Abstract
Recurrent respiratory papillomatosis (RRP) is a debilitating neoplastic disorder of the upper aerodigestive tract caused by chronic infection with low-risk human papillomavirus types 6 or 11. Patients with severe RRP can require hundreds of lifetime surgeries to control their disease and pulmonary papillomatosis can be fatal. Here we report the comprehensive genomic and transcriptomic characterization of respiratory papillomas. We discovered and characterized distinct subtypes with transcriptional resemblance to either a basal or differentiated cell state that associate with disease aggressiveness and differ in key molecular, immune and APOBEC mutagenesis profiles. Through integrated comparison with high-risk HPV-associated head and neck squamous cell carcinoma, our analysis revealed divergent molecular and immune papilloma subtypes that form independent of underlying genomic alterations. Cumulatively our results support the development of dysregulated cellular proliferation and suppressed anti-viral immunity through distinct programs of squamous cell differentiation and associated expression of low-risk HPV genes. These analyses provide insight into the pathogenesis of respiratory papillomas and provide a foundation for the development of therapeutic strategies.
Highlights
Recurrent respiratory papillomatosis (RRP) is a debilitating neoplastic disorder of the upper aerodigestive tract caused by chronic infection with low-risk human papillomavirus types 6 or 11
We describe distinct molecular subtypes of RRP that appeared to be independent of underlying genomic alterations, correlate with disease severity and differ based on the expression of human papillomavirus (HPV) genes as well as genes related to cellular differentiation, underlying anti-viral immune response and APOBEC cytidine deaminases
Peripheral blood mononuclear cells (PBMC) and papilloma samples were collected from all patients
Summary
Recurrent respiratory papillomatosis (RRP) is a debilitating neoplastic disorder of the upper aerodigestive tract caused by chronic infection with low-risk human papillomavirus types 6 or 11. Our results support the development of dysregulated cellular proliferation and suppressed anti-viral immunity through distinct programs of squamous cell differentiation and associated expression of low-risk HPV genes. These analyses provide insight into the pathogenesis of respiratory papillomas and provide a foundation for the development of therapeutic strategies. We describe distinct molecular subtypes of RRP that appeared to be independent of underlying genomic alterations, correlate with disease severity and differ based on the expression of HPV genes as well as genes related to cellular differentiation, underlying anti-viral immune response and APOBEC cytidine deaminases. Our findings indicate that varying levels of HPV-mediated deregulation of proliferation, cellular differentiation and immunity underlie the heterogeneous RRP phenotype, and suggest that patients could benefit from the development of personalized treatment strategies taking into account such molecular differences
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