Abstract 4342: Inverted sinonasal papilloma and associated carcinoma-transcriptome analysis and out-hoxing developmental genes

Abstract Introduction Sinonasal papillomas, a group of benign epithelial tumors of the sinonasal tract, are classified into 3 distinct histologic types: exophytic, endophytic and oncocytic . Associated clinical problems include a tendency towards local destruction, recurrence and malignant transformation. While controversy persists in determining the optimal therapeutic approach in a given patient, prognostic markers identifying patients who will benefit from more aggressive treatment and novel molecular targeted therapies are urgently needed. The majority of endophytic papillomas require a lengthy period for malignant transformation, but the trigger underlying the malignant changes remains obscure. The present study aimed to identify underlying mechanisms in the malignant transformation of sinonasal inverted papillomas using RNA seq. Material and methods Samples from 36 consecutive patients formed the study material and were microdisected from FFPE. Pools of RNA were subjected to expression profiling using whole-transcriptome shotgun sequencing. For validation, differentially expressed candidates were analyzed by IHC. Results The studied cohort showed a continuum, with 14 sinonasal papilloma (11 inverted type, 2 oncocytic and 1 exophytic type), 2 sinonasal papilloma with dysplastic changes, 3 carcinoma in situ and 17 invasive squamous cell carcinoma arising in a papillomatous background (majority being associated with inverted type papilloma). Differential gene expression profiles from 14 papillomas, 14 squamous carcinomas versus 4 normal sinonasal mucosa were generated and compared to each other. 1447 genes and noncoding transcripts were detected as differentially expressed with fold change >2 and false discovery rate < 0.035. These genes and transcripts were annotated and computationally analyzed using the Ingenuity Pathway Analysis program. The highest expressed genes and potential drivers were predominantly development- and differentiation-related genes. To validate the RNA-Seq results, we used IHC assessing the protein expression of 5 highly upregulated genes considered important. These candidate genes were HOXA9, EN1, DUX4, CA-IX, and CK5/6 with expressions at 30%, 50%, 60%, 60% and 95% respectively. Conclusion We assume that sinonasal papillomas are mainly defined by high number of overexpressed developmental/homeobox genes, which provide the potential for transformation/ plasticity, along with differentiation and proliferation behavior of neoplastic cells. The data form the basis for understanding cell fate determination and cellular homeostasis in the normal sinonasal mucosa and the contribution of different mucosal components to the etiology/ molecular pathology of sinonasal dysplasia and carcinoma. Citation Format: Achim H. Bell, Ehab Y. Hanna, Randal S. Weber, Victor G. Prieto, Diana Bell. Inverted sinonasal papilloma and associated carcinoma-transcriptome analysis and out-hoxing developmental genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4342.