Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas

Newman, Scott; Fan, Liying; Pribnow, Allison; Silkov, Antonina; Rice, Stephen V.; Lee, Seungjae; Shao, Ying; Shaner, Bridget; Mulder, Heather L.; Nakitandwe, Joy; Shurtleff, Sheila; Azzato, Elizabeth M.; Wu, Gang; Zhou, Xin; Barnhill, Raymond L.; Easton, John; Nichols, Kim E.; Ellison, David W.; Downing, James R.; Pappo, Alberto S.; Potter, Philip M.; Zhang, Jinghui; Bahrami, Armita

doi:10.1038/s41591-019-0373-y

Cited by 69 publications

(91 citation statements)

References 44 publications

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“…Similar to BRAF fusion cases, they tend to be epithelioid with high grade nuclear atypia and have a higher likelihood of notable melanin pigment compared to other fusions (Figure ) . One patient with a MAP3K8‐GNG2 fusion Spitz melanoma and metastatic disease showed a transient response to trametinib for 1 month, but developed cardiotoxicity and eventually died of metastatic disease …”

Section: Spitz Neoplasmsmentioning

confidence: 98%

“…For example, while the vast majority of Spitz neoplasms with ALK , NTRK1 , NTRK3 , RET, and ROS1 fusions are diagnosed as either Spitz nevus or ASTs, with only a small percentage diagnosed as Spitz melanoma, a significantly greater proportion of BRAF , MET, and in particular, MAP3K8 fusions are diagnosed as Spitz melanoma. Two recent independent publications identified MAP3K8 fusions as the most common fusion in Spitz melanomas …”

Section: Spitz Neoplasmsmentioning

confidence: 99%

“…Two recent independent studies identified structural alterations in MAPK genes in 9% to 33% of Spitz neoplasms, using transcriptome sequencing to detect MAP2K1 in‐frame deletions, MAP3K3 fusions, and MAP3K8 kinase fusions and truncations as initiating oncogenic events. In both, structural alterations in non‐ BRAF MAPK genes were identified as the single most frequent driver in their Spitz melanomas (22%) . Non‐ BRAF MAPK fusions, consisting mostly of MAP3K8 fusions, can occur in ASTs and Spitz melanomas.…”

Section: Spitz Neoplasmsmentioning

confidence: 99%

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The role of gene fusions in melanocytic neoplasms

et al. 2019

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Recent advances in next generation sequencing (NGS) have allowed for efficient whole transcriptome sequencing, leading to the identification of important kinase fusions as the primary driver in some melanocytic neoplasms. These fusions typically occur mutually exclusively of one another and other well-known initiating mutations such as BRAF, NRAS, NF1, KIT, and GNAQ. Fusions are found in over 50% of Spitz neoplasms, including ALK, BRAF, NTRK1, NTRK3, ROS1, MET, MAP3K8, and RET. Familiarity with the typical morphologic features of certain fusion-driven melanocytic neoplasms can help with classification, diagnosis, and identification of targeted molecular therapies in malignant cases. Spitz tumors with ALK, NTRK1, and NTRK3 fusions have characteristic morphologic features. BRAF and MAP3K8 fusions, in particular, tend to be epithelioid, high grade, and more frequent in Spitz melanoma than other fusion subtypes. Sporadic cases of pigmented epithelioid melanocytoma may have PRKCA fusions and sheets of monomorphic epithelioid melanocytes. Fusion events are also enriched among melanomas without the key mutations BRAF, NRAS, or NF1. Although NGS is the most reliable method to detect fusions, immunohistochemistry and fluorescence in situ hybridization are costeffective alternatives in some cases. We describe recent discoveries regarding the role of kinase fusions in melanocytic neoplasms and their associated morphologies. K E Y W O R D S fusions, genomics, melanocytic lesions, melanoma, spitzoid 2 | MECHANISM OF FUSIONS Kinase fusions result from genomic rearrangements: (a) translocations, (b) inversions, (c) deletions, (d) duplications, or (e) complex Victor L. Quan and Elnaz Panah should be considered joint authors.

