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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Melanocytic tumors with MAP3K8 fusions: report of 33 cases with morphological-genetic correlations
Aurelie Houlier1,2, Daniel Pissaloux1,2, Ingrid Masse2
1Department of Biopathology, Centre Léon Bérard, Lyon, France.
Abstract:
We report a series of 33 skin tumors harboring a gene fusion of the MAP3K8 gene, which encodes a serine/threonine kinase. The MAP3K8 fusions were identified by RNA sequencing in 28 cases and by break-apart FISH in five cases. Cases in which fusion genes were fully characterized demonstrated a fusion of the 5' part of MAP3K8 comprising exons 1-8 in frame to one of several partner genes at the 3' end. The fusion genes invariably encoded the intact kinase domain of MAP3K8, but not the inhibitory domain at the C-terminus. In 13 (46%) of the sequenced cases, the 3' fusion partner was SVIL. Other recurrent 3' partners were DIP2C and UBL3, with additional fusion partners that occurred only in a single tumor. Clinically, the lesions appeared mainly in young adults (2-59 years of age; median = 18), most commonly involving the lower limbs (55%). Five cases were diagnosed as Spitz nevus, 13 as atypical Spitz tumor, and 15 as malignant Spitz tumor. Atypical and malignant cases more commonly occurred in younger patients. Atypical Spitz tumors and malignant Spitz tumors cases tended to show epidermal ulceration (32%), a dermal component with giant multinucleated cells (32%), and clusters of pigmented cells in the dermis (32%). Moreover, in atypical and malignant cases, a frequent inactivation of CDKN2A (21/26; 77%) was identified either by p16 immunohistochemistry, FISH, or comparative genomic hybridization. Gene expression analysis revealed that MAP3K8 expression levels were significantly elevated compared to a control group of 57 Spitz lesions harboring other known kinase fusions. Clinical follow-up revealed regional nodal involvement in two of six cases, in which sentinel lymph node biopsy was performed but no distant metastatic disease after a median follow-up time of 6 months.
Insights
Skin tumors with MAP3K8 gene fusions are identified in young adults, often on lower limbs. These fusions may indicate atypical or malignant Spitz tumors, with CDKN2A inactivation common in aggressive cases.
Area of Science:
- Oncology
- Genetics
- Dermatopathology
Background:
- Gene fusions involving MAP3K8, encoding a serine/threonine kinase, are implicated in various cancers.
- Spitz tumors represent a spectrum of melanocytic neoplasms with unpredictable behavior.
Purpose of the Study:
- To characterize the clinicopathological and molecular features of skin tumors harboring MAP3K8 gene fusions.
- To investigate the association between MAP3K8 fusions and tumor behavior, including malignancy and CDKN2A inactivation.
Main Methods:
- RNA sequencing and break-apart FISH were used to identify MAP3K8 fusions in 33 skin tumors.
- Comprehensive clinicopathological analysis, including immunohistochemistry and comparative genomic hybridization, was performed.
- Gene expression analysis compared MAP3K8 levels in fusion-positive tumors versus controls.
Main Results:
- MAP3K8 fusions were identified in 33 skin tumors, predominantly in young adults (median age 18) and on lower limbs.
- Fusion genes invariably encoded the intact MAP3K8 kinase domain, frequently fused with SVIL.
- Atypical and malignant Spitz tumors showed increased frequency of epidermal ulceration, multinucleated giant cells, pigmented dermal clusters, and CDKN2A inactivation (77%).
- MAP3K8 expression was significantly elevated in fusion-positive tumors.
Conclusions:
- MAP3K8 gene fusions are recurrent molecular alterations in a subset of Spitz tumors, particularly in younger individuals.
- These fusions are associated with specific clinicopathological features and frequent CDKN2A inactivation in atypical and malignant cases.
- Further investigation into the role of MAP3K8 in Spitz tumor tumorigenesis and potential therapeutic strategies is warranted.
