Classification and characterization of microsatellite instability across 18 cancer types
Classification and characterization of microsatellite instability across 18 cancer types
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DOI：
10.1038/nm.4191
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发表时间：
2016-11-01
期刊：
影响因子：
82.9
通讯作者：
Salipante, Stephen J.
中科院分区：
文献类型：
--
作者：
Hanse, Ronald J.;Pritchard, Colin C.;Salipante, Stephen J.
微卫星不稳定性（MSI），即重复DNA片段中核苷酸的自发丢失或获得，是胃肠道、子宫内膜和结直肠肿瘤的诊断表型，但对更广泛的癌症类型中的不稳定性事件仍知之甚少。为了探索恶性肿瘤中的MSI，我们检查了来自18种癌症类型的5，930个癌症外显子，超过200，000个微卫星位点，并构建了MSI的基因组分类器。我们在18种癌症类型中的14种中发现了MSI阳性肿瘤。我们还确定了在特定癌症类型中更可能不稳定的基因座，导致涉及癌症相关基因的特定不稳定特征，这表明不稳定模式反映了选择压力，并可能识别新的癌症驱动因素。我们还观察到生存结果与不稳定微卫星的总体负担之间的相关性，这表明MSI可能是一种连续的，而不是离散的，在癌症类型中提供信息的表型。这些分析提供了对MSI的保守和癌症特异性特性的深入了解，并揭示了改进临床MSI诊断和癌症基因发现方法的机会。
Microsatellite instability (MSI), the spontaneous loss or gain of nucleotides from repetitive DNA tracts, is a diagnostic phenotype for gastrointestinal, endometrial, and colorectal tumors, yet the landscape of instability events across a wider variety of cancer types remains poorly understood. To explore MSI across malignancies, we examined 5,930 cancer exomes from 18 cancer types at more than 200,000 microsatellite loci and constructed a genomic classifier for MSI. We identified MSI-positive tumors in 14 of the 18 cancer types. We also identified loci that were more likely to be unstable in particular cancer types, resulting in specific instability signatures that involved cancer-associated genes, suggesting that instability patterns reflect selective pressures and can potentially identify novel cancer drivers. We also observed a correlation between survival outcomes and the overall burden of unstable microsatellites, suggesting that MSI may be a continuous, rather than discrete, phenotype that is informative across cancer types. These analyses offer insight into conserved and cancer-specific properties of MSI and reveal opportunities for improved methods of clinical MSI diagnosis and cancer gene discovery.