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The NF1 gene in tumor syndromes and melanoma.

ABSTRACT: Activation of the RAS/MAPK pathway is critical in melanoma. Melanoma can be grouped into four molecular subtypes based on their main genetic driver: BRAF-mutant, NRAS-mutant, NF1-mutant, and triple wild-type tumors. The NF1 protein, neurofibromin 1, negatively regulates RAS proteins through GTPase activity. Germline mutations in NF1 cause neurofibromatosis type I, a common genetic tumor syndrome caused by dysregulation of the RAS/MAPK pathway, ie, RASopathy. Melanomas with NF1 mutations typically occur on chronically sun-exposed skin or in older individuals, show a high mutation burden, and are wild-type for BRAF and NRAS. Additionally, NF1 mutations characterize certain clinicopathologic melanoma subtypes, specifically desmoplastic melanoma. This review discusses the current knowledge of the NF1 gene and neurofibromin 1 in neurofibromatosis type I and in melanoma.

SUBMITTER: Kiuru M

PROVIDER: S-EPMC5413358 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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The NF1 gene in tumor syndromes and melanoma.

Kiuru Maija M Busam Klaus J KJ

Laboratory investigation; a journal of technical methods and pathology 20170109 2

Activation of the RAS/MAPK pathway is critical in melanoma. Melanoma can be grouped into four molecular subtypes based on their main genetic driver: BRAF-mutant, NRAS-mutant, NF1-mutant, and triple wild-type tumors. The NF1 protein, neurofibromin 1, negatively regulates RAS proteins through GTPase activity. Germline mutations in NF1 cause neurofibromatosis type I, a common genetic tumor syndrome caused by dysregulation of the RAS/MAPK pathway, ie, RASopathy. Melanomas with NF1 mutations typicall ...[more]

PMID: 28067895

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Project description:BackgroundNeurofibromatosis type 1 (NF1), which is caused by heterozygous inactivating pathogenic variants in the NF1, has poor phenotypic expressivity in the early years of life and there are numerous conditions, including many other tumor predisposition syndromes, that can mimic its appearance. These are collectively termed NF1-like syndromes and are also connected by their genetic background. Therefore, the NF1's clinical diagnostic efficiency in childhood could be difficult and commonly should be completed with genetic testing.MethodsTo estimate the number of syndromes/conditions that could mimic NF1, we compiled them through an extensive search of the scientific literature. To test the utility of NF1's National Institutes of Health (NIH) clinical diagnostic criteria, which have been in use for a long time, we analyzed the data of a 40-member pediatric cohort with symptoms of the NF1-like syndromes' overlapping phenotype and performed NF1 genetic test, and established the average age when diagnostic suspicion arises. To facilitate timely identification, we compiled strongly suggestive phenotypic features and anamnestic data.ResultsIn our cohort the utility of NF1's clinical diagnostic criteria were very limited (sensitivity: 80%, specificity: 30%). Only 53% of children with clinically diagnosed NF1 had a detectable NF1 pathogenic variation, whereas 40% of patients without fulfilled clinical criteria tested positive. The average age at first genetic counseling was 9 years, and 40% of children were referred after at least one tumor had already been diagnosed. These results highlight the need to improve NF1-like syndromes' diagnostic efficiency in childhood. We collected the most extensive spectrum of NF1-like syndromes to help the physicians in differential diagnosis. We recommend the detailed, non-invasive clinical evaluation of patients before referring them to a clinical geneticist.ConclusionsEarly diagnosis of NF1-like syndromes can help to prevent severe complications by appropriate monitoring and management. We propose a potential screening, diagnostic and management strategy based on our findings and recent scientific knowledge.

Dataset Information

The NF1 gene in tumor syndromes and melanoma.

Publications

The NF1 gene in tumor syndromes and melanoma.

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