Frequent mutations in the MITF pathway in melanoma.
Frequent mutations in the MITF pathway in melanoma.
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DOI：
10.1111/j.1755-148x.2009.00578.x
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发表时间：
2009-08
影响因子：
4.3
通讯作者：
Samuels Y
中科院分区：
文献类型：
--
作者：
Cronin JC;Wunderlich J;Loftus SK;Prickett TD;Wei X;Ridd K;Vemula S;Burrell AS;Agrawal NS;Lin JC;Banister CE;Buckhaults P;Rosenberg SA;Bastian BC;Pavan WJ;Samuels Y
MITF（小眼症相关转录因子）参与黑素细胞的发育、色素沉着和肿瘤形成。为了确定MITF是否在黑色素瘤中发生体细胞突变，我们将原发性和转移性病变的MITF序列与患者匹配的正常DNA进行了比较。在分析的50个转移性黑色素瘤肿瘤系中，我们发现4个样本具有MITF的基因组扩增，4个样本在编码反式激活、DNA结合或基本螺旋-环-螺旋结构域的区域中具有MITF突变。SOX 10是一种既作用于MITF上游又与MITF协同作用的转录因子，对SOX 10的序列分析鉴定了另外三个具有移码或无义突变的样品。发现MITF和SOX 10以相互排斥的方式突变，可能表明共同遗传途径的破坏。总之，我们发现超过20%的转移性黑色素瘤病例在MITF通路中发生了改变。我们发现MITF通路在原发性黑色素瘤中也发生了改变：2/26例MITF突变，6/55例SOX 10突变。我们的研究结果表明，改变MITF功能在黑色素瘤可以通过MITF扩增，MITF单碱基取代或突变的调控SOX 10。
MITF (Microphthalmia-associated transcription factor) is involved in melanocyte cell development, pigmentation and neoplasia. To determine whether MITF is somatically mutated in melanoma, we compared the sequence of MITF from primary and metastatic lesions to patient matched normal DNA. In the 50 metastatic melanoma tumor lines analyzed, we discovered four samples that had genomic amplifications of MITF and four had MITF mutations in the regions encoding the transactivation, DNA binding or basic, helix-loop-helix domains. Sequence analysis for SOX10, a transcription factor which both acts upstream of MITF and synergizes with MITF, identified an additional three samples with frameshift or nonsense mutations. MITF and SOX10 were found to be mutated in a mutually exclusive fashion, possibly suggesting disruption in a common genetic pathway. Taken together we found that over 20% of the metastatic melanoma cases had alterations in the MITF pathway. We show that the MITF pathway is also altered in primary melanomas: 2/26 demonstrated mutations in MITF and 6/55 demonstrated mutations in SOX10. Our findings suggest that altered MITF function during melanomagenesis can be achieved by MITF amplification, MITF single base substitutions or by mutation of its regulator SOX10.