ABSTRACT

Physiological ageing and tumorigenesis are both associated with epigenomic alterations in human tissue cells, the most extensively investigated of which entails de novo cytosine methylation (i.e., hypermethylation) within the CpG dinucleotides of CpG islands. Genomic regions that become hypermethylated during tumorigenesis are generally believed to overlap regions that acquire methylation in normal tissues as an effect of ageing. To define the extension of this overlap, we analysed the DNA methylomes of 48 large-bowel tissue samples taken from women of different ages during screening colonoscopy: 18 paired samples of normal and lesional tissues from donors harbouring a precancerous lesion and 12 samples of normal mucosa from tumour-free donors. Each sample was subjected to targeted, genome-wide bisulphite sequencing of ~2.5% of the genome, including all CpG islands. In terms of both its magnitude and extension along the chromatin, tumour-associated DNA hypermethylation in these regions was much more conspicuous than that observed in the normal mucosal samples from older (vs. younger) tumour-free donors. 83% of the ageing-associated hypermethylated regions (n = 2501) coincided with hypermethylated regions observed in tumour samples. However, 86% of the regions displaying hypermethylation in precancerous lesions (n = 16,772) showed no methylation changes in the ageing normal mucosa. The tumour-specificity of this latter hypermethylation was validated using published sets of data on DNA methylation in normal and neoplastic colon tissues. This extensive set of genomic regions displaying tumour-specific hypermethylation represents a rich vein of putative biomarkers for the early, non-invasive detection of colorectal tumours in women of all ages.

摘要

生理衰老和肿瘤发生都与人类组织细胞的表观基因组改变有关，其中最广泛研究的需要 CpG 岛的 CpG 二核苷酸内的从头胞嘧啶甲基化（即高甲基化）。通常认为在肿瘤发生过程中变得高甲基化的基因组区域与正常组织中由于衰老而获得甲基化的区域重叠。为了确定这种重叠的延伸，我们分析了在结肠镜检查期间取自不同年龄女性的 48 个大肠组织样本的 DNA 甲基化组：18 对来自携带癌前病变供体的正常和病变组织样本和 12 个正常粘膜样本来自无肿瘤捐赠者。每个样本都对约 2.5% 的基因组进行有针对性的全基因组亚硫酸氢盐测序，包括所有 CpG 岛。就其幅度和沿染色质的延伸而言，这些区域中与肿瘤相关的 DNA 高甲基化比在来自较老（与较年轻）无肿瘤供体的正常粘膜样本中观察到的要明显得多。83% 的衰老相关高甲基化区域 (n = 2501) 与肿瘤样本中观察到的高甲基化区域一致。然而，在癌前病变（n = 16,772）中显示高甲基化的区域中有 86% 在老化的正常黏膜中没有甲基化变化。使用已发表的关于正常和肿瘤结肠组织中 DNA 甲基化的数据集验证了后一种高甲基化的肿瘤特异性。这组显示肿瘤特异性高甲基化的广泛基因组区域代表了丰富的早期推定生物标志物，