The mutational landscape of mucosal melanoma

Abstract

Mucosal melanoma is a rare and aggressive subtype of melanoma that has a less favorable prognosis due to the lack of understanding and identification of oncogenic drivers. Recently, whole genome and whole exome sequencing have unveiled the molecular landscape and potential oncogenic drivers of mucosal melanoma, which remains distinct from cutaneous melanoma. In this review, we provide an overview of the genomic landscape of mucosal melanoma, with a focus on molecular studies identifying potential oncogenic drivers allowing for a better mechanistic understanding of the biology of mucosal melanoma. We summarized the published genomics and clinical data supporting the observations that mucosal melanoma harbors distinct genetic alterations and oncogenic drivers from cutaneous melanoma, and thus should be treated accordingly. The common drivers (BRAF and NRAS) found in cutaneous melanoma have lower mutation rate in mucosal melanoma. In contrast, SF3B1 and KIT have higher mutation rate in mucosal melanoma as compared to cutaneous melanoma. From the meta-analysis, we also observed that the mutational profiles are slightly different between the "upper" and "lower" regions of mucosal melanoma, providing new insights and therapeutic options for the mucosal melanoma patients. Mutations identified in mucosal melanoma should be incorporated into routine clinical testing, as there are targeted therapies already developed for treating patients with these mutations in the precision medicine era.

Keywords: Druggable targets; KIT; Mucosal melanoma; Mutational landscape; SF3B1.

Figure 1:

Mutational landscape of Mucosal Melanoma. Molecular classification of melanoma with BRAF (V600), NRAS (G12, G13, Q61), NF1, KIT and SF3B1 mutations in (A) Mucosal melanoma meta-analysis from 64 studies (B) cutaneous melanoma from TCGA. (C-D) The difference in molecular classifications between mucosal melanomas arising in upper and lower anatomical sites (C) Upper sites include: Head and neck and upper GI. (D) Lower sites include: Lower GI, anorectal, and genital.

Figure 2:

SF3B1 mutations in cancer. (A) Mutations in SF3B1 are associated with alternative branch point usage and result in increases in alternative 3’ splice sites. (B) Hotspot SF3B1 mutations represented in SF3B1 protein, highlighting the locations that predominate in specific cancer types. (C) Kaplan-Meier curve of overall survival comparing SF3B1 Mutant (n=16) and SF3B1-WT (n=37) from 3 studies (Hintzsche et. al. 2017, Yang et. al. 2017, Quek et. al. 2019), p-value is calculated by log-rank test.

Figure 3:

Oncogenic signaling and therapeutic targets in Mucosal Melanoma.