Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets

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.

Distinct genomic traits of acral and mucosal melanomas revealed by targeted mutational profiling

“…On the focal level, KIT, CCND1, CDK4, NOTCH2 amplification, CDKN2A/2B, and PTEN deletion were recurrently seen, in line with previous findings reported by others (Newell et al, ; Zhou et al, ). Noteworthy, amplification of CDK4/CCND1 was also more frequent in patients lacking common driver mutations in cutaneous melanomas (Cancer Genome Atlas, ).…”

“…In addition, we did not observe the concurrence of NOTCH2 and NRAS amplification as previously reported (Garman et al, ) despite the fact that both genes are located nearby on 1p. Lastly, NOTCH2 amplification was exclusive to acral melanomas in our data, although it has previously been reported in mucosal melanomas (Newell et al, ; Zhou et al, ), which may be attributed to the limited cohort size.…”

“…We also observed that RAS represented the top affected gene (46%) in mucosal melanoma, and moreover, concurrent pathogenic mutations tended to be enriched (38%) in mucosal melanomas. These phenomena seem to be recurrent in mucosal melanoma in a recent study by Newell et al (Newell et al, ) although at a relatively lower frequency (Figure , data adapted from Newell et al ). These notions also find support in the evidence that mucosal melanomas had the poorest prognosis (Furney et al, ; Lian et al, ), but further investigations are required to support these notions.…”

“…In summary, this study reports distinctive genomic traits including driver mutation status and genomic instability in cutaneous and two other major subtypes—acral and mucosal melanomas—in a Chinese melanoma population. The limitations of the study included the following: (a) the cohort size is limited, and melanoma subtypes were not equally represented; (b) genes that were previously reported to be significantly mutated in melanoma, including PPP6C ( Hayward et al, ) , STK19 ( Hodis et al, ) , SNX31 ( Hodis et al, ) , and SPRED1 ( Newell et al, ) , were not covered by the panel used for sequencing, thus reducing the comprehensiveness of genomic profiling of the current study; and (c) we acknowledge that the heterogeneity of post‐surgery treatments may contribute to the difference seen in patients’ outcomes.…”

MDM2, MDM4 and EGFR Amplifications and Hyperprogression in Metastatic Acral and Mucosal Melanoma

“…We furthermore evaluated other oncogenes or tumor suppressor genes, known to be frequently amplified or deleted in acral or mucosal melanoma [35,36] and performed a comparison with the Cancer Genome Interpreter database. Oncogenes with amplifications (copy number ≥4) and tumor suppressor genes with deletions (copy number <1), respectively are presented in Figure 2A.…”