BRAF somatic mutations in malignant melanoma and melanocytic naevi.
BRAF somatic mutations in malignant melanoma and melanocytic naevi.
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恶性黑色素瘤和黑素细胞痣中的 BRAF 体细胞突变。
DOI：
10.1097/01.cmr.0000215035.38436.87
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发表时间：
2006
影响因子：
2.2
通讯作者：
Thomas,NancyE
中科院分区：
文献类型：
--
作者：
Thomas,NancyE
BRAF体细胞突变经常在原发性和转移性黑色素瘤和黑色素细胞痣中发现。常见的BRAF突变体刺激组成型RAF/MEK（促分裂原活化的ERK活化激酶）/ERK（细胞外信号调节激酶）途径活化，并在NIH-3 T3细胞和永生化鼠黑素细胞中充当转化癌基因。最常见的BRAF突变是V600 E改变，但已发现超过30种不同的BRAF突变，生物学活性不同，可预测临床相关的肿瘤差异。这些获得性突变的起源仍然未知，但黑色素瘤具有与其他肿瘤不同的BRAF突变谱，可能是由于独特的环境暴露。在黑色素瘤病例中，BRAF突变经常发现于浅表扩散或结节组织学亚型、间歇性阳光暴露部位的肿瘤和年轻患者中。尽管有证据表明RAF/MEK/ERK通路的激活影响体外黑色素瘤细胞的增殖、侵袭和存活，但BRAF突变在黑色素瘤肿瘤进展、维持和结局中的确切作用仍存在争议。此外，虽然BRAF和NRAS突变在黑色素瘤中是相互排斥的，但其他遗传事件可能补充BRAF突变，产生与NRAS突变相似的生物学活性。尽管如此，临床前和早期临床研究预测RAF/MEK/ERK通路抑制剂将对黑色素瘤具有治疗活性，但可能需要通过BRAF/NRAS突变状态进行肿瘤亚分类以评估其疗效。
BRAF somatic mutations are frequently found in primary and metastatic melanomas and melanocytic naevi. Commonly found BRAF mutants stimulate constitutive RAF/MEK (mitogen-activated ERK-activating kinase)/ERK (extracellular signal-regulated kinase) pathway activation and act as transforming oncogenes in NIH-3T3 cells and immortalized murine melanocytes. The most common BRAF mutation is the V600E alteration, but over 30 distinct BRAF mutations, varying in biological activity, have been found and may be predictive of clinically relevant tumour differences. The origin of these acquired mutations remains unknown, but melanomas have a different BRAF mutational spectrum from other tumours, possibly resulting from unique environmental exposures. In melanoma cases, BRAF mutations are frequently found in superficial spreading or nodular histological subtypes, in tumours on intermittently sun-exposed sites and in younger patients. Although evidence indicates that the activation of the RAF/MEK/ERK pathway influences the proliferation, invasion and survival of melanoma cells in vitro, the exact role of BRAF mutation in melanoma tumour progression, maintenance and outcome remains controversial. In addition, although BRAF and NRAS mutations are mutually exclusive in melanomas, other genetic events may complement BRAF mutation to produce biological activity similar to NRAS mutation. Nonetheless, preclinical and early clinical studies predict that RAF/MEK/ERK pathway inhibitors will have therapeutic activity towards melanoma, but that tumour subclassification by BRAF/NRAS mutational status may be necessary to evaluate their efficacy.