Molecular markers
Melanoma mutations
KIT

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

Revised: 12 June 2018, last major update March 2014

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

PubMed Search: KIT[TI] melanoma mutations free full text[sb]

See also: CD117
Cite this page: Bradish, J. KIT. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/molecularpathKIT.html. Accessed July 22nd, 2018.
Definition / general
  • KIT is the gene encoding a transmembrane tyrosine kinase receptor, involved in both the MAP kinase and AKT pathways, which are intimately involved with cell proliferation and survival (J Clin Oncol 2013;31:3176, Int J Biol Sci 2013;9:435)
  • KIT activation occurs after binding of stem cell factor (SCF), a hematopoietic cytokine
  • Binding of SCF leads to dimerization of 2 KIT receptors, leading to downstream signal transduction
  • KIT is necessary for the normal development of melanocytes
  • KIT mutations occur in melanoma subtypes (see table below)
Diagrams / tables

Images hosted on other servers:

KIT dimerization

MAP kinase and AKT pathways

KIT mutations in melanoma subtypes

Mutations
  • KIT mutations are found in only 3% of melanomas overall
  • A disproportionate amount of KIT aberrations are identified in melanoma arising from chronically sun damaged skin, acral and mucosal sites (23% overall)
  • KIT mutations are rarely found in melanoma arising on nonchronically sun damaged skin (those melanomas containing frequent BRAF mutations) (J Clin Oncol 2013;31:3176)
  • Types of KIT mutations include: K642E*, L576P*, D816H, V559A, A829P, intronic deletion, R634W, Y553N and N566D (* two most common mutations)
  • KIT mutations are nearly always mutually exclusive with NRAS or BRAF
Associated histological findings
  • In general, the 3 types of melanomas enriched with KIT mutations (acral, mucosal and those with chronic sun damage) typically show a lentiginous growth pattern with single melanocytes distributed along the basal epidermis (J Invest Dermatol 2010;130:20)
Detection methods
  • KIT mutation detection is difficult because there is a wide range of possible, nonrecurring aberrations (J Clin Oncol 2013;31:3176)
  • Aberrations include: increased copy number, amplification or specific mutations
  • Specific mutations are only detectible through sequencing of relevant exons (9, 11, 13, 17 and 18) (Clin Cancer Res 2012;18:1195)
  • For melanoma, using CD117 as a marker for KIT overexpression is NOT reliable and should NOT be used
  • To date, there has been no significant discordance between primary and metastatic KIT melanomas
Inhibitor therapy
  • KIT testing is recommended after a mucosal or acral melanoma has been determined to be BRAF- (Clin Cancer Res 2012;18:1195, J Clin Oncol 2013;31:3176)
  • Sequencing of exons 9, 11, 13, 17 and 18 is performed
  • Imatinib is a tyrosine kinase inhibitor used to treat multiple neoplasms including: CML (Ph+), advanced GIST, ALL (Ph+), DFSP and others
  • Evidence from multiple phase II trials suggests that only certain KIT mutations, specifically those in exon 11 and exon 13, are responsive to inhibitor therapy, while others are not
  • Exon 11 contains the mutation L576P while exon 13 contains K642E; these are the 2 most commonly identified KIT mutations in melanoma
  • Ipilimumab, a monoclonal antibody which targets CTLA4, is another drug which shows some promise in melanomas known to be enriched with KIT mutations, and has been approved by the EU as a second line treatment of melanoma
  • Ipilimumab decreases inhibition of cytotoxic T cells and increases their ability to destroy cancer cells
Mechanisms of resistance
  • Resistance mechanisms in melanoma have not been well documented as the evaluation of imatinib is only in phase II trials
  • Criteria defining resistance have not been established (J Clin Oncol 2012;30:e37, J Invest Dermatol 2010;130:20)
  • In GIST, up to 50% of patients treated with imatinib develop resistance
  • Resistance mechanisms include: tyrosine kinase switching, resistance in wild type KIT, amplification and overexpression, efflux of imatinib by cells and acquired secondary KIT mutations
  • Secondary mutations in KIT are the most common mechanisms by which GISTs acquire resistance, typically through interefering with the drug binding site or activating a different locus of the receptor (J Clin Oncol 2006;24:4764, J Invest Dermatol 2010;130:20)
  • Future studies and clinical trials will evaluate responses with KIT inhibitors
Resistance therapies
  • Patients with GIST who demonstrate resistance on imatinib are either treated with dose escalation or an alternative tyrosine kinase inhibitor (J Invest Dermatol 2010;130:20)
  • Sunitinib is effective in KIT mutations, especially those with exon 9 mutations, V654A and T670I mutations (Clin Cancer Res 2006;12:2622)
  • Other KIT inhibitors used include nilotinib, dasatinib and sorafenib