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Absence of BRAF mutations in UV-protected mucosal melanomas
  1. R H Edwards1,
  2. M R Ward1,
  3. H Wu2,
  4. C A Medina1,
  5. M S Brose1,
  6. P Volpe1,
  7. S Nussen-Lee3,
  8. H M Haupt3,
  9. A M Martin3,
  10. M Herlyn4,
  11. S R Lessin2,
  12. B L Weber1
  1. 1Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA
  2. 2Fox Chase Cancer Center, Philadelphia, PA, USA
  3. 3Pennsylvania Hospital, Philadelphia, PA, USA
  4. 4The Wistar Institute, Philadelphia, PA, USA
  1. Correspondence to:
 B L Weber
 MD, Abramson Family Cancer Research Institute, University of Pennsylvania Medical Center, 514 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA; weberbmail.med.upenn.edu

Abstract

Background: Mutations in BRAF have recently been identified in a significant percentage of primary and metastatic cutaneous malignant melanomas. As ultraviolet (UV) exposure may play a role in the development of cutaneous melanoma lesions with BRAF mutations, BRAF mutation frequency in melanomas arising in sites protected from sun exposure may be lower than those from sun-exposed areas. Thus, we determined the BRAF mutation frequency in a panel of 13 mucosal melanomas and compared those data with data from all currently published series of cutaneous melanomas.

Methods:BRAF exon 15 DNA from 13 archival primary mucosal melanomas (eight vulvar, four anorectal, and one laryngeal) was sequenced using intron-based primers. As archival DNA occasionally produces poor-quality template, results were confirmed with a TspRI restriction fragment length polymorphism (RFLP) that distinguishes wild-type BRAF from the common mutant form V599E. A binomial test was used to compare the mutation frequency in the mucosal melanomas with the published mutation frequency in cutaneous melanomas.

Results: None of the 13 mucosal melanomas in this series had an exon 15 BRAF mutation, as compared to 54/165 (33%) primary cutaneous melanomas with BRAF mutations in a compilation of all current published studies (p = 0.006).

Discussion: These data suggest that UV exposure, plays a role in the genesis of BRAF mutations in cutaneous melanoma, despite the absence of the characteristic C>T or CC>TT mutation signature associated with UV exposure, and suggests mechanisms other than pyrimidine dimer formation are important in UV-induced mutagenesis.

  • BRAF
  • melanoma
  • ultraviolet exposure
  • CPD, cyclobutane pyrimidine dimers
  • RFLP, restriction fragment length polymorphism
  • UV, ultraviolet

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Footnotes

  • Research support was received from the National Cancer Institute, grant numbers 1K08CA93748 (to RHE) and P50CA093372 (to MH), the National Institute of Arthritis and Musculoskeletal and Skin Diseases, grant number K24 AR02102 (to SRL), and from the Abramson Family Cancer Research Institute (to BLW).

  • Conflict of interest: none declared.