Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma
Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma
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DOI：
10.1038/ng.1026
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发表时间：
2012-02-01
期刊：
影响因子：
30.8
通讯作者：
Antonarakis, Stylianos E.
中科院分区：
文献类型：
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作者：
Nikolaev, Sergey I.;Rimoldi, Donata;Antonarakis, Stylianos E.
我们进行了外显子组测序，以检测在7个黑色素瘤细胞系和供体匹配的生殖细胞的蛋白质编码区的体细胞突变。所有的黑色素瘤样本都有大量的体细胞突变，这表明了紫外线诱导的DNA修复的标志。在来自同一个体的两个转移瘤的肿瘤样品特异性突变中不存在这种标志。两个具有非典型BRAF突变的黑色素瘤具有功能获得性MAP2K1和MAP2K2（分别为MEK 1和MEK 2）突变，导致组成性ERK磷酸化和对MEK抑制剂的更高抗性。对更大规模的黑色素瘤患者队列进行筛查，发现存在复发的体细胞MAP 2K1和MAP 2K2突变，其发生率为8%。此外，错义和无义体细胞突变频繁地发现在三个候选黑色素瘤基因，FAT4，LRP 1B和DSC1。
We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.