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Frequent mutations in the MITF pathway in melanoma.

Microphthalmia-associated transcription factor (MITF) is involved in melanocyte cell development, pigmentation and neoplasia. To determine whether MITF is somatically mutated in melanoma, we compared the sequence of MITF from primary and metastatic lesions to patient-matched normal DNA. In the 50 metastatic melanoma tumor lines analysed, we discovered four samples that had genomic amplifications of MITF and four that had MITF mutations in the regions encoding the transactivation, DNA binding or basic, helix-loop-helix domains. Sequence analysis for SOX10, a transcription factor, which both acts upstream of MITF and synergizes with MITF, identified an additional three samples with frameshift or nonsense mutations. Microphthalmia-associated transcription factor and SOX10 were found to be mutated in a mutually exclusive fashion, possibly suggesting disruption in a common genetic pathway. Taken together we found that over 20% of the metastatic melanoma cases had alterations in the MITF pathway. We show that the MITF pathway is also altered in primary melanomas: 2/26 demonstrated mutations in MITF and 6/55 demonstrated mutations in SOX10. Our findings suggest that altered MITF function during melanomagenesis can be achieved by MITF amplification, MITF single base substitutions or by mutation of its regulator SOX10.

Pubmed ID: 19422606


  • Cronin JC
  • Wunderlich J
  • Loftus SK
  • Prickett TD
  • Wei X
  • Ridd K
  • Vemula S
  • Burrell AS
  • Agrawal NS
  • Lin JC
  • Banister CE
  • Buckhaults P
  • Rosenberg SA
  • Bastian BC
  • Pavan WJ
  • Samuels Y


Pigment cell & melanoma research

Publication Data

August 23, 2009

Associated Grants

  • Agency: Intramural NIH HHS, Id: Z01 HG200337-01
  • Agency: Intramural NIH HHS, Id: Z99 HG999999

Mesh Terms

  • Cell Line, Tumor
  • Codon, Nonsense
  • Frameshift Mutation
  • Genes, ras
  • Humans
  • Melanoma
  • Microphthalmia-Associated Transcription Factor
  • Mutation
  • Neoplasm Metastasis
  • Proto-Oncogene Proteins B-raf
  • SOXE Transcription Factors
  • Skin Neoplasms