Ye Kai, Wang Jiayin, Jayasinghe Reyka, Lameijer Eric-Wubbo, McMichael Joshua F, Ning Jie, McLellan Michael D, Xie Mingchao, Cao Song, Yellapantula Venkata, Huang Kuan-lin, Scott Adam, Foltz Steven, Niu Beifang, Johnson Kimberly J, Moed Matthijs, Slagboom P Eline, Chen Feng, Wendl Michael C, Ding Li
McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, USA.
Nat Med. 2016 Jan;22(1):97-104. doi: 10.1038/nm.4002. Epub 2015 Dec 14.
Complex insertions and deletions (indels) are formed by simultaneously deleting and inserting DNA fragments of different sizes at a common genomic location. Here we present a systematic analysis of somatic complex indels in the coding sequences of samples from over 8,000 cancer cases using Pindel-C. We discovered 285 complex indels in cancer-associated genes (such as PIK3R1, TP53, ARID1A, GATA3 and KMT2D) in approximately 3.5% of cases analyzed; nearly all instances of complex indels were overlooked (81.1%) or misannotated (17.6%) in previous reports of 2,199 samples. In-frame complex indels are enriched in PIK3R1 and EGFR, whereas frameshifts are prevalent in VHL, GATA3, TP53, ARID1A, PTEN and ATRX. Furthermore, complex indels display strong tissue specificity (such as VHL in kidney cancer samples and GATA3 in breast cancer samples). Finally, structural analyses support findings of previously missed, but potentially druggable, mutations in the EGFR, MET and KIT oncogenes. This study indicates the critical importance of improving complex indel discovery and interpretation in medical research.
复杂插入和缺失（indels）是通过在共同的基因组位置同时删除和插入不同大小的DNA片段而形成的。在此，我们使用Pindel-C对来自8000多例癌症病例样本的编码序列中的体细胞复杂indels进行了系统分析。我们在约3.5%的分析病例中发现癌症相关基因（如PIK3R1、TP53、ARID1A、GATA3和KMT2D）中有285个复杂indels；在之前对2199个样本的报告中，几乎所有复杂indels实例都被忽视（81.1%）或错误注释（17.6%）。框内复杂indels在PIK3R1和EGFR中富集，而移码在VHL、GATA3、TP53、ARID1A、PTEN和ATRX中普遍存在。此外，复杂indels表现出很强的组织特异性（如肾癌样本中的VHL和乳腺癌样本中的GATA3）。最后，结构分析支持了在EGFR、MET和KIT癌基因中先前遗漏但可能可靶向的突变的发现。这项研究表明在医学研究中改善复杂indel发现和解释的至关重要性。
