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Lack of distinct molecular profile of Primary Dermal Melanoma.

ABSTRACT: Primary dermal melanoma (PDM) is a rare variant of melanoma which simulates metastatic melanoma to the skin. Diagnosis of PDM cannot be established on histologic grounds alone but requires absence of evidence of melanoma elsewhere by clinical history and/or imaging studies. Despite this entity being clinically well documented, limited data on molecular characterization are available. We performed comprehensive mutation and copy number variation analysis in a series of PDMs in search for distinctive molecular features.Studies were approved by respective institutional review boards. Six cases fulfilling strict histologic criteria of PDM were identified in patients with absent history of melanoma elsewhere, negative sentinel lymph node biopsies and imaging studies. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue, and five cases passed quality control measures and were subjected to targeted exon sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets 410 panel. Two of five PDM carried NRAS hotspot mutations characteristic of cutaneous melanoma (CM) genomic subtypes. One case showed a probable low-activating NRAS mutation in combination with additional aberrations in other mitogen-activated protein kinase (MAPK) pathway effectors. Hotspot mutations were also identified in the TERT promoter region, and one tumor showed a mutation in the SWI/SNF remodeling complex. No oncogenic mutations were identified in one case. Furthermore, none of the tumors analyzed showed activating mutations in Gα subunits, including GNAQ and GNA11. Copy number alterations included deletions of Chr 9p, characteristic of CM.Despite PDM showing mutational heterogeneity, our findings suggest predominance of MAPK pathway aberrations in agreement with the mutational profile of CMs in general. Given the absence of genetic overlap with other distinct primary dermal melanocytic proliferations, mutational profiling will unlikely aid in the difficult differential diagnosis of PDM versus melanoma metastasis. Thorough metastatic workup remains crucial in establishing this rare diagnosis.

SUBMITTER: Shaigany S

PROVIDER: S-EPMC8370683 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the "RTK I (PDGFRA)" group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.

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Lack of distinct molecular profile of Primary Dermal Melanoma.

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