Abstract
Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.
Highlights
Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type
We identified genes with significant copy number variations (CNVs) identified by GISTIC, and genes recurrently affected by structural variants (SVs) breakpoints that are COSMIC cancer census genes, genes identified by significantly mutated genes (SMGs) analysis in this study, or previously identified melanoma driver genes (Fig. 4, Supplementary Fig. 6)
We show different mutational signatures occur in mucosal melanomas arising in facial sites compared to those arising in lower body sites and signatures 7 and 17 occur more often in patients of East Asian ancestry
Summary
Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. Studies using exome[2,3,4,5,6] or whole-genome sequencing[2,7] have shown that mucosal melanomas have a much lower burden of point mutations and a greater load of structural chromosomal variants compared to cutaneous melanomas, and that these mutations bear essentially no signatures of UVR or any other known carcinogen. In this they resemble acral melanomas, those of the volar surfaces of hands, feet, fingers, and toes, for which etiology is unknown. We identify diverse drivers that indicate the majority of mucosal melanomas are potentially susceptible to CDK4/6 and/or MEK inhibitors
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