Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA.
Department of Women's Cancer, University College London, London, UK.
Brief Bioinform. 2019 Jan 18;20(1):47-57. doi: 10.1093/bib/bbx097.
DNA methylation plays an essential role in cancer. Differential variability (DV) in cancer was recently observed that contributes to cancer heterogeneity and has been shown to be crucial in detecting epigenetic field defects, DNA methylation alterations happening early in carcinogenesis. As neighboring CpG sites are highly correlated, here, we present a new method to detect differentially methylated regions (DMRs) that uses combined signals from differential methylation and DV between sample groups. We demonstrated in simulation studies the superior performance of the new method than existing methods that use only one type of signals when true DMRs have both. Applications to DNA methylation data of breast invasive carcinoma (BRCA) and kidney renal clear cell carcinoma (KIRC) from The Cancer Genome Atlas (TCGA) and BRCA from Gene Expression Omnibus (GEO) suggest that the new method identified additional cancer-related DMRs that were missed by methods using one type of signals. Replication analyses using two independent BRCA data sets suggest that DMRs detected based on DV are reproducible. Only the new method identified epigenetic field defects when comparing normal tissues adjacent to tumors and normal tissues from age-matched cancer-free women from the GEO BRCA data and confirmed their enrichment in the progression to breast cancer.
DNA 甲基化在癌症中起着至关重要的作用。最近观察到癌症中的差异可变性 (DV)，它有助于癌症异质性，并已被证明在检测表观遗传场缺陷、癌发生早期发生的 DNA 甲基化改变方面至关重要。由于相邻的 CpG 位点高度相关，因此，我们在这里提出了一种新方法来检测差异甲基化区域 (DMR)，该方法使用来自样本组之间的差异甲基化和 DV 的组合信号。我们在模拟研究中证明了，当真正的 DMR 同时具有这两种信号时，新方法的性能优于仅使用一种信号的现有方法。对来自癌症基因组图谱 (TCGA) 的乳腺浸润性癌 (BRCA) 和肾透明细胞癌 (KIRC) 的 DNA 甲基化数据以及基因表达综合数据库 (GEO) 的 BRCA 的应用表明，新方法识别出了其他被仅使用一种信号的方法遗漏的与癌症相关的 DMR。使用两个独立的 BRCA 数据集进行的复制分析表明，基于 DV 检测到的 DMR 是可重复的。只有新方法在比较肿瘤相邻的正常组织和来自 GEO BRCA 数据的年龄匹配的无癌女性的正常组织时识别出了表观遗传场缺陷，并证实它们在向乳腺癌进展中富集。
