Tian Sun, Roepman Paul, Popovici Vlad, Michaut Magali, Majewski Ian, Salazar Ramon, Santos Cristina, Rosenberg Robert, Nitsche Ulrich, Mesker Wilma E, Bruin Sjoerd, Tejpar Sabine, Delorenzi Mauro, Bernards Rene, Simon Iris
Agendia NV, Amsterdam, The Netherlands; and Agendia Inc., Irvine, CA, USA.
J Pathol. 2012 Dec;228(4):586-95. doi: 10.1002/path.4092. Epub 2012 Oct 12.
Microsatellite instability (MSI) occurs in 10-20% of colorectal tumours and is associated with good prognosis. Here we describe the development and validation of a genomic signature that identifies colorectal cancer patients with MSI caused by DNA mismatch repair deficiency with high accuracy. Microsatellite status for 276 stage II and III colorectal tumours has been determined. Full-genome expression data was used to identify genes that correlate with MSI status. A subset of these samples (n = 73) had sequencing data for 615 genes available. An MSI gene signature of 64 genes was developed and validated in two independent validation sets: the first consisting of frozen samples from 132 stage II patients; and the second consisting of FFPE samples from the PETACC-3 trial (n = 625). The 64-gene MSI signature identified MSI patients in the first validation set with a sensitivity of 90.3% and an overall accuracy of 84.8%, with an AUC of 0.942 (95% CI, 0.888-0.975). In the second validation, the signature also showed excellent performance, with a sensitivity 94.3% and an overall accuracy of 90.6%, with an AUC of 0.965 (95% CI, 0.943-0.988). Besides correct identification of MSI patients, the gene signature identified a group of MSI-like patients that were MSS by standard assessment but MSI by signature assessment. The MSI-signature could be linked to a deficient MMR phenotype, as both MSI and MSI-like patients showed a high mutation frequency (8.2% and 6.4% of 615 genes assayed, respectively) as compared to patients classified as MSS (1.6% mutation frequency). The MSI signature showed prognostic power in stage II patients (n = 215) with a hazard ratio of 0.252 (p = 0.0145). Patients with an MSI-like phenotype had also an improved survival when compared to MSS patients. The MSI signature was translated to a diagnostic microarray and technically and clinically validated in FFPE and frozen samples.
微卫星不稳定性（MSI）在10%-20%的结直肠癌肿瘤中出现，且与良好的预后相关。在此，我们描述了一种基因组特征的开发与验证，该特征能高精度地识别由DNA错配修复缺陷导致MSI的结直肠癌患者。已确定276例II期和III期结直肠癌肿瘤的微卫星状态。利用全基因组表达数据来识别与MSI状态相关的基因。这些样本中的一个子集（n = 73）有615个基因的测序数据。开发了一个由64个基因组成的MSI基因特征，并在两个独立的验证集中进行验证：第一个验证集由132例II期患者的冷冻样本组成；第二个验证集由PETACC-3试验中的FFPE样本组成（n = 625）。这个由64个基因组成的MSI特征在第一个验证集中识别MSI患者的灵敏度为90.3%，总体准确率为84.8%，曲线下面积（AUC）为0.942（95%置信区间，0.888 - 0.975）。在第二次验证中，该特征也表现出色，灵敏度为94.3%，总体准确率为90.6%，AUC为0.965（95%置信区间，0.943 - 0.988）。除了正确识别MSI患者外，该基因特征还识别出一组MSI样患者，这些患者通过标准评估为错配修复功能完整（MSS），但通过特征评估为MSI。MSI特征可能与错配修复缺陷表型相关，因为MSI和MSI样患者与分类为MSS的患者相比，均显示出高突变频率（分别为所检测的615个基因的8.2%和6.4%）。MSI特征在II期患者（n = 215）中显示出预后能力，风险比为0.252（p = 0.0145）。与MSS患者相比，具有MSI样表型的患者生存率也有所提高。MSI特征被转化为诊断性微阵列，并在FFPE和冷冻样本中进行了技术和临床验证。
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