Melanomas and Mesenchymal Tumors Arising in Giant Congenital Melanocytic Nevi: Clinico‐Pathological and Molecular Characterization of a Case Series

Giant congenital melanocytic nevi (GCMN) are benign mosaic disorders that may give rise to various tumor types through incompletely understood mechanisms. We characterized a series of two melanomas and four mesenchymal tumors (two embryonal rhabdomyosarcomas, one small round cell sarcoma, one low-grade mesenchymal tumor) arising in GCMN. Median onset age was 3.5 years and 3 months for melanoma and mesenchymal tumor patients, respectively. Both melanoma patients succumbed within 27 months from diagnosis, whereas no patients progressed in the mesenchymal group (median follow-up 46 months). NRAS Q61, BRAF V600E mutation, and a novel in frame BIN1::BRAF fusion were detected in four, one, and one cases, respectively, with a higher variant allele frequency in the tumors compared with the matched GCMN. Copy number alterations and/or copy-neutral loss of heterozygosity were exclusively found in the tumors in all cases. An inactivating ASXL1 variant and an in-frame KDM5B::LPGAT1 fusion were identified in one melanoma; paternal disomy of 11p15.5 in both embryonal rhabdomyosarcomas. Mesenchymal tumors and melanomas showed distinct transcriptional profiles enriched in muscle and synapse organization and epidermal differentiation genes, respectively.