Molecular markers
Melanoma mutations

Author: Joshua Bradish, M.D. (see Authors page)
Editor: Liang Cheng, M.D.

Revised: 12 June 2018, last major update June 2014

Copyright: (c) 2014-2018,, Inc.

PubMed Search: NF1[TI] melanoma mutations

See also: Stains - neurofibromin
Page views in 2018: 149
Page views in 2019 to date: 217
Cite this page: Bradish, J. NF1. website. Accessed October 16th, 2019.
Definition / general
  • NF1, neurofibromin 1, is a tumor suppressor gene found on chromosome 17q11.2 which negatively regulates RAS signaling
  • NF1 increases the intrinsic GTPase activity of the RAS enzyme which leads to inactivation
  • If an NF1 mutation causes subsequent inactivation, it leads to an increase in RAS activity (Cancer Discov 2013;3:260)
  • In melanocytes, the NF1 protein regulates differentiation and development (J Cell Sci 2008;121:167)
Diagrams / tables

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NF1 pathway

  • Many different types of NF1 mutations have been described including frameshift, missense, nonsense, splicing and deletion mutations
  • An inactivating mutation of the NF1 gene leads to RAS activation (Monogr Hum Genet 2008;16:63)
Clinical features
  • While classically NF1 is associated with an increase in numerous neoplasms, both benign and malignant, NF1 is not associated with an increased risk of melanoma
  • There is, however, a well known strong association with pigmentation aberrations (cafe au lait spots, ephelides, etc.) in patients with NF1 germline mutations (Cancer Discov 2013;3:260)
Detection methods
  • Comprehensive testing using RNA / cDNA core assay with copy number analysis is the preferred method, as it is more sensitive and specific (Monogr Hum Genet 2008;16:63)
  • DNA based sequence analysis is also used
  • Other techniques can be used if either a complex or rare mutation is present (total gene mutations, multiple deletions, multiple duplications) (UAB: Neurofibromatosis Type 1 [Accessed 12 June 2018])
Inhibitor therapy
Mechanisms of resistance
  • NF1 mutations in BRAF mutated melanocytes has been shown to decrease the response of these melanocytes to RAF inhibitor therapy (PLX4720, the precursor molecule of vemurafenib) (Cancer Discov 2013;3:260, Cancer Res 2014;74:2340)
  • One study demonstrated a response to MEK inhibition in melanocytes containing both BRAF and NF1 mutations (Cancer Res 2014;74:2340)
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