Hypermethylation of Chfr and hMLH1 in gastric noninvasive and early invasive neoplasias.
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.
Homma
Naoyuki
N
Department of Pathology, Yamagata University School of Medicine, 990-9585, Yamagata, 2-2-2 Iida-nishi, Japan.
Tamura
Gen
G
Honda
Teiichiro
T
Jin
Zhe
Z
Ohmura
Kiyonari
K
Kawata
Sumio
S
Motoyama
Teiichi
T
D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000375:Aging; D002352:Carrier Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D043171:Chromosomal Instability; D019175:DNA Methylation; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins; D010641:Phenotype; D000075223:Poly-ADP-Ribose Binding Proteins; D016133:Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; D000070957:MutL Protein Homolog 1
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