正常结肠黏膜中MLH1基因5'区域的年龄相关高甲基化与微卫星不稳定型结直肠癌的发生有关。

Age-related hypermethylation of the 5' region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colorectal cancer development.

作者信息

Nakagawa H, Nuovo G J, Zervos E E, Martin E W, Salovaara R, Aaltonen L A, de la Chapelle A

机构信息

Division of Human Cancer Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.

出版信息

Cancer Res. 2001 Oct 1;61(19):6991-5.

PMID:11585722

Abstract

Hypermethylation of the MLH1 promoter underlies most sporadic colorectal cancers with microsatellite instability (MSI). To investigate the role of hypermethylation in the normal colonic mucosa as a possible precursor lesion, we studied 700 bp upstream of MLH1 covering 51 CpG sites. We found partially methylated alleles in 15 of 34 (44%) patients <60 years of age and 20 of 24 (83%) patients > or =80 years of age (P = 0.0026). Fully methylated alleles were present in 18 of 33 (55%) patients with MSI+ tumors but in only 18 of 90 (20%) patients with MSI- tumors (P = 0.00019). By in situ analysis, methylation was patchy and located mainly in the cryptal regions close to the lumen. We conclude that the spread of methylation in the MLH1 promoter in the normal colonic mucosa is closely associated with age and the development of sporadic MSI+ colorectal cancers.

摘要

MLH1启动子的高甲基化是大多数具有微卫星不稳定性（MSI）的散发性结直肠癌的基础。为了研究作为可能的前驱病变的正常结肠黏膜中高甲基化的作用，我们研究了MLH1上游700 bp，其涵盖51个CpG位点。我们在34名年龄<60岁的患者中有15名（44%）以及24名年龄≥80岁的患者中有20名（83%）发现了部分甲基化的等位基因（P = 0.0026）。在33名MSI+肿瘤患者中有18名（55%）存在完全甲基化的等位基因，但在90名MSI-肿瘤患者中仅有18名（20%）存在完全甲基化的等位基因（P = 0.00019）。通过原位分析，甲基化呈斑片状，主要位于靠近管腔的隐窝区域。我们得出结论，正常结肠黏膜中MLH1启动子甲基化的扩散与年龄以及散发性MSI+结直肠癌的发生密切相关。