Abstract
BackgroundPrimary mucosal melanoma (MM) is a rare subtype of melanoma that arises from melanocytes in the mucosa. MM has not been well profiled for mutations and its etiology is not well understood, rendering current treatment strategies unsuccessful. Hence, we investigated mutational landscape for MM to understand its etiology and to clarify mutations that are potentially relevant for MM treatment.MethodsForty one MM and 48 cutaneous melanoma (CM) tissues were profiled for mutations using targeted deep next-generation sequencing (NGS) for 89 cancer-related genes. A total of 997 mutations within exons were analyzed for their mutational spectrum and prevalence of mutation, and 685 non-synonymous variants were investigated to identify mutations in individual genes and pathways. PD-L1 expression from 21 MM and 18 CM were assessed by immunohistochemistry.ResultsMutational spectrum analysis revealed a lower frequency of UV-induced DNA damage in MM than in CM (p = 0.001), while tobacco exposure was indicated as a potential etiologic factor for MM. In accordance with low UV damage signatures, MM demonstrated an overall lower number of mutations compared to CM (6.5 mutations/Mb vs 14.8 mutations/Mb, p = 0.001), and less PD-L1 expression (p = 0.003). Compared to CM, which showed frequent mutations in known driver genes (BRAF 50.0%, NRAS 29.2%), MM displayed lower mutation frequencies (BRAF; 12.2%, p < 0.001, NRAS; 17.1%), and was significantly more enriched for triple wild-type (no mutations in BRAF, RAS, or NF1, 70.7% vs 25.0%, p < 0.001), IGF2R mutation (31.7% vs 6.3%, p = 0.002), and KIT mutation (9.8% vs 0%, p = 0.042). Of clinical relevance, presence of DCC mutations was significantly associated with poorer overall survival in MM (log-rank test, p = 0.02). Furthermore, mutational spectrum analysis distinguished primary anorectal MM from CM metastasized to the bowel (spectrum analysis p < 0.001, number of mutations p = 0.002).ConclusionsThese findings demonstrated a potential etiologic factor and driver mutation for MM and strongly suggested that MM initiation or progression involves distinct molecular-mechanisms from CM. This study also identified mutational signatures that are clinically relevant for MM treatment.
Highlights
Primary mucosal melanoma (MM) is a rare subtype of melanoma that arises from melanocytes in the mucosa
Compared to cutaneous melanoma (CM), MM is relatively asymptomatic or lacks early clinical visibility, which is important for early detection of CM, it is often diagnosed at more advanced stages and exhibiting poor prognosis
In a recent study [5], CM was stratified into four molecular subtypes: BRAF mutated, RAS mutated (NRAS/KRAS/HRAS), NF1 mutated, and triple wild-type (Triple-WT, a subgroup that lacks above mutations) using the Cancer Genome Atlas (TCGA) database
Summary
Primary mucosal melanoma (MM) is a rare subtype of melanoma that arises from melanocytes in the mucosa. In a recent study [5], CM was stratified into four molecular subtypes: BRAF mutated, RAS mutated (NRAS/KRAS/HRAS), NF1 mutated (a regulator of RAS pathway [6]), and triple wild-type (Triple-WT, a subgroup that lacks above mutations) using the Cancer Genome Atlas (TCGA) database. Molecular targeted therapies, such as BRAF inhibitors or MEK inhibitors, are applicable for CM treatment based on these genetic subtypes [7]. Our knowledge about the cancer-related gene mutations in MM, in all exonic regions, is still limited and warrants further investigation into the mutational landscape to understand the etiology of the disease and better treatment strategies for MM
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
