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NF1 and Neurofibromin: Emerging Players in the Genetic Landscape of Desmoplastic Melanoma

Mahalingam, Meera MD, PhD, FRCPath

Advances In Anatomic Pathology: January 2017 - Volume 24 - Issue 1 - p 1–14
doi: 10.1097/PAP.0000000000000131
Review Articles

Neurofibromatosis type I (NF1), a monogenic disorder with an autosomal dominant mode of inheritance, is caused by alterations in the NF1 gene which codes for the protein neurofibromin. Functionally, NF1 is a tumor suppressor as it is GTPase-activating protein that negatively regulates the MAPK pathway. More recently, much attention has focused on the role of NF1 and neurofibromin in melanoma as mutations in NF1 have been found to constitute 1 of the 4 distinct genomic categories of melanoma, with the other 3 comprising BRAF, NRAS, and “triple–wild-type” subtypes. In this review, we parse the literature on NF1 and neurofibromin with a view to clarifying and gaining a better understanding of their precise role/s in melanomagenesis. We begin with a historic overview, followed by details regarding structure and function and characterization of neural crest development as a model for genetic reversion in neoplasia. Melanogenesis in NF1 sets the stage for the discussion on the roles of NF1 and neurofibromin in neural crest-derived neoplasms including melanoma with particular emphasis on NF1 and neurofibromin as markers of melanocyte dedifferentiation in desmoplastic melanoma.

VA Consolidated Laboratories, Department of Pathology and Laboratory Medicine, Dermatopathology Section, West Roxbury, MA

The author has no funding or conflicts of interest to disclose.

Reprints: Meera Mahalingam, MD, PhD, FRCPath, VA Consolidated Laboratories, Department of Pathology and Laboratory Medicine (113), Dermatopathology Section, 1400 VFW PKWY, West Roxbury, MA 02132 (e-mail:

All figures can be viewed online in color at

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