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

Abstract

The incidence of melanoma is rising globally including China. Comparing to Caucasians, the incidence of non‐cutaneous melanomas is significantly higher in Chinese. Herein, we performed genomic profiling of 89 Chinese surgically resected primary melanomas, including acral (n = 54), cutaneous (n = 22), and mucosal (n = 13), by hybrid capture‐based next‐generation sequencing. We show that mucosal melanomas tended to harbor more pathogenic mutations than other types of melanoma, though the biological significance of this finding remains uncertain. Chromosomal arm‐level alterations including 6q, 9p, and 10p/q loss were highly recurrent in all subtypes, but mucosal melanoma was significantly associated with increased genomic instability. Importantly, 7p gain significantly correlated with unfavorable clinical outcomes in non‐cutaneous melanomas, representing an intriguing prognostic biomarker of those subtypes. Furthermore, focal amplification of 4q12 (KIT, KDR, and PDGFRα) and RAD51 deletion were more abundant in mucosal melanoma, while NOTCH2 amplification was enriched in acral melanoma. Additionally, cutaneous melanomas had higher mutation load than acral melanomas, while mucosal melanomas did not differ from other subtypes in mutation burden. Together, our data revealed important features of acral and mucosal melanomas in Chinese including distinctive driver mutation pattern and increased genomic instability. These findings highlight the possibilities of combination therapies in the clinical management of melanoma.

The Molecular Landscape of Primary Acral Melanoma: A Multicenter Study of the Italian Melanoma Intergroup (IMI)

“…TP53 mutation is considered a pivotal event in tumor progression, since it impairs the function of the gene protein product preventing the activation of apoptosis or the arrest of the cell cycle in response to DNA damage. However, its occurrence was less frequent in melanoma than in other cancers and it was rarely reported in AM [16,19,29]. Interestingly, in the present series, nine cases (accounting for 30% of analyzed samples) harbored TP53 mutations and most were acral lentiginous melanomas.…”

“…Mutated NRAS and KIT have been detected in about 15% of cases, with a respective range of 7-47% and 6-21% among the studies [16,17,[22][23][24][25][26][27][28]. TP53 mutations have been reported as a rare and late event in AM [16,19,29]. Instead, mutations in NF1 and amplification of KIT, CCND1, PAK1, GAB2, CDK4, RICTOR, and TERT, have been more commonly found in AM than in other skin melanomas [16,19,20,28].…”

Genetic alteration of Chinese patients with rectal mucosal melanoma

“…In a retrospective cohort involving 446 Chinese patients with melanoma, melanoma was shown to be more aggressive and had a shorter OS than cutaneous lesions [ 22 ]. Although similar research has been reported in previous studies, no comprehensive analysis of specific mucosal site has been carried out [ 15 , 23 , 24 ]. In this study, NGS technology was applied to depict the mutation spectrum of 36 RMM patients to provide a reference for the clinical prognosis and further targeted intervention therapy.…”

Genetic Alteration of Chinese Patient With Rectal Mucosal Melanoma

“…MM is rare, in a retrospective cohort involving 446 Chinese patients with melanoma, they were known to behave more aggressive and were associated with shorter survival than cutaneous lesions [15]. Although similar research has been reported in the literature before, no speci c mucosal site has been under investigation [13,16,17]. In this study, we retrospectively performed genomic pro ling of 36 cases with RMM using NGS in order to provide a reference for the clinical prognosis of the tumor and further targeted intervention therapy.…”