22O - Sinonasal cancer: Molecular biomarkers for tumor classification and targeted treatment

Background

The sinonasal cavities harbor a great variety of rare epithelial and neuroendocrine tumors. Many subtypes are poorly differentiated and difficult to diagnose, while their clinical behavior can differ greatly. In spite of advances with endoscopic surgery and radiotherapeutic, recurrences remain frequent and 5-year survival lies between 20-60% or lower. Therefore, there is an unmet clinical need for better diagnostic biomarkers and novel therapeutic approaches. Our aim was to apply whole exome sequencing (WES) to identify such biomarkers.

Methods

Tumor and germline DNA of 96 patients with 7 different subtypes of sinonasal cancer comprising 39 intestinal-type adenocarcinoma (ITAC), 22 squamous cell carcinoma (SNSCC), 15 mucosal melanoma (MMM), 10 undifferentiated carcinoma (SNUC), 7 olfactory neuroblastoma (ONB), 2 neuroendocrine carcinoma (SNEC) and 1 teratocarcinosarcoma (TCS) was obtained and analyzed by WES, selecting somatic variants. NF1 and FGFR1 gene copy number changes were studied by MLPA.

Results

All histological tumor subtypes carried distinct genetic profiles. Recurrent subtype-unique mutations included: APC, CTNNB1, PIK3CA and KRAS in ITAC; EGFR and CDKN2A in SNSCC; NRAS and NF1 in MMM, IDH2 in SNUC/SNEC/ONB, and ARID1A, SMARCB1 and SMARCA4 in SNUC/TCS. Alterations commonly observed in most subtypes were mutations in TP53, NOTCH1/2, BRCA1/2 and FANCA, and amplifications in FGFR1.

Conclusions

Our results confirm that classification of sinonasal cancer subtypes can be aided by genetic analysis to optimize patient care. Indeed the WHO Classification of Head and Neck Tumors already recognizes a number of subtypes solely based on specific mutation, protein expression or chromosomal translocation. In addition, recent DNA methylation profiling studies have shown great diagnostic potential. Our WES data also reveal molecular targets for personalized treatment strategies. Candidate therapies include inhibitors of PI3K/MTOR for ITAC, of EGFR and CDK4/6 for SNSCC, of MEK for MMM, of IDH2 for SNUC/SNEC/ONB, and of EZH2 for SNUC/TCS, while DNA repair and FGFR inhibitors may be considered for many of the sinonasal tumor subtypes.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The author.

Funding

Instituto de Salud Carlos III grant PI19/00191.

Disclosure

The author has declared no conflicts of interest.