Homma Naoyuki, Tamura Gen, Honda Teiichiro, Jin Zhe, Ohmura Kiyonari, Kawata Sumio, Motoyama Teiichi
Department of Pathology, Yamagata University School of Medicine, 990-9585, Yamagata, 2-2-2 Iida-nishi, Japan.
Virchows Arch. 2005 Feb;446(2):120-6. doi: 10.1007/s00428-004-1146-6. Epub 2004 Dec 10.
Human tumors are genetically unstable, and the instability exists at two distinct levels-the chromosomal level and the nucleotide level. Chfr and hMLH1 hypermethylation, which may lead to chromosomal instability (CIN) and microsatellite instability (MSI), respectively, was analyzed in gastric noninvasive neoplasias (NIN, Padova international classification) and submucosal invasive adenocarcinomas and in their corresponding non-neoplastic gastric epithelia. Results were compared with microsatellite status, p53 immunoreactivity, and cellular phenotype. Hypermethylation of Chfr and hMLH1 was observed in: 10% (1/10) and 0% (0/10) of low-grade NIN (L-NIN); 63% (5/8) and 63% (5/8) of high-grade NIN, including suspicion for carcinoma without invasion (H-NIN); 36% (5/14) and 57% (8/14) of high-grade NIN, including carcinoma without invasion; and 35% (7/20) and 25% (5/20) of submucosal invasive adenocarcinomas, respectively. Hypermethylation was less frequent in L-NIN than H-NIN (P<0.05) for Chfr and was also less frequent in L-NIN than the others (P<0.05) for hMLH1. We failed to find a significant correlation between Chfr hypermethylation and chromosomal loss of heterozygosity, although hypermethylation of hMLH1 was significantly associated with high-frequency MSI (P<0.01). Expression of p53 was not associated with Chfr or hMLH1 methylation. As for cellular phenotype, hypermethylation of Chfr and hMLH1 was frequent in tumors exhibiting the foveolar epithelial phenotype (50%, 2/4 and 75%, 3/4, respectively) and the ordinary phenotype (40%, 16/40 and 38%, 15/40, respectively), but never in those with the complete-type intestinal metaplastic phenotype (0%, 0/8 for both). In addition, hypermethylation of Chfr and hMLH1 occurred concurrently (P<0.01); methylation was more frequent in patients over 70 years of age (P<0.01), and it was also present in some samples of non-neoplastic gastric epithelia from elderly patients. Thus, some gastric tumors with the foveolar or ordinary phenotype may develop as a result of age-related methylation of Chfr and hMLH1, although Chfr methylation was not associated with CIN.
人类肿瘤具有基因不稳定性，且这种不稳定性存在于两个不同层面——染色体层面和核苷酸层面。在胃非侵袭性肿瘤（NIN，帕多瓦国际分类法）、黏膜下浸润性腺癌及其相应的非肿瘤性胃上皮中，分析了Chfr和hMLH1的高甲基化情况，其可能分别导致染色体不稳定性（CIN）和微卫星不稳定性（MSI）。将结果与微卫星状态、p53免疫反应性及细胞表型进行比较。在以下情况中观察到Chfr和hMLH1的高甲基化：低级别NIN（L-NIN）中分别为10%（1/10）和0%（0/10）；高级别NIN（包括可疑无侵袭性癌，H-NIN）中分别为63%（5/8）和63%（5/8）；高级别NIN（包括无侵袭性癌）中分别为36%（5/14）和57%（8/14）；黏膜下浸润性腺癌中分别为35%（7/20）和25%（5/20）。Chfr的高甲基化在L-NIN中比在H-NIN中更少见（P<0.05），hMLH1的高甲基化在L-NIN中也比在其他情况中更少见（P<0.05）。尽管hMLH1的高甲基化与高频MSI显著相关（P<0.01），但未发现Chfr高甲基化与染色体杂合性缺失之间存在显著相关性。p53的表达与Chfr或hMLH1甲基化无关。至于细胞表型，Chfr和hMLH1的高甲基化在呈现小凹上皮表型的肿瘤中较为常见（分别为50%，2/4和75%，3/4）以及普通表型的肿瘤中（分别为40%，16/40和38%，15/40），但在具有完全型肠化生表型的肿瘤中从未出现（两者均为0%，0/8）。此外，Chfr和hMLH1的高甲基化同时出现（P<0.01）；甲基化在70岁以上患者中更常见（P<0.01），并且在老年患者的一些非肿瘤性胃上皮样本中也存在。因此，一些具有小凹或普通表型的胃肿瘤可能是由于Chfr和hMLH1与年龄相关的甲基化而发生，尽管Chfr甲基化与CIN无关。
