Comprehensive Genomic Profiling of Sinonasal Carcinomas: Identification of Common Mutations and Potential Targets for Therapy

Gabriel Bitar; Beau Hsia; Saif Alshaka; Mariko Sato; John Crawford; Michael L. Levy; Danielle Levy; Bastien A. Valencia; Jeeho Kim; Farhoud Faraji; Sean Polster; Vijay A. Patel

doi:10.1055/s-0045-1803103

Journal of Neurological Surgery Part B: Skull Base, Table of Contents

J Neurol Surg B Skull Base 2025; 86(S 01): S1-S576
DOI: 10.1055/s-0045-1803103

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Oral Presentations

Comprehensive Genomic Profiling of Sinonasal Carcinomas: Identification of Common Mutations and Potential Targets for Therapy

Gabriel Bitar

¹Creighton University, Omaha, Nebraska, United States

,

Beau Hsia

¹Creighton University, Omaha, Nebraska, United States

,

Saif Alshaka

¹Creighton University, Omaha, Nebraska, United States

,

Mariko Sato

²Pediatrics, University of California Irvine, Irvine, California, United States

,

John Crawford

²Pediatrics, University of California Irvine, Irvine, California, United States

,

Michael L. Levy

³Department of Neurosurgery, University of California San Diego, San Diego, California, United States

,

Danielle Levy

³Department of Neurosurgery, University of California San Diego, San Diego, California, United States

,

Bastien A. Valencia

⁴Department of Otolaryngology—Head and Neck Surgery, Mayo Clinic

,

Jeeho Kim

⁵Department of Otolaryngology, Naval Medical Center San Diego, San Diego, California, United States

,

Farhoud Faraji

⁶Department of Otolaryngology—Head and Neck Surgery, University of California San Diego, San Diego, California, United States

,

Sean Polster

⁷Department of Neurosurgery, University of Chicago, Chicago, Illinois, United States

,

Vijay A. Patel

⁶Department of Otolaryngology—Head and Neck Surgery, University of California San Diego, San Diego, California, United States

› Author Affiliations

Abstract

Full Text

Purpose: Sinonasal cancers are malignant neoplasms arising from the epithelial cells of the nasal cavity and paranasal sinuses, encompassing diverse tumor types such as squamous cell carcinoma, adenocarcinoma, and undifferentiated carcinoma. Despite their clinical significance, comprehensive data on their somatic mutational landscape is limited due to their rarity. Common treatments for sinonasal cancers include surgery, radiation therapy, and chemotherapy. Current chemotherapies in clinical trials for sinonasal carcinomas include cetuximab, cisplatin, 5FU, and leucovorin. Additionally, some clinical trials are investigating the efficacy of novel chemotherapeutic agents targeting DNA methylation, such as tazemetostat. In this study, we utilized a publicly available genomic database to profile the somatic mutations in sinonasal cancer patients, aiming to identify common mutations and genetic alterations. Moreover, we compared the mutational profiles across different histological subtypes to uncover subtype-specific mutations and pathways.

Methods: The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database was accessed from cBioPortal (v16.1-public) on July 22, 2024 to identify all patients with sinonasal cancer. The most common gene mutations, gene correlations, and mutual exclusivities were assessed using a two-sided T-test and nonparametric tests, with Benjamini-Hochberg False Discovery Rate (FDR) correction.

Results: Of the 2,595 head and neck cancer samples, 122 (4.7%) had sinonasal carcinoma. Of these 125 samples, 70 (57.4%) had sinonasal squamous cell carcinoma, 31 (25.4%) had sinonasal undifferentiated carcinoma, and 21 (17.2%) had sinonasal adenocarcinoma. In this sample, 78 patients were male (66.7%) and 39 were female (33.3%). The majority of patients in this sample were white (n = 76, 65%). The majority of patients were adult patients (98%). The most common mutations in the cohort across all different subtypes were: TP53 (n = 49; 40%), PIK3CA (n = 17; 14%), KMT2D (n = 14; 11%), CDKN2A (n = 11; 9%), FANCA (n = 10; 8%), and NOTCH1, IDH2, and PTEN (each n = 9; 8%). Subtype-specific mutations were observed:

• Squamous cell carcinoma (SCC): TP53 (n = 29, 43%), PIK3CA (n = 12, 18%), KMT2D (n = 11, 16%).

• Undifferentiated carcinoma: TP53 (n = 14, 47%), IDH2 (n = 9, 30%), NF1 (n = 5, 17%).

• Adenocarcinoma: TP53 (n = 6, 30%), LRP1B and FAT1 (n = 3, 15% each).

TP53 was the most common mutation across all subtypes. In this cohort, TP53 mutations tended to co-occur with PRKDC (n = 4, p = 0.020), and KMT2D tended to co-occur with PIK3CA (n = 4, p = 0.018).

Conclusion: TP53, PIK3CA, and KMT2D mutations account for a significant portion of somatic mutations in sinonasal carcinoma, suggesting potential opportunities for targeted therapies. For instance, tazemetostat, which targets DNA methylation, in which KMT2D plays a key role, is currently being tested in clinical trials. Similarly, cetuximab, targeting EGFR upstream of the commonly mutated PIK3CA signaling cascade, is a first-line chemotherapy agent in sinonasal cancers. Identifying specific point mutations and secondary drivers may advance the development of novel preclinical models for testing targeted therapies.