Absence of BRAF and NRAS mutations in uveal melanoma.
Uveal melanoma (UM) and cutaneous melanoma (CM) differ significantly in their epidemiological, clinical, immunophenotypical, and cytogenetic features, but the molecular basis for these differences has not been delineated. CMs frequently harbor an activating mutation in either NRAS or the RAS-regulated kinase BRAF, suggesting that either of these oncogenes may increase signaling through the mitogen-activated protein (MAP) kinase pathway and promote melanoma development. The aim of this study was to examine BRAF and NRAS gene mutations in UM. Genomic DNA from CM and UM was screened for mutations in BRAF exons 11 and 15 and NRAS exons 1 and 2 using a combination of denaturing high-performance liquid chromatography and direct sequencing. Mutations in BRAF exon 15 were detected in 16 (36.4%) of 44 CMs and 0 (0%) of 62 UMs. The most common mutation in CM was V599E, but a novel point mutation (L596Q) was identified in two cases and an in-frame deletion/insertion (VKSRWK599-604D) was discovered in one case. No BRAF exon 11 mutations were observed among seven CMs and nine UMs that were wild-type for exon 15. Mutation of NRAS exon 2 was rare in CM [1 (3.7%) of 27] and absent in UM [0 (0%) of 47]. No NRAS exon 1 mutations were detected in either type of melanoma. We conclude that UMs arise independent of oncogenic BRAF and NRAS mutations, an observation that may have implications for therapies targeted to the NRAS-BRAF pathway.
Cruz
Frank
F
Oregon Health and Science University (OHSU) Cancer Institute, Department of Pathology, OHSU and Portland Veterans Affairs Medical Center, Portland, Oregon 97239, USA.
Rubin
Brian P
BP
Wilson
David
D
Town
Ajia
A
Schroeder
Arin
A
Haley
Andrea
A
Bainbridge
Troy
T
Heinrich
Michael C
MC
Corless
Christopher L
CL
D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000556:secondary; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf; D012878:Skin Neoplasms / Q000235:genetics; D014604:Uveal Neoplasms / Q000235:genetics*
D015513:Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf