The Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Nat Genet. 2011 May;43(5):442-6. doi: 10.1038/ng.810. Epub 2011 Apr 15.
The incidence of melanoma is increasing more than any other cancer, and knowledge of its genetic alterations is limited. To systematically analyze such alterations, we performed whole-exome sequencing of 14 matched normal and metastatic tumor DNAs. Using stringent criteria, we identified 68 genes that appeared to be somatically mutated at elevated frequency, many of which are not known to be genetically altered in tumors. Most importantly, we discovered that TRRAP harbored a recurrent mutation that clustered in one position (p. Ser722Phe) in 6 out of 167 affected individuals (∼4%), as well as a previously unidentified gene, GRIN2A, which was mutated in 33% of melanoma samples. The nature, pattern and functional evaluation of the TRRAP recurrent mutation suggest that TRRAP functions as an oncogene. Our study provides, to our knowledge, the most comprehensive map of genetic alterations in melanoma to date and suggests that the glutamate signaling pathway is involved in this disease.
黑色素瘤的发病率比其他任何癌症都要高，但其遗传改变的知识却很有限。为了系统地分析这些改变，我们对 14 对匹配的正常和转移肿瘤 DNA 进行了全外显子组测序。使用严格的标准，我们鉴定出 68 个似乎以高频率发生体细胞突变的基因，其中许多基因在肿瘤中未知发生遗传改变。最重要的是，我们发现 TRRAP 含有一个复发性突变，在 167 个受影响个体中的 6 个（约 4%）中聚集在一个位置（p.Ser722Phe），以及一个以前未识别的基因 GRIN2A，在 33%的黑色素瘤样本中发生突变。TRRAP 复发性突变的性质、模式和功能评估表明，TRRAP 作为一种癌基因发挥作用。我们的研究提供了迄今为止黑色素瘤中最全面的遗传改变图谱，并表明谷氨酸信号通路参与了这种疾病。
