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. 2013 Mar;15(2):220-6.
doi: 10.1016/j.jmoldx.2012.10.002. Epub 2012 Dec 27.

Frequency and spectrum of BRAF mutations in a retrospective, single-institution study of 1112 cases of melanoma

Wesley O Greaves  1 , Shalini Verma, Keyur P Patel, Michael A Davies, Bedia A Barkoh, John M Galbincea, Hui Yao, Alexander J Lazar, Kenneth D Aldape, L Jeffrey Medeiros, Rajyalakshmi Luthra
Affiliations

Frequency and spectrum of BRAF mutations in a retrospective, single-institution study of 1112 cases of melanoma

Wesley O Greaves et al. J Mol Diagn. 2013 Mar.

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 = 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.

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Figures

Figure 1
Figure 1
Detection of BRAF c.1798_1799delinsAA (p.V600K) by single-base primer extension MALDI-TOF MS. A two-primer strategy was used to detect the variant nucleotides in the first and second base positions of codon 600. A and C: Single peaks representing the WT nucleotides at the first and second positions of codon 600, G and T, respectively (black arrows). B and D: Heterozygous variant peaks (white arrows) representing an indel (GT>AA) involving positions 1 and 2 of BRAF codon 600, resulting in a p.V600K change.
Figure 2
Figure 2
Detection of BRAF c.1799_1800delinsAA (the so-called p.V600E2) in melanoma by pyrosequencing and Sanger sequencing. A: Pyrosequencing tracing shows the WT BRAF codon 600 as GTG. B: In mutant BRAF codon 600, a prominent peak represents A after the first G (white arrow), and a reduced peak represents the third base G (black arrow). C: The precise variant sequence (GAA) is confirmed by Sanger sequencing, which demonstrates a heterozygous pattern of T/A G/A at the second and third base positions of codon 600 (arrows).
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References

    1. Davies H., Bignell G.R., Cox C., Stephens P., Edkins S., Clegg S. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954. - PubMed
    1. Rubinstein J.C., Sznol M., Pavlick A.C., Ariyan S., Cheng E., Bacchiocchi A., Kluger H.M., Narayan D., Halaban R. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med. 2010;8:67. - PMC - PubMed
    1. Flaherty K.T., Puzanov I., Kim K.B., Ribas A., McArthur G.A., Sosman J.A., O’Dwyer P.J., Lee R.J., Grippo J.F., Nolop K., Chapman P.B. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–819. - PMC - PubMed
    1. Ribas A., Kim K.B., Schuchter L.M., Gonzalez R., Pavlick A.C., Weber J.S., McArthur G.A., Hutson T.E., Flaherty K.T., Moschos S.J., Lawrence D.P., Hersey P., Kefford R.F., Chmielowski B., Puzanov I., Li J., Nolop K.B., Lee R.J., Joe A.K., Sosman J.A. BRIM-2: An open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma (abstract) J Clin Oncol. 2011;29(15 Suppl):8509.
    1. Chapman P.B., Hauschild A., Robert C., Haanen J.B., Ascierto P., Larkin J., Dummer R., Garbe C., Testori A., Maio M., Hogg D., Lorigan P., Lebbe C., Jouary T., Schadendorf D., Ribas A., O’Day S.J., Sosman J.A., Kirkwood J.M., Eggermont A.M., Dreno B., Nolop K., Li J., Nelson B., Hou J., Lee R.J., Flaherty K.T., McArthur G.A., collaborators Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–2516. - PMC - PubMed

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