Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas

Jour, George; Andeen, Nicole K.; Al‐Rohil, Rami N.; Aung, Phyu P.; Mehrotra, Meenakshi; Hoch, Benjamin; Argenyi, Zolt; Luthra, Rajyalakshmi; Wistuba, Ignacio I.; Prieto, Víctor G.

doi:10.1002/path.4996

Cited by 18 publications

(13 citation statements)

References 48 publications

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“…2b). These findings are concordant to the perturbed pathways identified in a previous study using network analysis 11 . Following identification of disparate immune signatures encountered in these two entities, we subsequently carried out GSEA to elucidate affected cancer immune pathways.…”

Section: Differential Gene Expression In C-mpnst and Scm Reveals Distsupporting

confidence: 91%

“…The tumor microenvironment (TME) establishes an intricate niche whereby tumor cells interact with neighboring stromal and extracellular matrix elements to create a collaborative setting that promotes tumor progression and an aptitude for metastasis 9,10 . Exploration of these entities has provided dynamic insights into the molecular classification and methylome signatures that aid in distinguishing between C-MPNSTs and SCMs, while further laying the foundation for potential future targeted therapies 11,12 . Recently, our group identified pivotal immune pathway perturbations in the TME detected in both C-MPNSTs and SCMs that included the janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, nuclear factor-κB (NF-κB), and CXCL12-CXCR4, in addition to CD274 (PD-L1) and CTLA4 overexpression 11 .…”

mentioning

confidence: 99%

“…Exploration of these entities has provided dynamic insights into the molecular classification and methylome signatures that aid in distinguishing between C-MPNSTs and SCMs, while further laying the foundation for potential future targeted therapies 11,12 . Recently, our group identified pivotal immune pathway perturbations in the TME detected in both C-MPNSTs and SCMs that included the janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, nuclear factor-κB (NF-κB), and CXCL12-CXCR4, in addition to CD274 (PD-L1) and CTLA4 overexpression 11 . Furthermore, subsequent interrogation of genomic methylation profiles identified a distinct methylome signature implicating the promoter region of the Branched-Chain Aminotransferase 1 (BCAT1) gene.…”

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confidence: 99%

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Correlative study of epigenetic regulation of tumor microenvironment in spindle cell melanomas and cutaneous malignant peripheral nerve sheath tumors

Vougiouklakis¹,

Aung

Vasudevaraja

et al. 2020

Sci Rep

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the tumor microenvironment (tMe) plays critical roles in tumor growth and progression, however key regulators of gene expression in the tMe of cutaneous malignant peripheral nerve sheath tumor (c-MpnSt) and spindle cell melanoma (ScM) have not been well elucidated. Herein, we investigate the epigenetic regulation of promoters and gene bodies and their effect on the TME composition of C-MPNSTs and SCMs. A cohort of 30 patients was analyzed using differential gene expression (DGE) and gene set enrichment analysis (GSeA) using the nanostring platform. Methylation analysis was carried out utilizing an Infinium Methylation EPIC array targeting 866,562 methylation site (CpG) islands. DGE revealed overexpression of genes related to mast cells in the TME of SCMs, and a predominance of exhausted CD8 + t cells and macrophages in the tMe of c-MpnSts. interestingly, we further observed promoter hypermethylation in key overexpressed genes and corresponding gene body hypomethylation. Analysis using ENCODE ChIP-sequencing data identified CTCF as the common transcription factor at the site of the hypomethylated probe. These findings support that the TME composition of c-MpnSts and ScMs is at least partially independent on promoter methylation status, suggesting a possible relationship between gene body enhancers and expression of key tMe genes in both entities. Significant histomorphologic challenges frequently arise in the distinction between cutaneous malignant peripheral nerve sheath tumor (C-MPNST) and spindle cell melanoma (SCM) on account that both entities display immunopositivity for S100 and typically do not exhibit immunoreactivity for more specific markers of melanocytic differentiation 1-3. Morphologic infidelity further presents diagnostic hurdles in discriminating between C-MPNSTs and certain amelanotic SCMs, particularly in sun-damaged areas of the skin 2. Rendering the correct diagnosis is crucial as prognosis and patient management are different among these lesions. MPNSTs constitute approximately 3-10% of all soft tissue sarcomas and portend dismal prognosis with propensity for local invasion 4,5. These neoplasms have the proclivity to arise from the deep soft tissues of the upper and lower limbs, and from the trunk 6. C-MPNSTs represent a rare subtype localized to the dermis and/or subcutis with unusual clinical presentation arising primarily in association with neurofibromas 7. The mainstay of

