Melanocytic tumors

2025-03-16   Paola Dal Cin, PhD 

1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)

Classification

Definition

Mucosal melanoma is a rare and aggressive subtype of melanoma, which harbors distinct genetic alterations and oncogenic drivers from cutaneous and uveal melanoma. In general the common drivers BRAF  and NRAS mutations  found in cutaneous melanoma have lower mutation rate , in contrast mutation of  SF3B1 and KIT  have higher mutation rate in mucosal melanoma. 1  Mucosal melanomas are rare, often aggressive tumors that can arise at any mucosal site but most frequently occur in the head and neck, vulvovaginal, and anorectal regions.  In general, mucosal melanoma have also difference in molecular findings if arising in upper (head and neck and upper GI)  and lower (lower GI, anorectal, and genital) anatomical sites.1,2  


Melanocytic tumorsGenetic marker(s}
Mucosal melanoma In the head and neck areas , mucosal melanomas arise in the sinonasal region, oral cavity, and larynx, and the mutational profile is similar to upper gastrointestinal tract melanomas. 1 Overall, the common MAPK activating mutations e.g. BRAF, NRAS found in cutaneous melanoma) are much less common (~28%) in mucosal melanoma. NF1 mutations are more common in mucosal melanoma once structural variants are included, with a significantly higher rate of mucosal cases with co-mutation of KIT and NF1. SF3B1 mutations have been almost exclusively found in cases from vulvovaginal and anorectal sites and not in the head and neck. 1,3,4
Mucosal melanomas have been shown by whole genomic sequencing to have also higher number aberrations compared with cutaneous melanomas, including POM21 amplification and , recurrent focal amplifications of several oncogenes at 12q13-15 e.g. CDK4, MDM2 and AGAP2. 5 Interesting, most of these changes have been found at oral sites of East Asian ethnicity, with a worse clinical outcome 5. Co-amplification of CDK4 and TERT , due to due to complex genomic rearrangement between 5p and 12q, were more common in oral lesions than in sinonasal ones. 6
Sinonasal melanomas were commonly driven by NRAS mutations, and rarely displayed BRAF, and more frequent among paranasal sinuses than nasal tumors. Addtional alterations of other Ras-MAPK signaling pathwa , e.g. NF1 mutations/deletions, SPRED1, PIK3CA, PTEN and mTOR mutations, occurring in a mutually exclusive manner of WNT-pathway,e.g. APC and CTNNB1. Rarely fusions were also detected e.g. TERT:: CNOT4 orTERT::NUP50.7
Interesting , in some head and neck areas,  especially conjunctival, there was a predominance of UVR-associated single base substitution signature 7 (SBS7), also in cutaneous melanoma, and are al so present in the majority of the samples carrying BRAF mutations.8

Article Bibliography

Reference NumberPubmed IDLast YearTitleAuthors
1316551182020The mutational landscape of mucosal melanoma.Nassar KW et al
2337073072021Meta-Analysis and Systematic Review of the Genomics of Mucosal Melanoma.Broit N et al
3282967132017Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma.Hintzsche JD et al
4340231072021Mucosal Melanoma: A Review Emphasizing the Molecular Landscape and Implications for Diagnosis and Management.Rawson RV et al
5307826162019Analysis of Mucosal Melanoma Whole-Genome Landscapes Reveals Clinically Relevant Genomic Aberrations.Zhou R et al
6337978272021CDK4 and TERT amplification in head and neck mucosal melanoma.Lyu J et al
7359780132022Alterations in key signaling pathways in sinonasal tract melanoma. A molecular genetics and immunohistochemical study of 90 cases and comprehensive review of the literature.Chłopek M et al
8334318152021Ultraviolet radiation drives mutations in a subset of mucosal melanomas.Mundra PA et al

Citation

Paola Dal Cin, PhD

Melanocytic tumors

Atlas Genet Cytogenet Oncol Haematol. 2025-03-16

Online version: http://atlasgeneticsoncology.org/solid-tumor/209313/melanocytic-tumors