Mutations in BRAF codons 594 and 596 predict good prognosis in melanoma

Wu,Xiaowen; Yan,Junya; Dai,Jie; Ma,Meng; Tang,Huan; Yu,Jiayi; Xu,Tianxiao; Yu,Huan; Si,Lu; Chi,Zhihong; Sheng,Xinan; Cui,Chuanliang; Kong,Yan; Guo,Jun

doi:10.3892/ol.2017.6608

Mutations in BRAF codons 594 and 596 predict good prognosis in melanoma

Authors:
- Xiaowen Wu
- Junya Yan
- Jie Dai
- Meng Ma
- Huan Tang
- Jiayi Yu
- Tianxiao Xu
- Huan Yu
- Lu Si
- Zhihong Chi
- Xinan Sheng
- Chuanliang Cui
- Yan Kong
- Jun Guo
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Affiliations: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
Published online on: July 19, 2017 https://doi.org/10.3892/ol.2017.6608
Pages: 3601-3605
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E is the most common kinase‑activating mutation and is associated with poor prognosis in melanoma. However, the clinical significance of kinase‑impairing mutations remains unclear. The present study aimed to analyze kinase‑impairing mutations in BRAF codons 594 and 596 in non‑Caucasian patients with melanoma and to investigate their possible clinical significance. To detect hotspot mutations, exon 15 of the BRAF gene was amplified using polymerase chain reaction in samples from 1,554 patients with melanoma. Among these patients, a total of 912 valid follow‑up data were obtained. These patients were divided into three groups according to their BRAF activation status: BRAF wild‑type (n=752), BRAF V600E (n=147); and BRAF D594/G596 (n=13). Then the correlation between BRAF activation status, and the clinicopathological features and overall survival (OS) of the patients were analyzed. The prevalence of BRAF mutations in non‑Caucasian patients with melanoma was 24.3% (377/1554). Three patients carried two mutations simultaneously. The overall mutation frequencies of kinase‑activating mutations, kinase‑impairing mutations, and mutations with unknown effects were 93.4 (355/380), 3.4 (13/380), and 3.2% (12/380), respectively. BRAF V600E was identified to be associated with a poor prognosis. Patients with BRAF mutations in codons 594 and 596 had a longer OS time compared with those with a BRAF V600E mutation [median OS, 45 vs. 25 months; HR, 0.45 (95% confidence interval, 0.31‑0.97); P=0.043]. To the best of our knowledge, this is the first study to examine a large number of samples from non‑Caucasian patients with melanoma and report the characteristics of BRAF mutations according to mutant kinase activity. Melanoma arising from a mutation in BRAF codon 594 or 596 can be differentiated from BRAF V600E‑induced melanoma, and mutations in these codons may be good prognostic factors for melanoma. The results of the present study are thus of significance for the development of accurate personalized medicine to treat melanoma.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
3	Zhang W and Liu HT: MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 12:9–18. 2002. View Article : Google Scholar : PubMed/NCBI
4	Wada T and Penninger JM: Mitogen-activated protein kinases in apoptosis regulation. Oncogene. 23:2838–2849. 2004. View Article : Google Scholar : PubMed/NCBI
5	Gray-Schopfer V, Wellbrock C and Marais R: Melanoma biology and new targeted therapy. Nature. 445:851–857. 2007. View Article : Google Scholar : PubMed/NCBI
6	Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, et al: Mutations of the BRAF gene in human cancer. Nature. 417:949–954. 2002. View Article : Google Scholar : PubMed/NCBI
7	Si L, Kong Y, Xu X, Flaherty KT, Sheng X, Cui C, Chi Z, Li S, Mao L and Guo J: Prevalence of BRAF V600E mutation in Chinese melanoma patients: Large scale analysis of BRAF and NRAS mutations in a 432-case cohort. Eur J Cancer. 48:94–100. 2012. View Article : Google Scholar : PubMed/NCBI
8	Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K and Chapman PB: Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 363:809–819. 2010. View Article : Google Scholar : PubMed/NCBI
9	Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, et al: Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, open-label, phase 3 randomised controlled trial. Lancet. 380:358–365. 2012. View Article : Google Scholar : PubMed/NCBI
10	Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, et al: Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): Updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 17:1248–1260. 2016. View Article : Google Scholar : PubMed/NCBI
11	Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, et al: Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 372:30–39. 2015. View Article : Google Scholar : PubMed/NCBI
12	Zheng G, Tseng LH, Chen G, Haley L, Illei P, Gocke CD, Eshleman JR and Lin MT: Clinical detection and categorization of uncommon and concomitant mutations involving BRAF. BMC Cancer. 15:7792015. View Article : Google Scholar : PubMed/NCBI
13	Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, Hussain J, Reis-Filho JS, Springer CJ, Pritchard C, et al: Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 140:209–221. 2010. View Article : Google Scholar : PubMed/NCBI
14	Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, et al: Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 116:855–867. 2004. View Article : Google Scholar : PubMed/NCBI
15	Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 363:711–723. 2010. View Article : Google Scholar : PubMed/NCBI
16	Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, et al: Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 373:23–34. 2015. View Article : Google Scholar : PubMed/NCBI
17	Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL and Herlyn M: CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene. 28:85–94. 2009. View Article : Google Scholar : PubMed/NCBI
18	Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Bröcker EB, LeBoit PE, et al: Distinct sets of genetic alterations in melanoma. N Engl J Med. 353:2135–2147. 2005. View Article : Google Scholar : PubMed/NCBI
19	Ikenoue T, Hikiba Y, Kanai F, Tanaka Y, Imamura J, Imamura T, Ohta M, Ijichi H, Tateishi K, Kawakami T, et al: Functional analysis of mutations within the kinase activation segment of B-Raf in human colorectal tumors. Cancer Res. 63:8132–8137. 2003.PubMed/NCBI
20	Bauer J, Büttner P, Murali R, Okamoto I, Kolaitis NA, Landi MT, Scolyer RA and Bastian BC: BRAF mutations in cutaneous melanoma are independently associated with age, anatomic site of the primary tumor, and the degree of solar elastosis at the primary tumor site. Pigment Cell Melanoma Res. 24:345–351. 2011. View Article : Google Scholar : PubMed/NCBI
21	Cremolini C, Di Bartolomeo M, Amatu A, Antoniotti C, Moretto R, Berenato R, Perrone F, Tamborini E, Aprile G, Lonardi S, et al: BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis. Ann Oncol. 26:2092–2097. 2015. View Article : Google Scholar : PubMed/NCBI