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Section: Differential Gene Expression In C-mpnst and Scm Reveals Distsupporting

confidence: 91%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Correlative study of epigenetic regulation of tumor microenvironment in spindle cell melanomas and cutaneous malignant peripheral nerve sheath tumors

Vougiouklakis¹,

Aung

Vasudevaraja

et al. 2020

Sci Rep

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“…In the Cancer Genome Atlas Research Network analysis, undifferentiated pleomorphic, myxofibrosarcoma, and dedifferentiated liposarcoma had the highest median macrophage scores [ 40 ]. Increased recruitment of macrophages in malignant peripheral nerve sheath tumors (MPNSTs) indicate that these tumors may be candidates for response with certain immunotherapy agents [ 41 ].…”

Section: Tumor Immune Microenvironmentmentioning

confidence: 99%

Addressing the Adult Soft Tissue Sarcoma Microenvironment with Intratumoral Immunotherapy

Raj

Miller

Triozzi

2018

Sarcoma

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Sarcoma is comprised of a heterogeneous group of tumors originating from the mesenchyme. Sarcoma is also the first tumor that responded to immunotherapeutic agents often termed as “Coley's toxins.” However, immunotherapy is yet to establish its presence in sarcomas. Complex interactions between tumor and immune cells in the tumor microenvironment play a crucial role in response to immunotherapy. There is a dynamic equilibrium created by the immune cells infiltrating the tumor, and this forms the basis of tumor evasion. Manipulating the intratumoral microenvironment will help overcome tumor evasion.

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“…While NOTCH1 expression is reduced in mature melanocytes, activated NOTCH1 and ERBB3 increase downstream protein kinase B (Akt) and NFκB signaling, promoting survival and growth of mutated and wild‐type BRAF melanomas . Activating mutations in the negative regulatory domain of NOTCH1 have been identified in the subsets of spindle cell/desmoplastic melanoma and malignant peripheral nerve sheath tumors . Deletions in NOTCH1 have also been documented in BRAF mutant melanomas .…”

Section: Discussionmentioning

confidence: 99%

Distant metastasis due to heavily pigmented epithelioid melanoma with underlying BRAF V600E, NOTCH1, ERBB3, and PTEN mutations

2019

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Pigment-synthesizing melanoma (PSM) describes a morphologically and genetically diverse group of melanomas. In contrast, pigmented epithelioid melanocytoma (PEM) encompasses a spectrum of indolent tumors now classified as borderline/intermediate melanocytic tumors. Herein, we report a case of widely metastatic heavily pigmented epithelioid melanoma with fatal outcome in a 36-year-old woman. Nextgeneration sequencing identified somatic (tumoral) mutations in BRAF V600E, PTEN, NOTCH1, and ERBB3. By contrast, GNAQ and GNA11 were wild type. Prkar1α and p16 expression were maintained. Identification of mutations in NOTCH1 and ERBB3 may support the diagnosis of heavily pigmented epithelioid melanoma. In contrast, PRKCA fusion genes and PRKAR1A mutations support the diagnosis of PEM. Given the heterogeneity, potential overlap (loss of Prkar1α expression), and evolving genetic profiles of these two distinct groups of tumors, careful appraisal of molecular profiles in the light of histomorphology and clinical history is necessary for distinction between PEM and PSMs including heavily pigmented epithelioid melanomas, with significant potential impact on prognosis and therapy. K E Y W O R D S BRAF V600E, ERBB3, next-generation sequencing, NOTCH1, pigmented epithelioid melanocytoma, pigment-synthesizing melanoma, PTEN

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Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas

Cited by 18 publications

References 48 publications

Correlative study of epigenetic regulation of tumor microenvironment in spindle cell melanomas and cutaneous malignant peripheral nerve sheath tumors

Correlative study of epigenetic regulation of tumor microenvironment in spindle cell melanomas and cutaneous malignant peripheral nerve sheath tumors

Addressing the Adult Soft Tissue Sarcoma Microenvironment with Intratumoral Immunotherapy

Distant metastasis due to heavily pigmented epithelioid melanoma with underlying BRAF V600E, NOTCH1, ERBB3, and PTEN mutations

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