Aberrant CpG island methylation in early-onset sporadic gastric carcinoma.
OBJECTIVE
Gastric carcinoma more commonly affects older patients, and it is thought that cases of early-onset gastric carcinoma may develop with a different molecular profile different from that of carcinoma occurring at a later age. We assayed the methylation status and genetic changes in genes associated with the APC-beta-catenin axis and the mismatch repair system in relatively early-onset gastric carcinoma samples to determine their association with gastric carcinogenesis.


METHODS
Tumor and normal tissue DNA samples were obtained from 40 patients with early-onset (< 50 y) gastric carcinomas and assayed for APC and CTNNB1 mutations, microsatellite instability, and methylation of the promoters of the hMLH1, TIMP3, THBS1, DAP- K, GSTP1 , APC, and MINT2.


RESULTS
Promoter methylation at these seven loci ranged from 12.5 to 62%, with 38/40 tumors (95%) showing promoter methylation at more than one locus. The CpG island methylation phenotype (CIMP) was classified as high in 16 tumors (40%), low in 22 tumors (55%), and negative in 2 tumors (5%). Two concurrent missense mutations (E1685G, R1763L) in the APC mutation cluster region were detected in two tumors, nine tumors showed loss of APC heterozygosity (LOH), and two showed both LOH and promoter methylation.


CONCLUSIONS
Our results indicate that, unlike in colorectal carcinoma, APC and CTNNB1 mutations do not appear to be highly implicated in early-onset gastric carcinogenesis. In contrast, our data show that promoter methylation is a prevalent phenomenon in early-onset gastric carcinoma and may be related to gastric carcinogenesis.
Kim
Hee Cheol
HC
Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Asan Medical Center 388-1, Pungnap-dong, Songpa-gu, Seoul, Korea. hckim@amc.seoul.kr
Kim
Jin Cheon
JC
Roh
Sun Ae
SA
Yu
Chang Sik
CS
Yook
Jeong Hwan
JH
Oh
Sung Tae
ST
Kim
Byung Sik
BS
Park
Kun Choon
KC
Chang
Rin
R
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D017668:Age of Onset; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000235:genetics*; D015820:Cadherins / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D005260:Female; D017491:Genes, APC; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics*; D019700:Thrombospondin 1 / Q000235:genetics; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
C491636:APBA2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D015820:Cadherins; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C088390:TIMP3 protein, human; D019700:Thrombospondin 1; D019717:Tissue Inhibitor of Metalloproteinase-3; D051176:beta Catenin; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000070957:MutL Protein Homolog 1