Integrating Next Generation Sequencing with Morphology Improves Prognostic and Biologic Classification of Spitz Neoplasms

Journal of Infectious Diseases Manuscript
Authors Victor L. Quan, Bin Zhang, Yongzhan Zhang, Lauren S. Mohan, Katherine Shi, Annette Wagner, Lacey Kruse, Timothy Taxter, Nike Beaubier, Kevin White, Lihua Zou, and Pedram Gerami

The newest WHO classification suggests eliminating cases with BRAF and NRAS mutations from the categories of Spitz tumors (ST) and Spitz melanoma (SM). We aimed to better characterize the genomics of Spitz neoplasms and assess whether integrating genomic data with morphologic diagnosis improves classification and prognostication. We performed DNA and RNA sequencing on 80 STs, 26 SMs, and 22 melanomas with Spitzoid features (MSF). NGS data was used to reclassify tumors by moving BRAF/NRAS-mutated cases to MSF. Eighty-one percent of STs harbored kinase fusions/truncations. Of SMs, 77% had fusions/truncations, 8 involving MAP3K8. Previously unreported fusions identified were MYO5AFGFR1MYO5AERBB4, and PRKDCCTNNB1. The majority of MSFs (84%) had BRAFNRAS, or NF1 mutations, and 62% had TERT promoter mutations. Only after reclassification, the following was observed: 1) mRNA expression showed distinct clustering of MSF; 2) 6/7 cases with recurrence and all distant metastases were MSFs; 3) RFS was worse in MSF than ST and SM groups (p=0.0073); 4) classification incorporating genomic data was highly predictive of recurrence (OR 13.20, p=0.0197). The majority of STs and SMs have kinase fusions as primary initiating genomic events. Eliminating BRAF/NRAS-mutated neoplasms from these categories results in improved classification and prognostication of melanocytic neoplasms with Spitzoid cytomorphology.