Judson H, Stewart A, Leslie A, Pratt N R, Baty D U, Steele R J C, Carey F A
Department of Human Genetics, Ninewells Hospital and University of Dundee, Dundee, UK.
J Pathol. 2006 Nov;210(3):344-50. doi: 10.1002/path.2044.
Epigenetic mechanisms in carcinogenesis may have a significant role in the development of colorectal cancer. To investigate this phenomenon in early-stage disease, promoter methylation status in the tumour suppressor genes APC, MGMT, hMLH1, P14/P14ARF, and CDKN2A/P16 was investigated in 78 colorectal adenomas. These had previously been characterized for mutations of APC, KRAS, and TP53 genes and for chromosomal abnormality by comparative genomic hybridization (CGH). APC hypermethylation was seen in 52 tumours (66.7%). APC showed either methylation or mutation in 66 lesions (84.6%), but these events were not statistically associated. MGMT methylation was detected in 39 cases (50%). Adenomas with this abnormality showed a significantly lower number of chromosomal changes by CGH (p < 0.02), confirming that DNA repair defect of this type is associated with a lower level of chromosomal instability. An hMLH1 methylation defect was seen in only one adenoma (1.3%), from a patient who had a synchronous cancer showing the same defect. Methylation of P14 (P14ARF) was seen in 31 adenomas (39.7%) and CDKN2A (P16) abnormality in 25 (32.1%). DNA methylation at two or more loci was seen in 46 tumours (59%), while 11 lesions (14.1%) showed no evidence of hypermethylation at any of the loci studied. Methylation at any or all of MGMT, P14 or P16 was significantly associated with APC methylation (p = 0.01). Those neoplasms with more than two methylated genes showed significantly fewer chromosomal abnormalities than adenomas with one or no methylated loci (p < 0.001). There was no association between specific individual chromosomal abnormalities, APC, KRAS or TP53 mutations and any pattern of methylation abnormality. We conclude that methylation abnormality is very common in pre-invasive colorectal neoplasia, and that high level methylation is associated with low level chromosomal instability.
表观遗传机制在致癌过程中可能在结直肠癌的发生发展中起重要作用。为了在疾病早期研究这一现象，我们对78例结直肠腺瘤的肿瘤抑制基因APC、MGMT、hMLH1、P14/P14ARF和CDKN2A/P16的启动子甲基化状态进行了研究。这些腺瘤先前已通过比较基因组杂交（CGH）对APC、KRAS和TP53基因的突变以及染色体异常进行了特征分析。52例肿瘤（66.7%）中可见APC高甲基化。66个病变（84.6%）中APC表现出甲基化或突变，但这些事件无统计学关联。39例（50%）检测到MGMT甲基化。有这种异常的腺瘤通过CGH显示出明显较少的染色体变化（p < 0.02），证实这种类型的DNA修复缺陷与较低水平的染色体不稳定性相关。仅在1例腺瘤（1.3%）中发现hMLH1甲基化缺陷，该患者同时患有显示相同缺陷的癌症。31例腺瘤（39.7%）中可见P14（P14ARF）甲基化，25例（32.1%）中可见CDKN2A（P16）异常。46例肿瘤（59%）在两个或更多位点出现DNA甲基化，而11个病变（14.1%）在所研究的任何位点均未显示高甲基化证据。MGMT、P14或P16中任何一个或全部的甲基化与APC甲基化显著相关（p = 0.01）。那些有两个以上甲基化基因的肿瘤比有一个或没有甲基化位点的腺瘤显示出明显更少的染色体异常（p < 0.001）。特定的个体染色体异常、APC、KRAS或TP53突变与任何甲基化异常模式之间均无关联。我们得出结论，甲基化异常在结直肠浸润前肿瘤中非常常见，并且高水平甲基化与低水平染色体不稳定性相关。