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Section: Spitz Neoplasmsmentioning

confidence: 98%

Section: Spitz Neoplasmsmentioning

confidence: 99%

Section: Spitz Neoplasmsmentioning

confidence: 99%

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The role of gene fusions in melanocytic neoplasms

et al. 2019

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“…The distribution of pathogenic mutations in melanocytic skin neoplasms has suggested that they may arise in a certain typical sequence . In common nevi, a BRAF mutation may represent an initial event, just as other driver mutations in other melanocytic lesions do ( NRAS in congenital and some acquired nevi, GNAQ and GNA11 in blue nevi, kinase fusions of ALK, BRAF, ROS1, NTRK1, NTRK3, MET, RET, MAP3K8 in Spitz nevi) . The increase of cellular proliferation, induced by one or more driver mutations, increases the probability that an additional mutation is acquired.…”

mentioning

confidence: 99%

“…4 In common nevi, a BRAF mutation may represent an initial event, just as other driver mutations in other melanocytic lesions do (NRAS in congenital and some acquired nevi, GNAQ and GNA11 in blue nevi, kinase fusions of ALK, BRAF, ROS1, NTRK1, NTRK3, MET, RET, MAP3K8 in Spitz nevi). [5][6][7][8][9][10][11][12] The increase of cellular proliferation, induced by one or more driver mutations, increases the probability that an additional mutation is acquired. If this occurs, the additional increase of cellular proliferation produces an additional increase of the probability that other mutations take place.…”

mentioning

confidence: 99%

Certain and uncertain malignant potential in melanocytic skin neoplasms

Urso¹

2019

J Cutan Pathol

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A prospective, comprehensive registry that integrates the molecular analysis of pediatric and adolescent melanocytic lesions

Pappo

McPherson

Pan

et al. 2021

Cancer

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BACKGROUND: Childhood melanocytic tumors represent a diagnostic and therapeutic challenge, and additional research is needed to better define the natural history of these tumors. METHODS: The authors developed a comprehensive, prospective registry called Molecular Analysis of Childhood Melanocytic Tumors for children and adolescents with an atypical Spitz tumor/Spitz melanoma (AST/ SM), conventional or adult-type melanoma (CM), melanoma arising in a giant congenital nevus (MCM), or atypical melanocytic proliferation of other types (OT) to better define the clinical behavior of these lesions by incorporating an integrated clinicopathologic and molecular analysis using centralized pathology review and various platforms, including fluorescence in situ hybridization; array comparative genomic hybridization; and whole genome, exome, and capture targeted panels. RESULTS: From May 2016 to November 2019, 70 children were enrolled with a median age at diagnosis of 9.1 years. Thirty-seven had AST/SM, 17 had CM, 4 had MCM, and 12 had OT. Patients with AST/SM were younger (median age, 7 years), and their tumor most commonly arose in the extremities and trunk. The most common gene rearrangements included MAP3K8 and ALK. None of the 33 patients who underwent a TERT promoter mutation analysis had a mutation, and all patients were alive. Among the CM patients, the median age was 13 years; 11 had a BRAFV600E mutation, and 7 had a TERT promoter mutation. Three patients died of their disease. All 4 patients with MCM harbored an NRASQ61 mutation and died of their disease. The OT group was heterogenous, and all patients survived. CONCLUSIONS: The incorporation of an integrated clinicopathologic and genomic analysis identifies distinct subgroups of pediatric melanocytic lesions that have different clinical behaviors. The integration of this combined diagnostic modality can help to individualize diagnoses and treatments for these patients.

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Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas

Cited by 69 publications

References 44 publications

The role of gene fusions in melanocytic neoplasms

The role of gene fusions in melanocytic neoplasms

Certain and uncertain malignant potential in melanocytic skin neoplasms

A prospective, comprehensive registry that integrates the molecular analysis of pediatric and adolescent melanocytic lesions

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