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Updated: Oct 30, 2025

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
06:09

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Published on: June 7, 2019

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Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family

Kevin M Brown1, Mai Xu1, Michael Sargen1

  • 1Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, EPS 7106, Bethesda, MD, 20892, USA.

Familial Cancer
|July 3, 2021
PubMed

Insights

Researchers identified a novel NRAS gene variant in an Italian family with a history of melanoma. This NRAS variant impacts signaling pathways, warranting further investigation into NRAS

Area of Science:

  • Genetics
  • Oncology
  • Molecular Biology

Background:

  • Known high-penetrance melanoma risk genes do not explain all familial melanoma cases.
  • A significant proportion of melanoma susceptibility remains unexplained in high-risk families.

Purpose of the Study:

  • To identify novel genetic variants associated with familial melanoma risk.
  • To investigate the functional impact of a newly identified NRAS variant (c.170A>C, p.D57A) in melanoma-prone families.

Main Methods:

  • Sequencing of 435 Mediterranean melanoma-prone families.
  • In vitro functional assays to assess NRAS D57A pathway activation (MAPK, PI3K).
  • Molecular modeling to predict the effect of the D57A substitution on NRAS protein function.

Main Results:

  • A novel NRAS variant (c.170A>C, p.D57A) was identified in an Italian melanoma-prone family.
  • This variant was absent in large population and patient databases.
  • NRAS D57A did not activate the MAPK pathway but enhanced EGF-induced PI3K signaling in vitro, suggesting impaired GTP binding and reduced GTPase activity.

Conclusions:

  • The novel NRAS variant c.170A>C (p.D57A) warrants further investigation as a potential familial melanoma susceptibility gene.
  • NRAS may play a role in melanoma predisposition through mechanisms distinct from canonical RAS pathway activation.
  • Further research is needed to confirm the role of NRAS in familial melanoma.
Keywords:
Familial cancerIn vitro characterizationMelanomaMolecular modelingNRAS geneRare variant

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