Melanocytic tumors with MAP3K8 fusions: report of 33 cases with morphological-genetic correlations

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 5ʹ part of MAP3K8 comprising exons 1–8 in frame to one of several partner genes at the 3ʹ 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 3ʹ fusion partner was SVIL. Other recurrent 3ʹ 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.

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Acknowledgements

We thank the following pathologists for their case contribution: Drs. Paoletti, Plantier, de Mauroy, Niel, Habougit, Michiels marzais, Ziadé, Castillo, Petit, Vacheret, Voulat, Ducoin, Macagno, Palau, Rethers, Doumes-Lacoste, Gosset, Neumann, Palasse, Laurent-Roussel, Terrier, Arcin-Thoury, Carr, Godeneche, Martin de la Salle, and the following physicians for clinical and follow-up data: Drs. de Quatrebarbe, Diner, Chedeville, Pecheux, Perrot, Sage, Hauguel, Meyer, Rossi-Chouquet, Poeuf, Gillibert, Meyer, Berbis, Parrocel, Armingaud, Irani, Poddevin, Levy-Roi, de Berail, Chamain, Safia, Monteanu, Duval, Mortier, Dalle. Boris Bastian is supported by a grant from the National Cancer Institute (1R35CA220481). We also thank Florine Dreux, Elise Malandin, Cyril Py, Marlène Perrin-Niquet, Colline Taillandier, and Elodie Legrand for their technical help. We thank Sandrine Paindavoine and Pr Françoise Galateau for their assistance with the manuscript.

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Correspondence to Arnaud de la Fouchardière.

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Houlier, A., Pissaloux, D., Masse, I. et al. Melanocytic tumors with MAP3K8 fusions: report of 33 cases with morphological-genetic correlations. Mod Pathol (2019) doi:10.1038/s41379-019-0384-8

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