Frequency and Spectrum of BRAF Mutations in a Retrospective, Single-Institution Study of 1112 Cases of Melanoma

Abstract

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 Z 774), acral (n Z 111), mucosal (n Z 26), uveal (n Z 23), leptomeningeal (n Z 1), and metastatic melanomas of unknown primary site (n Z 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. (J Mol Diagn 2013, 15: 220e226; http://dx

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…An additional 3-5% of melanomas harbour other forms of genetic alteration in BRAF that are also considered to be oncogenic 5 . These aberrations are divided between missense mutations in the region adjacent to V600 (within exon 15) or distant from this site (within exon 11), and BRAF translocations (also referred to as fusions) [25][26][27][28] . In melanomas and other cancers, dozens of sites in BRAF exons 11 and 15 have been found to harbour missense mutations, but only a small number have been functionally characterized.…”

Assessment of BRAF V600E Status in Colorectal Carcinoma: Tissue-Specific Discordances between Immunohistochemistry and Sequencing

“…DNA had been extracted from microdissected unstained, formalin-fixed, paraffin-embedded whole tissue sections, and sequencing had been performed in the College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvements Amendments (CLIA)-certified Molecular Diagnostics Laboratory, as previously described (32)(33)(34), as a component of routine patient care or eligibility for integral-marker clinical trials. Several different sequencing assays had been employed during the years covered by our study: For all three sequencing techniques, a minimum cellularity of 20% (i.e., tumor nuclei represent 20% of total nuclei in the tested sample) was required to avoid false negative results.…”

Chinese Guidelines on the Diagnosis and Treatment of Melanoma (2015 Edition)

“…Many foreign studies with small sample sizes (161)(162)(163) found that the BRAF gene mutation rate was 0−10% in MM patients, KIT gene mutation rate was 5−27%, and NRAS gene mutation rate was 13−22%.…”