Melanocytic Neoplasms With MAP2K1 in Frame Deletions and Spitz Morphology

Sunshine, Joel C.; Kim, Daniel; Zhang, Bin; Compres, Elsy V.; Khan, Ayesha U.; Busam, Klaus J.; Gerami, Pedram

doi:10.1097/dad.0000000000001795

Cited by 21 publications

(37 citation statements)

References 30 publications

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“…In addition, genes encoding protein tyrosine kinases, KIT and EPHA5 , relevant receptors upstream of the MAPK pathway, are particularly highly expressed in the melanoma compared to BAP1 -inactivated nevus. Interestingly, a mutation in the MAP2K1 gene was identified in the BAPoma from our patient; similar mutations in this gene have been reported in a large spectrum of melanocytic lesions, including BAPomas [ 21 ].…”

Section: Discussionsupporting

confidence: 83%

Gene Expression and Mutational Profile in BAP-1 Inactivated Melanocytic Lesions of Progressive Malignancy from a Patient with Multiple Lesions

Zhou

Nelson

et al. 2021

Genes

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BAP-1 (BRCA1-associated protein 1) inactivated melanocytic lesions are a group of familial or sporadic lesions with unique histology and molecular features. They are of great clinical interest, at least in part due to the potential for malignant transformation and association with a familial cancer predisposition syndrome. Here, we describe a patient with multiple spatially and temporally distinct melanocytic lesions with loss of BAP1 expression by immunohistochemistry. RNA sequencing was performed on three independent lesions spanning the morphologic spectrum: a benign nevus, an atypical tumor, and a melanoma arising from a pre-existing BAP1-inactivated nevus. The three lesions demonstrated largely distinct gene expression and mutational profiles. Gene expression analysis revealed that genes involved in receptor protein kinase pathways were progressively upregulated from nevus to melanoma. Moreover, a clear enrichment of genes regulated in response to UV radiation was found in the melanoma from this patient, as well as upregulation of MAPK pathway-related genes and several transcription factors related to melanomagenesis.

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Section: Discussionsupporting

confidence: 83%

Gene Expression and Mutational Profile in BAP-1 Inactivated Melanocytic Lesions of Progressive Malignancy from a Patient with Multiple Lesions

Zhou

Nelson

et al. 2021

Genes

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“…are mostly associated with Spitz lesions, whereas mutations are typical for conventional melanocytic lesions. However, there are well-known exceptions such as HRAS mutation in desmoplastic Spitz nevus and MAP2K1 mutations in Spitz lesions [35][36][37] . RAF proto-oncogene serine/threonineprotein kinase encoded by RAF1 functions as an alternative MAPK signaling mechanism as it forms dimers with wild-type BRAF 38 .…”

Section: Discussionmentioning

confidence: 99%

Novel insights into the BAP1-inactivated melanocytic tumor

et al. 2022

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BAP1-inactivated melanocytic tumor (BIMT) is a group of melanocytic neoplasms with epithelioid cell morphology molecularly characterized by the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21, and a mutually exclusive mitogenic driver mutation, more commonly BRAF. BIMTs can occur as a sporadic lesion or, less commonly, in the setting of an autosomal dominant cancer susceptibility syndrome caused by a BAP1 germline inactivating mutation. Owing to the frequent identification of remnants of a conventional nevus, BIMTs are currently classified within the group of combined melanocytic nevi. "Pure" lesions can also be observed. We studied 50 BIMTs from 36 patients. Most lesions were composed of epithelioid melanocytes of varying size and shapes, resulting extreme cytomorphological heterogeneity. Several distinctive morphological variants of multinucleated/giant cells were identified. Some hitherto underrecognized microscopic features, especially regarding nuclear characteristics included nuclear blebbing, nuclear budding, micronuclei, shadow nuclei, peculiar cytoplasmic projections (ant-bear cells) often containing micronuclei and cell-in-cell structures (entosis). In addition, there were mixed nests of conventional and BAP1-inactivated melanocytes and squeezed remnants of the original nevus. Of the 26 lesions studied, 24 yielded a BRAF mutation, while in the remaining two cases there was a RAF1 fusion. BAP1 biallelic and singe allele mutations were found in 4/22 and 16/24 neoplasms, respectively. In five patients, there was a BAP1 germline mutation. Six novel, previously unreported BAP1 mutations have been identified. BAP1 heterozygous loss was detected in 11/22 lesions. Fluorescence in situ hybridization for copy number changes revealed a related amplification of both RREB1 and MYC genes in one tumor, whereas the remaining 20 lesions studied were negative; no TERT-p mutation was found in 14 studied neoplasms. Tetraploidy was identified in 5/21 BIMTs. Of the 21 patients with available follow-up, only one child had a locoregional lymph node metastasis. Our results support a progression of BIMTs from a conventional BRAF mutated in which the original nevus is gradually replaced by epithelioid BAP1-inactivated melanocytes. Some features suggest more complex underlying pathophysiological events that need to be elucidated.

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“…One of these, the C125S variant, was previously identified in melanoma patients who developed resistance to BRAF inhibitors [ 25 , 26 ]. In a recent study, MAP2K1 alterations were reported in neoplasms with heterogeneous cell morphology, including melanocytic tumors with Spitz cytomorphology, DPN-like architecture with a plexiform pattern, and heavy melanization [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

NGS-Based Analysis of Atypical Deep Penetrating Nevi

Manca

Sini

Cesinaro

et al. 2021

Cancers

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Deep penetrating nevi (DPNs) are rare melanocytic neoplasms consisting of pigmented spindled or epithelioid melanocytes with a distinctive wedge-shaped configuration showing activation of the WNT pathway, with unusual cyto-architectural features. It is unclear whether they show a distinct genomic profile associated with a diverse metastatic potential. We describe herein a cohort of 21 atypical DPNs analyzed by next-generation sequencing using the Ion AmpliSeq™ Comprehensive Cancer Panel. We found that β-catenin exon 3 was mutated in 95% and MAP kinase pathway genes in 71% of the cases. Less frequent mutations were observed in HRAS (19%) and MAP2K1 (24%). Isocitrate dehydrogenases 1 (IDH1) mutations, including R132C, V178I, and S278L, were identified in 38% of cases and co-existed with BRAF/HRAS mutations. The only case with progressive nodal disease carried alterations in the β-catenin pathway and mutations in IDH1 and NRAS (codon 61). By a comprehensive mutation analysis, we found low genetic heterogeneity and a lack of significant associations between specific gene mutations and histopathological features, despite atypical features. Whether the acquisition of an NRAS or IDH1 mutation in an atypical DPN may represent a molecular evolution implying a pathway to melanoma progression should be confirmed in a larger series.

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Melanocytic Neoplasms With MAP2K1 in Frame Deletions and Spitz Morphology

Cited by 21 publications

References 30 publications

Gene Expression and Mutational Profile in BAP-1 Inactivated Melanocytic Lesions of Progressive Malignancy from a Patient with Multiple Lesions

Gene Expression and Mutational Profile in BAP-1 Inactivated Melanocytic Lesions of Progressive Malignancy from a Patient with Multiple Lesions

Novel insights into the BAP1-inactivated melanocytic tumor

NGS-Based Analysis of Atypical Deep Penetrating Nevi

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