title: Hypermethylation of Chfr and hMLH1 in gastric noninvasive and early invasive neoplasias.
abstract: 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.
authors.affiliation: Department of Pathology, Yamagata University School of Medicine, 990-9585, Yamagata, 2-2-2 Iida-nishi, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Homma
authors.forename: Gen
authors.initials: G
authors.lastname: Tamura
authors.forename: Teiichiro
authors.initials: T
authors.lastname: Honda
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jin
authors.forename: Kiyonari
authors.initials: K
authors.lastname: Ohmura
authors.forename: Sumio
authors.initials: S
authors.lastname: Kawata
authors.forename: Teiichi
authors.initials: T
authors.lastname: Motoyama
mesh_terms: 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
chemical_list: 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
references.citation: EMBO J. 2003 May 1;22(9):2245-54
references.pmid: 12727890
references.citation: J Cell Biol. 2002 Jan 21;156(2):249-59
references.pmid: 11807090
references.citation: J Pathol. 2003 May;200(1):23-31
references.pmid: 12692837
references.citation: Int J Cancer. 1991 Jan 21;47(2):304-10
references.pmid: 1988372
references.citation: Jpn J Cancer Res. 1999 Aug;90(8):837-40
references.pmid: 10543255
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7818-23
references.pmid: 12810945
references.citation: Genomics. 1999 Jun 1;58(2):181-7
references.pmid: 10366450
references.citation: Am J Surg Pathol. 2000 Feb;24(2):167-76
references.pmid: 10680883
references.citation: Cancer Res. 1998 Nov 15;58(22):5248-57
references.pmid: 9823339
references.citation: Br J Cancer. 2002 Feb 12;86(4):564-7
references.pmid: 11870538
references.citation: Hum Pathol. 2000 Sep;31(9):1031-5
references.pmid: 11014567
references.citation: Cancer Res. 2001 Jul 1;61(13):5193-201
references.pmid: 11431359
references.citation: Cancer Res. 2002 Aug 1;62(15):4519-24
references.pmid: 12154064
references.citation: Nat Genet. 1999 Feb;21(2):163-7
references.pmid: 9988266
references.citation: Nature. 1998 Dec 17;396(6712):643-9
references.pmid: 9872311
references.citation: Anal Cell Pathol. 1998;16(4):223-31
references.pmid: 9762369
references.citation: J Pathol. 1998 May;185(1):38-43
references.pmid: 9713358
references.citation: J Pathol. 1996 Dec;180(4):371-7
references.pmid: 9014856
references.citation: Carcinogenesis. 2002 Oct;23(10):1695-9
references.pmid: 12376479
references.citation: Lab Invest. 2001 Apr;81(4):593-8
references.pmid: 11304579
references.citation: Eur J Cancer. 2003 Jun;39(9):1222-7
references.pmid: 12763209
references.citation: J Pathol. 2001 Jul;194(3):334-40
references.pmid: 11439366
references.citation: Histol Histopathol. 2002 Jan;17 (1):323-9
references.pmid: 11813881
references.citation: Nature. 2000 Jul 27;406(6794):430-5
references.pmid: 10935642
references.citation: Genes Chromosomes Cancer. 2000 Nov;29(3):213-8
references.pmid: 10992296
references.citation: Br J Cancer. 2004 May 17;90(10):2013-6
references.pmid: 15138487
references.citation: Nature. 1998 Mar 19;392(6673):300-3
references.pmid: 9521327
references.citation: Oncogene. 2002 Apr 4;21(15):2328-33
references.pmid: 11948416
references.citation: Cancer Res. 2002 Mar 15;62(6):1797-801
references.pmid: 11912157
references.citation: Am J Pathol. 2002 Aug;161(2):611-8
references.pmid: 12163385
references.citation: Cancer Res. 1995 Sep 1;55(17):3721-5
references.pmid: 7641183
references.citation: Science. 1996 Oct 11;274(5285):246-8
references.pmid: 8824189
references.citation: Lab Invest. 2002 Dec;82(12 ):1637-45
references.pmid: 12480914
references.citation: Pathol Int. 1996 Nov;46(11):834-41
references.pmid: 8970192
references.citation: Am J Pathol. 2000 Sep;157(3):717-22
references.pmid: 10980110
references.citation: CA Cancer J Clin. 1994 May-Jun;44(3):133-5
references.pmid: 7621066
references.citation: Carcinogenesis. 1999 Dec;20(12):2317-26
references.pmid: 10590226
references.citation: Gastroenterology. 1994 Nov;107(5):1352-63
references.pmid: 7926500
references.citation: Carcinogenesis. 2003 Jan;24(1):47-51
references.pmid: 12538348
references.citation: Am J Pathol. 2002 Aug;161(2):399-403
references.pmid: 12163364
references.citation: Cancer Res. 1991 Jun 1;51(11):3056-8
references.pmid: 2032245
references.citation: Biochem J. 1980 Nov 1;191(2):645-8
references.pmid: 7016112