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Genetic Abnormalities in Large to Giant Congenital Nevi: Beyond NRAS mutations

ABSTRACT: Large and giant congenital melanocytic nevi (CMN) are rare melanocytic lesions mostly caused by post-zygotic acquisition of NRAS alteration. However, large/giant CMN may exhibit phenotypic differences among distinct areas patients and in addition, patients differ in features such as presence of multiple CMN or Spilus-like lesions. Overall, 50 fresh-frozen biopsies corresponding to 37 phenotypically characterized areas of large/giant CMNs, 9 satellite lesions, 1 acquired nevus and 3 healthy skin biopsies were analyzed by a multigene panel and RNA sequencing (RNA-seq). Mutational screening showed mutations in 76.2% of large/giant CMN. NRAS mutation was found in 57.1% of cases, and mutations in other genes such as BRAF, KRAS, APC and MET were detected in 14.3% of patients. RNA-seq revealed the fusion transcript ZEB2-ALK and SOX5-RAF1 in large/giant CMN from two patients without point mutations. Both alterations were not detected in unaffected skin and were detected in different affected skin. These findings suggest that large/giant CMN may result from distinct molecular events in addition to NRAS mutations including point mutations and fusions transcripts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120597 | GEO | 2019/10/24

REPOSITORIES: GEO

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Project description:Multiple myeloma (MM) is a malignant disorder characterized by the clonal proliferation of plasma cells (PCs) in the bone marrow (BM). The genetic background and clinical course of the disease are largely heterogeneous, and MM pathophysiology ranges from the premalignant condition of monoclonal gammopathy of undetermined significance (MGUS) to smoldering MM, symptomatic MM, and extramedullary MM/plasma cell leukemia (PCL). Recent genome-wide sequencing efforts have provided the rationale for molecularly aimed treatment approaches, identifying mutations that can be specifically targeted, such as those in the mitogen-activated protein kinase (MAPK) pathway, which represent the most prevalent mutations in MM. Among these, mutations affecting BRAF gene, detected in 4-15% of patients, are of potential immediate clinical relevance due to the availability of effective inhibitors of this serine-threonine kinase which are in fact being explored also in myeloma. In this study, we screened by next generation sequencing (NGS) a large and representative series of intramedullary and extramedullary MM patients, including primary and secondary plasma cell leukemia (pPCL and sPCL, respectively), for mutations in BRAF, NRAS and KRAS genes. We evaluated the relationship of identified variants with other clinical and biological features and determined the transcriptional signature associated with MAPK pathway activation in MM. To identify transcriptomic profiles possibly related to BRAF, NRAS and KRAS mutations found in our study, we investigated by Affymetrix microarray technology a large fraction (n=142) of the samples analyzed by NGS, including wild-type patients for all the three genes and cases carrying mutations in at least one of them. Assuming that alterations present in a very limited number of malignant PCs might not appreciably affect gene expression, we chose to arbitrarily establish 20% as the lower variant allele frequency cut-off to perform supervised analyses.

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Genetic Abnormalities in Large to Giant Congenital Nevi: Beyond NRAS mutations

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