Genomic analysis of metastatic melanoma in an adult with giant congenital melanocytic nevus

: Giant congenital melanocytic nevi (GCMN) are benign cutaneous lesions associated with increased risk for developing melanoma. Genomic studies of congenital melanocytic nevi revealed NRAS mutation as the sole mutational event in these lesions. However, studies to date have focused on mutations of benign lesions but not the malignant counterparts. Here, we performed genomic analysis of metastatic melanoma in a patient with a GCMN. We used whole exome sequencing to confirm an identical NRASQ61R mutation in the GCMN and the metastatic tumor in the lung. We identified additional somatic mutations in the metastatic tumor that may have contributed to the malignant transformation and metastasis. Gene expression analysis comparing this patient's GCMN with NRAS-mutant melanoma from the Cancer Genome Atlas (TCGA) characterized dysregulated genes including tumor suppressors and those involved in development, cell fate determination, and stem cell pluripotency. Our results support further molecular and functional studies of melanoma arising in GCMN using matched benign and malignant samples from the same patients. Studying this distinct melanoma subset may shed light on the benign to malignant transformation and metastasis of NRAS-driven tumors.