ABSTRACT 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.
Rossi et al. (Thu,) studied this question.