Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
Nat Genet. 2011 Dec 25;44(2):133-9. doi: 10.1038/ng.1026.
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.
我们进行了外显子组测序，以检测 7 种黑素瘤细胞系和供体匹配的种系细胞中编码区的体细胞突变。所有黑素瘤样本都有大量的体细胞突变，这些突变显示了 UV 诱导的 DNA 修复的特征。在源自同一个体的两个转移瘤的肿瘤样本特异性突变中，没有这种特征。两个具有非典型 BRAF 突变的黑素瘤携带功能获得性 MAP2K1 和 MAP2K2（分别为 MEK1 和 MEK2）突变，导致 ERK 磷酸化的组成型和对 MEK 抑制剂的更高抗性。对更大的黑素瘤患者队列进行筛查揭示了反复出现的体细胞 MAP2K1 和 MAP2K2 突变，其总体发生率为 8%。此外，在三个候选黑素瘤基因 FAT4、LRP1B 和 DSC1 中经常发现错义和无义体细胞突变。
