The US Food and Drug Administration (FDA) approved vemurafenib to treat patients with
metastatic melanoma harboring the BRAF c.1799T>A (p.V600E) mutation. However, a subset
of melanomas harbor non-p.V600E BRAF mutations, and these data are of potential importance
regarding the efficacy of current targeted therapies. To better understand the BRAF
mutation profile in melanomas, we retrospectively analyzed data from 1112 primary
and metastatic melanomas at our institution. The cohort included nonacral cutaneous
(n = 774), acral (n = 111), mucosal (n = 26), uveal (n = 23), leptomeningeal (n =
1), and metastatic melanomas of unknown primary site (n = 177). BRAF mutation hotspot
regions in exons 11 and 15 were analyzed by pyrosequencing or with the primer extension
MassARRAY system. A total of 499 (44.9%) specimens exhibited BRAF mutations, involving
exon 15 [497 (99.6%)] or exon 11 [2 (0.4%)]. p.V600E was detected in 376 (75.4%) cases;
the remaining 123 (24.6%) cases exhibited non-p.V600E mutations, of which p.V600K
was most frequent [86 (17.2%)]. BRAF mutations were more frequent in nonacral cutaneous
(51.4%) than acral melanomas [18 (16.2%)] (P < 0.001); however, there was no significant
difference among cutaneous histological subtypes. All mucosal, uveal, and leptomeningeal
melanomas were BRAF wild type (WT). The high frequency of non-p.V600E BRAF mutations
in melanoma has important implications because the FDA-approved companion diagnostic
test for p.V600E detects some but not all non-p.V600E mutations. However, the therapeutic
efficacy of vemurafenib is not well established in these lesions.
Copyright © 2013 American Society for Investigative Pathology and the Association
for Molecular Pathology. Published by Elsevier Inc. All rights reserved.