Department of Molecular Medicine, Aarhus University Hospital, 8200, Aarhus, Denmark.
Epigenomic Unit, Health Research Institute La Fe (ISSLaFe), Valencia, Spain.
Nat Commun. 2020 Apr 24;11(1):2025. doi: 10.1038/s41467-020-16000-6.
Transcriptional characterization and classification has potential to resolve the inter-tumor heterogeneity of colorectal cancer and improve patient management. Yet, robust transcriptional profiling is difficult using formalin-fixed, paraffin-embedded (FFPE) samples, which complicates testing in clinical and archival material. We present MethCORR, an approach that allows uniform molecular characterization and classification of fresh-frozen and FFPE samples. MethCORR identifies genome-wide correlations between RNA expression and DNA methylation in fresh-frozen samples. This information is used to infer gene expression information in FFPE samples from their methylation profiles. MethCORR is here applied to methylation profiles from 877 fresh-frozen/FFPE samples and comparative analysis identifies the same two subtypes in four independent cohorts. Furthermore, subtype-specific prognostic biomarkers that better predicts relapse-free survival (HR = 2.66, 95%CI [1.67-4.22], P value < 0.001 (log-rank test)) than UICC tumor, node, metastasis (TNM) staging and microsatellite instability status are identified and validated using DNA methylation-specific PCR. The MethCORR approach is general, and may be similarly successful for other cancer types.
转录特征分析和分类有可能解决结直肠癌的肿瘤内异质性，并改善患者管理。然而，使用福尔马林固定、石蜡包埋（FFPE）样本进行稳健的转录谱分析非常困难，这使得在临床和存档材料中进行测试变得复杂。我们提出了 MethCORR，这是一种允许对新鲜冷冻和 FFPE 样本进行统一分子特征分析和分类的方法。MethCORR 在新鲜冷冻样本中识别 RNA 表达和 DNA 甲基化之间的全基因组相关性。该信息用于根据其甲基化谱推断 FFPE 样本中的基因表达信息。MethCORR 应用于 877 个新鲜冷冻/FFPE 样本的甲基化谱，比较分析在四个独立队列中鉴定出相同的两个亚型。此外，使用 DNA 甲基化特异性 PCR 鉴定并验证了比 UICC 肿瘤、淋巴结、转移（TNM）分期和微卫星不稳定性状态更能预测无复发生存（HR=2.66，95%CI[1.67-4.22]，P 值<0.001（对数秩检验））的亚型特异性预后生物标志物。MethCORR 方法具有通用性，对于其他癌症类型可能同样成功。
