Stains & CD markers
NF1 / NF2


Topic Completed: 1 June 2014

Minor changes: 18 June 2021

Copyright: 2014-2021, PathologyOutlines.com, Inc.

PubMed Search: NF1[TI] melanoma mutations


Liang Cheng, M.D.
Page views in 2021 to date: 415
Cite this page: Bradish, J., Cheng L. NF1 / NF2. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsNF1NF2.html. Accessed December 2nd, 2021.
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)
Neurofibromatosis type 1
  • Heterogeneous mutations seen in neurofibromatosis type 1 (NF1), the most common autosomal dominant inherited disorder in humans (1 per 3000)
    • Disorder characterized by benign tumors of peripheral nerves, cafe au lait spots, retinal hamartomas
    • Also increased risk of malignancy, gastrointestinal stromal tumors (Am J Surg Pathol 2005;29:1170)
NF2
  • Tumor suppressor protein at 22q11-13.1
  • Produces protein called merlin or schannomin
  • Deleted in soft tissue perineurioma
  • Both copies inactivated in up to 60% of sporadic meningiomas
  • Often no protein expression in schwannoma
  • May be involved in tumorigenesis of schwannoma and some meningiomas
Diagrams / tables

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NF1 pathway

Mutations
  • 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 23 April 2021])
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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