Activating Structural Alterations in MAPK Genes Are Distinct Genetic Drivers in a Unique Subgroup Of Spitzoid Neoplasms

Victor L. Quan, Bin Zhang, Lauren S. Mohan, Katherine Shi, Maria C. Isales, Elnaz Panah, Timothy J. Taxter, Nike Beaubier, Kevin White, Pedram Gerami*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)538-548
Number of pages11
JournalAmerican Journal of Surgical Pathology
Volume43
Issue number4
DOIs
StatePublished - Apr 1 2019

Fingerprint

Genes
Neoplasms
Melanoma
Phosphotransferases
Melanins
Lymph Node Excision
Fluorescence In Situ Hybridization
DNA Sequence Analysis
Transcriptome
Protein-Tyrosine Kinases
Databases
Recurrence
Messenger RNA
Proteins
Therapeutics

Keywords

  • MAP2K1
  • MAP3K3
  • MAP3K8
  • Spitzoid
  • Spitzoid melanoma
  • atypical Spitz tumor
  • fusions
  • genomics

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

Quan, Victor L. ; Zhang, Bin ; Mohan, Lauren S. ; Shi, Katherine ; Isales, Maria C. ; Panah, Elnaz ; Taxter, Timothy J. ; Beaubier, Nike ; White, Kevin ; Gerami, Pedram. / Activating Structural Alterations in MAPK Genes Are Distinct Genetic Drivers in a Unique Subgroup Of Spitzoid Neoplasms. In: American Journal of Surgical Pathology. 2019 ; Vol. 43, No. 4. pp. 538-548.
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abstract = "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.",
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Activating Structural Alterations in MAPK Genes Are Distinct Genetic Drivers in a Unique Subgroup Of Spitzoid Neoplasms. / Quan, Victor L.; Zhang, Bin; Mohan, Lauren S.; Shi, Katherine; Isales, Maria C.; Panah, Elnaz; Taxter, Timothy J.; Beaubier, Nike; White, Kevin; Gerami, Pedram.

In: American Journal of Surgical Pathology, Vol. 43, No. 4, 01.04.2019, p. 538-548.

Research output: Contribution to journalArticle

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AU - Quan, Victor L.

AU - Zhang, Bin

AU - Mohan, Lauren S.

AU - Shi, Katherine

AU - Isales, Maria C.

AU - Panah, Elnaz

AU - Taxter, Timothy J.

AU - Beaubier, Nike

AU - White, Kevin

AU - Gerami, Pedram

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AB - 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.

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