Decoding Mucosal Melanomas: Genetic Profiling for Advanced Therapeutic Strategies

Purpose: Head and neck mucosal melanomas (HNMM) are rare but aggressive and malignant neoplasms. Characterized by their propensity for local invasion and distant metastasis, HNMM pose unique diagnostic and therapeutic challenges, contributing to their poor prognosis. Current management for HNMM consists of radical surgical resection and/or adjuvant radiotherapy, which has shown to improve locoregional disease control but not survival. Current clinical trials for HNMM therapy utilize biologic agents such as nivolumab and ipilimumab, which function as immune checkpoint inhibitors (ICI). Given the lack of understanding of genetic alterations leading to development of HNMM, elucidating factors regulating immunogenicity are paramount to the development of other targeted therapies. This study utilizes a publicly available genomic database to explore the somatic mutational landscape of HNMM patients.

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 HNMM. The most common gene mutations, gene correlations, and mutual exclusivities were assessed using two-sided t-tests and nonparametric tests, with Benjamini-Hochberg False Discovery Rate (FDR) correction.

Results: Of the 8,500 melanoma samples, 140 (1.6%) were HNMM, collected from 132 unique patients. In this cohort, 60 (45.5%) patients were male, 72 (54.5%) were female. Majority (71.2%) of the patients were white (N = 94). All samples in this cohort were adults 18 years or older. The most common mutations in this cohort were: NRAS (n = 29; 20.7%), NF1 (n = 19; 14.0%), TERT (n = 16; 13.0%), ROS1 (n = 16; 11.4%), KIT (n = 15; 9.3%), TP53 (n = 14; 7.9%), BRAF (n = 13; 9.3%), KMT2C (n = 11; 7.5%), and KMT2D (n = 9; 6.0%). Specifying by mutation types, NRAS and BRAF were all missense mutations, with V600X point mutations being the most common (n = 7; 53.8%) on BRAF. The other mutations were mostly missense mutations: ROS1 (n = 14; 87.5%), KMT2C (n = 9; 81.2%), KIT (n = 11; 73.3%), TP53 (n = 8; 57.4%), BRAF (n = 7; 53.8%). Moreover, KMT2C mutations tended to co-occur with TP53 (n = 3/9; p = 0.016), BRAF (n = 3/10; p = 0.022), and ROS1 (n = 3/11; p = 0.029), suggesting that KMT2C mutations may be associated with genes integral to tumor suppression (TP53), cell growth/division (BRAF), and receptor tyrosine kinase signaling pathway (ROS1). Of the top nine most commonly mutated genes, there were no other statistically significant co-occurrences or mutual exclusivities.

Conclusion: NRAS, NF1, TERT, ROS1, KIT, TP53, BRAF, KMT2C, and KMT2D mutations account for the majority of somatic mutations in head and neck mucosal melanoma (HNMM), with NRAS being the most common. This analysis has identified several mutations in HNMM that may serve as potential targets for novel therapies. Understanding the genetic alterations mentioned above may help elucidate pathogenesis of HNMM and potentially guide the development of targeted therapies.

Publication History

Article published online:
07 February 2025