Institute of Pathology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
Genes Chromosomes Cancer. 2019 Nov;58(11):783-797. doi: 10.1002/gcc.22787. Epub 2019 Aug 10.
Aberrant methylation of DNA is supposed to be a major and early driver of colonic adenoma development, which may result in colorectal cancer (CRC). Although gene methylation assays are used already for CRC screening, differential epigenetic alterations of recurring and nonrecurring colorectal adenomas have yet not been systematically investigated. Here, we collected a sample set of formalin-fixed paraffin-embedded colorectal low-grade adenomas (n = 72) consisting of primary adenomas without and with recurrence (n = 59), recurrent adenomas (n = 10), and normal mucosa specimens (n = 3). We aimed to unveil differentially methylated CpG positions (DMPs) across the methylome comparing not only primary adenomas without recurrence vs primary adenomas with recurrence but also primary adenomas vs recurrent adenomas using the Illumina Human Methylation 450K BeadChip array. Unsupervised hierarchical clustering exhibited a significant association of methylation patterns with histological adenoma subtypes. No significant DMPs were identified comparing primary adenomas with and without recurrence. Despite that, a total of 5094 DMPs (false discovery rate <0.05; fold change >10%) were identified in the comparisons of recurrent adenomas vs primary adenomas with recurrence (674; 98% hypermethylated), recurrent adenomas vs primary adenomas with and without recurrence (241; 99% hypermethylated) and colorectal adenomas vs normal mucosa (4179; 46% hypermethylated). DMPs in cytosine-phosphate-guanine (CpG) islands were frequently hypermethylated, whereas open sea- and shelf-regions exhibited hypomethylation. Gene ontology analysis revealed enrichment of genes associated with the immune system, inflammatory processes, and cancer pathways. In conclusion, our methylation data could assist in establishing a more robust and reproducible histological adenoma classification, which is a prerequisite for improving surveillance guidelines.
DNA 的异常甲基化被认为是结直肠腺瘤发展的主要和早期驱动因素，可能导致结直肠癌（CRC）。虽然基因甲基化检测已用于 CRC 筛查，但尚未系统研究复发性和非复发性结直肠腺瘤的差异表观遗传改变。在这里，我们收集了一组福尔马林固定石蜡包埋的结直肠低级别腺瘤的样本集（n = 72），包括无复发和有复发的原发性腺瘤（n = 59）、复发性腺瘤（n = 10）和正常黏膜标本（n = 3）。我们的目的是使用 Illumina Human Methylation 450K BeadChip 阵列，不仅比较无复发的原发性腺瘤与有复发的原发性腺瘤，而且比较原发性腺瘤与复发性腺瘤，揭示整个甲基组中差异甲基化的 CpG 位置（DMP）。无监督层次聚类显示，甲基化模式与组织学腺瘤亚型显著相关。比较无复发和有复发的原发性腺瘤未发现显著的 DMP。尽管如此，在复发性腺瘤与有复发的原发性腺瘤（674 个；98%呈高甲基化）、复发性腺瘤与有复发和无复发的原发性腺瘤（241 个；99%呈高甲基化）以及结直肠腺瘤与正常黏膜（4179 个；46%呈高甲基化）的比较中，共鉴定出 5094 个 DMP（错误发现率 <0.05；倍数变化>10%）。CpG 岛中的 DMP 常呈高甲基化，而开放海和架区则呈低甲基化。基因本体论分析显示，与免疫系统、炎症过程和癌症途径相关的基因富集。总之，我们的甲基化数据可以帮助建立更稳健和可重复的组织学腺瘤分类，这是改进监测指南的前提。
