Activating Structural Alterations in MAPK Genes Are Distinct Genetic Drivers in a Unique Subgroup Of Spitzoid Neoplasms
| Autor: | Kevin P. White, Elnaz Panah, Maria Cristina Isales, Nike Beaubier, Lauren S. Mohan, Victor L. Quan, Timothy Taxter, Bin Zhang, Pedram Gerami, Katherine Shi |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine MAPK/ERK pathway Skin Neoplasms Adolescent MAP3K3 Biology MAP3K8 Pathology and Forensic Medicine Young Adult 03 medical and health sciences 0302 clinical medicine Nevus Epithelioid and Spindle Cell MAP2K1 Humans Oncogene Fusion Child Extracellular Signal-Regulated MAP Kinases Gene Genetics Kinase Middle Aged Fusion protein 030104 developmental biology Child Preschool 030220 oncology & carcinogenesis Female Surgery Anatomy Tyrosine kinase |
| Zdroj: | American Journal of Surgical Pathology. 43:538-548 |
| ISSN: | 0147-5185 |
| Popis: | Recent studies have described kinase fusions as the most common initiating genomic events in Spitzoid neoplasms. Each rearrangement generates a chimeric protein with constitutive activation of the tyrosine kinase domain, resulting in the development of a Spitzoid neoplasm. Identifying key initiating genomic events and drivers may assist in diagnosis, prognostication, and management. Retrospective, consecutive search of our database between 2009 and 2018 for Spitzoid neoplasms identified 86 cases. Whole transcriptome mRNA and DNA sequencing (1714 genes) detected 9% of cases (8/86) with structural rearrangements in MAPK genes other than BRAF and 47% (40/86) with kinase fusions previously described in Spitzoid neoplasms. We identified in-frame fusions of MAP3K8-DIPC2, MAP3K8-PCDH7, MAP3K8-UBL3, MAP3K8-SVIL (n=6), and ATP2A2-MAP3K3 (n=1) as well as a p.I103_K104 in-frame deletion of MAP2K1 (n=1), in the absence of well-recognized drivers of melanocytic neoplasia. Fluorescence in situ hybridization validated all cases (n=7) with available tissue. Cases occurred in younger patients (median age 18 y). Morphologically, cases were predominantly epithelioid (P=0.0032), often with some melanin pigment (P=0.0047), and high-grade nuclear atypia (P=0.012). A significant proportion were thought to be Spitzoid melanomas (3/8). Average follow-up time was 11 months. One MAP3K8-DIP2C Spitzoid melanoma involved 4/5 sentinel lymph nodes and led to a complete lymph node dissection with unremarkable follow-up at 9 months. One MAP3K8-DIPC2 atypical Spitz tumor raised concern for recurrence at 10 months and was reexcised. We present a distinct subtype of Spitzoid neoplasm characterized by structural alterations in MAPK genes, which are important to recognize given the potential for treatment with MAPK inhibitors in metastatic cases. |
| Databáze: | OpenAIRE |
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