Importance of BRAF Testing in Unresectable or Metastatic Melanoma

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Hong Kong J Radiol 2013;16(Suppl):S29-33

BRAF is a protein kinase in the mitogen-activated protein kinase pathway that regulates cell proliferation, differentiation, and survival. Mutation in the BRAF gene can lead to aberrant activation of the pathway, which occurs in a variety of human cancers such as melanoma, papillary thyroid cancer, colorectal cancer, and hairy cell leukaemia. BRAF mutations have been reported to occur in 40 to 60% of melanoma tumours, most often affecting codon 600. The most common mutation is a prooncogenic valine-to-glutamic acid (V600E) conversion that drives melanoma cell proliferation. BRAF mutation represents an attractive target for molecular therapy and, in recent years, BRAF inhibitors have created a paradigm shift in melanoma treatment as they significantly improve tumour response and prolong survival of patients with BRAF-mutant unresectable, metastatic melanoma. Accurate and rapid detection of BRAF mutations thus plays a central role in patient selection for optimal, personalised therapy. Several molecular methods are available to analyse BRAF mutation status and these include Sanger DNA sequencing, real-time polymerase chain reaction, pyrosequencing, and high-resolution melting curve analysis. Each of these methods has differing sensitivities, specificities, and costs. This article highlights the key methods for BRAF mutation analysis and summarises the clinical significance of BRAF V600E mutation in melanoma.



對不可切除或有轉移性黑色素瘤中BRAF 基因測試的重要性


BRAF是絲裂原活化蛋白激酶通路中的一種蛋白激酶,負責調節細胞增生、分裂和存活。BRAF基因突變可引致通路異常激活,出現於多種人類癌症中,例如黑色素瘤、乳頭狀甲狀腺癌、結直腸癌及毛細胞白血病。在黑色素瘤中,有40%至60%出現BRAF基因突變,通常影響codon 600。最常見的突變是一種驅動黑色素瘤細胞增生的促致癌性纈氨酸-谷氨酸(V600E)轉換。BRAF基因突變是分子治療中一個具吸引力的標靶;在有BRAF基因突變、不可切除轉移性黑色素瘤的病人中,由於BRAF抑制劑能顯著改善腫瘤反應及延長存活,在近年間已經造成黑色素瘤治療的思維典範轉移。因此,BRAF基因突變的準確快速檢測,在選擇病人接受最適切的個人化治療中擔當了核心的角色。現已有幾種分子方法分析BRAF基因突變狀態,包括桑格DNA測序(Sanger DNA sequencing)、實時聚合酶鏈反應(real-time polymerase chain reaction)、焦磷酸測序技術(pyrosequencing)及高分辨率熔解曲線分析(high-resolution melting curve analysis)。這些方法的敏感度、特異性及成本各有不同。本文重點介紹BRAF基因突變分析的主要方法,並總結了BRAF V600E突變在黑色素瘤中的臨床顯著性。