Dataset Information

Identification of NTRK3 Fusions in Childhood Melanocytic Neoplasms.

ABSTRACT: Spitzoid neoplasms are a distinct group of melanocytic tumors. Genetically, they lack mutations in common melanoma-associated oncogenes. Recent studies have shown that spitzoid tumors may contain a variety of kinase fusions, including ROS1, NTRK1, ALK, BRAF, and RET fusions. We report herein the discovery of recurrent NTRK3 gene rearrangements in childhood melanocytic neoplasms with spitzoid and/or atypical features, based on genome-wide copy number analysis by single-nucleotide polymorphism array, which showed intragenic copy number changes in NTRK3. Break-apart fluorescence in situ hybridization confirmed the presence of NTRK3 rearrangement, and a novel MYO5A-NTRK3 transcript, representing an in-frame fusion of MYO5A exon 32 to NTRK3 exon 12, was identified using a rapid amplification of cDNA ends-based anchored multiplex PCR assay followed by next-generation sequencing. The predicted MYO5A-NTRK3 fusion protein consists of several N-terminal coiled-coil protein dimerization motifs encoded by MYO5A and C-terminal tyrosine kinase domain encoded by NTRK3, which is consistent with the prototypical structure of TRK oncogenic fusions. Our study also demonstrates how array-based copy number analysis can be useful in discovering gene fusions associated with unbalanced genomic aberrations flanking the fusion points. Our findings add another potentially targetable kinase fusion to the list of oncogenic fusions in melanocytic tumors.

SUBMITTER: Wang L

PROVIDER: S-EPMC5417047 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Identification of NTRK3 Fusions in Childhood Melanocytic Neoplasms.

Wang Lu L Busam Klaus J KJ Benayed Ryma R Cimera Robert R Wang Jiajing J Denley Ryan R Rao Mamta M Aryeequaye Ruth R Mullaney Kerry K Cao Long L Ladanyi Marc M Hameed Meera M

The Journal of molecular diagnostics : JMD 20170501 3

Spitzoid neoplasms are a distinct group of melanocytic tumors. Genetically, they lack mutations in common melanoma-associated oncogenes. Recent studies have shown that spitzoid tumors may contain a variety of kinase fusions, including ROS1, NTRK1, ALK, BRAF, and RET fusions. We report herein the discovery of recurrent NTRK3 gene rearrangements in childhood melanocytic neoplasms with spitzoid and/or atypical features, based on genome-wide copy number analysis by single-nucleotide polymorphism arr ...[more]

PMID: 28433076

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Project description:The "multidimensional" World Health Organization (WHO) classification 2018 of melanocytic tumors encompasses nine melanoma pathways (seven of which for cutaneous melanoma) according to a progression model in which morphologically intermediate melanocytic tumors are cosidered as simulators and/or precursors to melanoma. These "intermediates" can be subclassified into: i) a "classical" subgroup (superficial/thin compound: dysplastic nevus), which is placed within the morphologic and molecular progression spectrum of classical (Clark's and McGovern's) melanoma subtypes (superficial spreading and, possibly, nodular); and ii) a "non-classical" subgroup (thick compound/dermal: "melanocytomas") whose genetic pathways diverge from classical melanoma subtypes. Such a progression model is aimed at giving a conceptual framework for a histopathological classification; however, routine clinicopathological practice strongly suggests that most melanomas arise de novo and that the vast majority of nevi are clinically stable or even involuting over time. Clinicopathological correlation can help identify some severely atypical but benign tumors (e.g.: sclerosing nevus with pseudomelanomatous features) as well as some deceptively bland melanomas (e.g.: lentiginous melanoma; nested melanoma), thereby addressing some ambiguous cases to a correct clinical management. The recently available adjuvant therapy regimens for melanoma raise the problem of a careful distinction between severely atypical (high grade) melanocytoma and "classical" melanoma: conventional morphology can guide an algorithmic approach based on an antibody panel (anti-mutated BRAF, BAP1, PRAME, ALK, TRKA, MET, HRAS-WT, ROS; beta catenin; R1alpha; p16; HMB45; Ki67), a first-line molecular study (identification of hot spot mutations of BRAF and NRAS) and an advanced molecular study (sequencing of NF1, KIT, BRAF, MAP2K1, GNAQ, GNA11, PLCB4, CYSLTR2, HRAS; fusions studies of BRAF, RET, MAP3K8, PRKCA); as a final step, next-generation sequencing can identify melanocytic tumors with rare genetic signatures and melanocytic tumors with a high tumor mutation burden which should be definitely ascribed to the category of classical melanoma with the respective therapeutic options.

Project description:AimsThe role of inflammation in conventional cutaneous melanoma has been extensively studied, whereas only little is known about the inflammatory microenvironment and immunogenic properties of spitzoid melanocytic neoplasms. The composition of infiltrating immune cells and the architectural distribution of the inflammation, in particular, are still obscure. This is the first study, to our knowledge, to systematically characterise the inflammatory patterns and the leucocyte subsets in spitzoid melanocytic lesions.Methods and resultsWe examined 79 spitzoid neoplasms including banal Spitz naevi (SN, n = 50), atypical Spitz tumours (AST, n = 17) and malignant Spitz tumours (MST, n = 12) using histopathological analysis and immunohistochemistry. Spitzoid melanocytic lesions showed a high frequency (67.1%, n = 53 of 79) of inflammation. Four inflammatory patterns were identified according to architectural composition, distribution and intensity of inflammation. The majority of the inflammatory infiltrate corresponded to CD3+ /CD8+ T lymphocytes (56.1%), followed by CD3+ /CD4+ T cells (35.7%) and CD68+ histiocytes (20.3%). CD3+ /TIA-1+ cytotoxic T lymphocytes constituted 3.7% of inflammatory cells. Rarely, CD3+ / granzyme B+ cytotoxic T lymphocytes (2.7%) and CD138+ plasma cells (0.5%) were detected in the infiltrating immune cells. There was no significant difference in the inflammatory cellular composition among the spitzoid melanocytic subgroups (SN versus AST versus MST).ConclusionOur findings demonstrate that Spitz tumours are highly immunogenic lesions. Inflammation with the presence of lymphocytic aggregates predominated in SN, but was not distinctive for this melanocytic category. A strong and intense inflammation was suggestive of an underlying malignancy. The infiltrating cytotoxic T lymphocyte subsets in Spitz tumours deserve further investigation in larger study cohorts to elucidate prognostic and immuno-oncological therapeutic relevance.

Dataset Information

Identification of NTRK3 Fusions in Childhood Melanocytic Neoplasms.

Publications

Identification of NTRK3 Fusions in Childhood Melanocytic Neoplasms.

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