Comparative transcriptome analysis of sinonasal inverted papilloma and associated squamous cell carcinoma: Out-HOXing developmental genes

Background: Sinonasal papilloma has a tendency toward local destruction, recurrence, and malignant transformation. This study aimed to unravel mechanisms in the malignant transformation of sinonasal papillomas using RNA-seq. Methods: The cohort consisted of 37 consecutive patients; tumor histology included a continuum spectrum (sinonasal papillomas/dysplastic/carcinomas-in-situ/invasive squamous cell carcinomas). These were microdissected and RNA was subjected to whole-transcriptome shotgun sequencing. Results: RNA-seq and pathway analysis showed that the highest expressed genes/potential drivers were development- and differentiation-related genes. The protein expression of six highly upregulated genes (HOXA9, EN1, DUX4, CA9, CD1a, and CK5/6) validated the RNA-seq results. HOXA9 and CA9 were found to be expressed in most of the carcinoma samples but were largely negative in papillomas; all of the CA9-negative carcinomas were recurrent. Conclusions: We conclude that sinonasal carcinomas arising from papillomas are mainly defined by overexpressed developmental/homeobox genes, which provide the potential for transformation/plasticity, along with differentiation and proliferation behavior of neoplastic cells. Our results support HOXA9 and CA9 as biomarkers for carcinomas, with CA9 emerging as a predictive marker of recurrence.