Missense mutation of NRAS is associated with malignant progression in neurocutaneous melanosis

Acta Neuropathol Commun.2024 Jan 22;12(1):14. doi: 10.1186/s40478-024-01723-0.

Takahashi H1, Natsumeda M1,2, Hara N3, Koyama A4, Shimizu H5, Miyashita A3, Satake D1, Mouri Y1, Tsukano J1, Kawabe K1, Tsukamoto Y1, Okada M1, Ogura R1, Yuki A6, Umezu H7, Kakita A5, Ikeuchi T3, Oishi M1.

1Department of Neurosurgery, Brain Research Institute, Niigata University
2Advanced Treatment of Neurological Diseases Branch, Brain Research Institute, Niigata University
3Department of Molecular Genetics, Brain Research Institute, Niigata University
4Department of Legal Medicine, Graduate School of Medical and Dental Science, Niigata University
5Department of Pathology, Brain Research Institute, Niigata University
6Division of Dermatology, Graduate School of Medical and Dental Sciences, Niigata University
7Division of Pathology, Niigata University Medical and Dental Hospital, Niigata University


Neurocutaneous melanosis (NCM) is a rare congenital neurocutaneous syndrome characterized by congenital melanocytic nevus of skin and abnormal proliferation of leptomeningeal melanocytes. Early acquisition of post-zygotic somatic mutations has been postulated to underlie the pathogenesis of NCM. The pathogenesis of NCM remains to be fully elucidated, and treatment options have not been established. Here, we report for the first time, multiregional genomic analyses in a 3-year-old autopsied girl with leptomeningeal melanomatosis associated with NCM, in which a ventriculo-peritoneal (VP) shunt was inserted for the treatment of hydrocephalus. The patient expired six months after the onset due to respiratory failure caused by abdominal dissemination via VP shunt. We performed multiregional exome sequencing to identify genomic differences among brain and abdominal tumors, nevus, and normal tissues. A total of 87 somatic mutations were found in 71 genes, with a significantly large number of gene mutations found in the tumor site. The genetic alterations detected in the nevus were only few and not shared with other sites. Three mutations, namely GNAQ R183Q, S1PR3 G89S and NRAS G12V, considered pathogenic, were found, although S1PR3 mutations have not been previously reported in melanocytic tumors. GNAQ and S1PR3 mutations were shared in both tumor and normal sites. Moreover, the mutant allele frequencies of the two mutations were markedly higher in tumor sites than in normal sites, with copy-neutral loss-of-heterozygosity (CN-LOH) occurring in tumor. NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discovering novel driver mutations associated with tumorigenesis and targeted therapy.

Keywords: Droplet digital polymerase chain reaction; Multiregional genomic analysis; Neurocutaneous melanosis; Whole exome sequencing.

*Reprinted under the terms of the Creative Commons Attribution License (CC BY).

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