Dataset Information

Prognostic Roles of BRAF, KIT, NRAS, IGF2R and SF3B1 Mutations in Mucosal Melanomas.

ABSTRACT: The prognostic value of commonly recurrent mutations remains unclear in mucosal melanomas. Clinicopathologic parameters of 214 cases of mucosal melanomas diagnosed in 1989-2020 in several clinical institutions were analyzed. NRAS, KIT, BRAF, IGF2R and SF3B1 mutational analyses by Sanger sequencing and next generation sequencing-based assay were performed in a subset of cases. Of the triple (BRAF, NRAS, NF1)-negative cases, APC, KIT and KRAS are detected mainly in sinonasal, vulvovaginal and anorectal melanomas, respectively. NRAS, KIT, BRAF, IGF2R and SF3B1 mutations are detected in 19% (37/198), 22% (44/197), 12% (25/201), 16% (22/138) and 15% (20/133) of cases, respectively. In univariate analyses, advanced stage (p = 0.016), 65 years or older (p = 0.048) and presence of ulceration (p = 0.027) are significantly correlated with worse overall survival (OS), respectively. NRAS mutation significantly correlates with worse OS (p = 0.028) and worse melanoma-specific survival (MSS) (p = 0.03) for all cases of mucosal melanomas. In multivariate analyses, NRAS mutation remains as an independent predictor of worse OS (p = 0.036) and worse MSS (p = 0.024). NRAS mutation is a predictor of worse survival, independent of stage in mucosal melanomas. The significance of frequently mutated IGF2R in mucosal melanomas remains unclear.

SUBMITTER: Wroblewska JP

PROVIDER: S-EPMC8468625 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Prognostic Roles of <i>BRAF</i>, <i>KIT</i>, <i>NRAS</i>, <i>IGF2R</i> and <i>SF3B1</i> Mutations in Mucosal Melanomas.

Wróblewska Joanna P JP Dias-Santagata Dora D Ustaszewski Adam A Wu Cheng-Lin CL Fujimoto Masakazu M Selim M Angelica MA Biernat Wojciech W Ryś Janusz J Marszalek Andrzej A Hoang Mai P MP

Cells 20210827 9

<h4>Background</h4>The prognostic value of commonly recurrent mutations remains unclear in mucosal melanomas.<h4>Methods</h4>Clinicopathologic parameters of 214 cases of mucosal melanomas diagnosed in 1989-2020 in several clinical institutions were analyzed. <i>NRAS</i>, <i>KIT</i>, <i>BRAF</i>, <i>IGF2R</i> and <i>SF3B1</i> mutational analyses by Sanger sequencing and next generation sequencing-based assay were performed in a subset of cases.<h4>Results</h4>Of the triple (<i>BRAF</i>, <i>NRAS</ ...[more]

PMID: 34571863

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Project description:BackgroundPrimary mucosal melanoma (MM) is a rare subtype of melanoma that arises from melanocytes in the mucosa. MM has not been well profiled for mutations and its etiology is not well understood, rendering current treatment strategies unsuccessful. Hence, we investigated mutational landscape for MM to understand its etiology and to clarify mutations that are potentially relevant for MM treatment.MethodsForty one MM and 48 cutaneous melanoma (CM) tissues were profiled for mutations using targeted deep next-generation sequencing (NGS) for 89 cancer-related genes. A total of 997 mutations within exons were analyzed for their mutational spectrum and prevalence of mutation, and 685 non-synonymous variants were investigated to identify mutations in individual genes and pathways. PD-L1 expression from 21 MM and 18 CM were assessed by immunohistochemistry.ResultsMutational spectrum analysis revealed a lower frequency of UV-induced DNA damage in MM than in CM (p = 0.001), while tobacco exposure was indicated as a potential etiologic factor for MM. In accordance with low UV damage signatures, MM demonstrated an overall lower number of mutations compared to CM (6.5 mutations/Mb vs 14.8 mutations/Mb, p = 0.001), and less PD-L1 expression (p = 0.003). Compared to CM, which showed frequent mutations in known driver genes (BRAF 50.0%, NRAS 29.2%), MM displayed lower mutation frequencies (BRAF; 12.2%, p < 0.001, NRAS; 17.1%), and was significantly more enriched for triple wild-type (no mutations in BRAF, RAS, or NF1, 70.7% vs 25.0%, p < 0.001), IGF2R mutation (31.7% vs 6.3%, p = 0.002), and KIT mutation (9.8% vs 0%, p = 0.042). Of clinical relevance, presence of DCC mutations was significantly associated with poorer overall survival in MM (log-rank test, p = 0.02). Furthermore, mutational spectrum analysis distinguished primary anorectal MM from CM metastasized to the bowel (spectrum analysis p < 0.001, number of mutations p = 0.002).ConclusionsThese findings demonstrated a potential etiologic factor and driver mutation for MM and strongly suggested that MM initiation or progression involves distinct molecular-mechanisms from CM. This study also identified mutational signatures that are clinically relevant for MM treatment.

Dataset Information

Prognostic Roles of BRAF, KIT, NRAS, IGF2R and SF3B1 Mutations in Mucosal Melanomas.

Publications

Prognostic Roles of <i>BRAF</i>, <i>KIT</i>, <i>NRAS</i>, <i>IGF2R</i> and <i>SF3B1</i> Mutations in Mucosal Melanomas.

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