Gao Jianjiong, Chang Matthew T, Johnsen Hannah C, Gao Sizhi Paul, Sylvester Brooke E, Sumer Selcuk Onur, Zhang Hongxin, Solit David B, Taylor Barry S, Schultz Nikolaus, Sander Chris
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Genome Med. 2017 Jan 23;9(1):4. doi: 10.1186/s13073-016-0393-x.
Many mutations in cancer are of unknown functional significance. Standard methods use statistically significant recurrence of mutations in tumor samples as an indicator of functional impact. We extend such analyses into the long tail of rare mutations by considering recurrence of mutations in clusters of spatially close residues in protein structures. Analyzing 10,000 tumor exomes, we identify more than 3000 rarely mutated residues in proteins as potentially functional and experimentally validate several in RAC1 and MAP2K1. These potential driver mutations (web resources: 3dhotspots.org and cBioPortal.org) can extend the scope of genomically informed clinical trials and of personalized choice of therapy.
癌症中的许多突变其功能意义尚不清楚。标准方法将肿瘤样本中具有统计学意义的突变复发作为功能影响的指标。我们通过考虑蛋白质结构中空间上相邻残基簇中的突变复发情况，将此类分析扩展到罕见突变的长尾部分。通过分析10000个肿瘤外显子组，我们在蛋白质中鉴定出3000多个罕见突变残基，认为它们具有潜在功能，并在RAC1和MAP2K1中对其中几个进行了实验验证。这些潜在的驱动突变（网络资源：3dhotspots.org和cbioportal.org）可以扩大基于基因组信息的临床试验范围以及个性化治疗选择的范围。
