Abstract 3420: Discovery of genetic alterations governing sinonasal squamous cell carcinoma tumorigenesis
Authors: Schubert Adrian D. , London Nyall R. , Bishop Justin A. , Broner Esther C. , Sidransky David , Izumchenko Evgeny 
Published: August 2018

Tumors of the sinonasal tract are uncommon, and comprise 5% of all cancers of the head and neck (H&N). Approximately 50-80% of sinonasal malignancies are sinonasal squamous cell carcinoma (SNSCC). Unlike H&N cancers, tobacco smoking does not seem to play a key role in the development of sinonasal tumors and the exact etiology and molecular mutations governing SNSCC tumorigenesis are not well understood. Inverted sinonasal papilloma (ISP) is a locally aggressive, benign epithelial neoplasm arising in the paranasal sinuses which has a high recurrence rate and transforms to SNSCC in 10% to 25% of cases, and therefore represent an intermediate step in SNSCC progression. Due to its uncommon nature, there is still a significant knowledge gap in our understanding of SNSCC pathogenesis and genetic mutations associated with SNSCC progression have not yet been characterized. To this end, we performed whole exome sequencing (WES) and RNA-Seq on 4 ISPs and matched SCCs samples collected from the same patients. For each patient, DNA extracted from matched lymphocytes was used as a DNA sequencing control, whereas matched uninvolved mucosa was used as a tissue specific control for RNA-Seq. 285 and 602 non-synonymous aberrations were identified across the preneoplastic lesions and tumors respectively. Interestingly, genes associated with adverse survival in HNSCC patients (such as EGFR, FAT1 and IGF1R) were mutated in more than 1 dysplastic lesion. PIK3CA was among the most mutated genes in invasive neoplasms. Notably, in three patients we identified mutations that were present in both preneoplastic and invasive neoplasms, which included cancer driver genes actionable in HNSCC and other solid malignancies (such as PIK3CA, TP53, FAT1 and EGFR). RNA-Seq analysis of the same samples revealed a subset of genes whose expression level sequentially increased or decreased from normal tissue, to early lesions to SNSCC. Interestingly, expression of genes associated with survival, migration, invasiveness and inhibition of apoptosis (such as SET, RAD21, NPM1, PTPN11, CLIP1, KIF5B, EGFR, NRAS, KRAS, MET, MYCL and CCND1) consecutively increased along the tumor progression in all three analyzed, whereas expression of tumor suppressors (such as PTCH1, IKZF1, GAS7, FOXP1, NTRK3 and LRP1B) was downregulated. Although our data suggest that preneoplastic ISP lesions may be clonally related to SCC in some cases, validation of these observations in a larger specimens' cohort is warranted to further delineate the mechanisms underlying the SNSCC tumorigenesis.

Citation Format: Adrian D. Schubert, Nyall R. London, Justin A. Bishop, Esther C. Broner, David Sidransky, Evgeny Izumchenko. Discovery of genetic alterations governing sinonasal squamous cell carcinoma tumorigenesis [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 3420.