as well as the TCGA Kandoth & Tang datasets. Gene targets were validated by Immunohistochemistry and qPCR.
Results: Initial unsupervised hierarchical clustering analysis of our HNSC cohort revealed a separation of HPV+ HPV+E7-(HPV-inactive: HPVin), and HPV- tumors with changes in the expression of key neurogenesis-related genes. For example, POU4F1, NGFR, and GRIN2C were significantly up-regulated (P<0.05) in HPV+ vs HPVin cancers. Additional analysis of TCGA data revealed divergence of the mutational spectra in HNSC with and without perineural invasion.
Conclusion: Our preliminary findings indicate the emerging importance of neurogenesis-related genes and perineural involvement in HNSC and support a divergence of HPV+, HPVin, and HPV- HNSC sub-types.
Citation Format: Christian A. Graves, Swati Tomar, Diego Altomare, James R. Wells, Kim E. Creek, Lucia Pirisi. Head and neck cancer and HPV infection: A potential role for peritumoral neurogenesis in HPV-associated malignancy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 450. doi:10.1158/1538-7445.AM2014-450