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Integrating Next-Generation Sequencing with Morphology Improves Prognostic and Biologic Classification of Spitz
Victor L Quan1, Bin Zhang1, Yongzhan Zhang2
1Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
The Journal of Investigative Dermatology
|February 1, 2020
Summary
The newest WHO skin tumor classification removes BRAF/NRAS mutations from Spitz tumors (ST) and Spitz melanoma (SM). Integrating genomic data improves classification and prognostication of Spitz neoplasms, identifying kinase fusions in STs/SMs and mutations in melanomas with Spitzoid features.
Area of Science:
- Dermatopathology
- Oncology
- Genomics
Background:
- The World Health Organization's latest skin tumor classification excludes Spitz tumors (ST) and Spitz melanoma (SM) with BRAF and NRAS mutations.
- Spitzoid neoplasms present diagnostic challenges, necessitating refined classification and prognostication methods.
Purpose of the Study:
- To genomically characterize Spitz neoplasms.
- To evaluate if integrating genomic data with morphology improves the classification and prognosis of these tumors.
Main Methods:
- DNA and RNA sequencing were performed on 80 STs, 26 SMs, and 22 melanomas with Spitzoid features (MSFs).
- Tumors were reclassified based on next-generation sequencing data, moving BRAF/NRAS mutated cases to MSF.
- Genomic alterations including kinase fusions, truncations, and mutations were analyzed.
Main Results:
- 81% of STs and 77% of SMs showed kinase fusions/truncations; eight SMs involved MAP3K8.
- Previously unreported fusions: MYO5A-FGFR1, MYO5A-ERBB4, PRKDC-CTNNB1.
- Post-reclassification, MSFs showed distinct mRNA expression, higher recurrence rates (6/7 cases), and worse recurrence-free survival (P=0.0073).
- Genomic data integration significantly predicted recurrence (OR 13.20, P=0.0197).
Conclusions:
- Spitz tumors and Spitz melanoma predominantly harbor kinase fusions as initiating genomic events.
- Excluding BRAF/NRAS mutated neoplasms from ST/SM categories enhances classification and prognostication.
- Genomic profiling is crucial for accurate diagnosis and risk assessment of melanocytic neoplasms with Spitzoid features.
