Aberrant CpG island methylation in early-onset sporadic gastric carcinoma

• Published in: Journal of cancer research and clinical oncology Vol. 131; no. 11; pp. 733 - 740
• Main Authors: HEE CHEOL KIM, JIN CHEON KIM, SUN AE ROH, CHANG SIK YU, JEONG HWAN YOOK, SUNG TAE OH, BYUNG SIK KIM, KUN CHOON PARK, CHANG, Rin
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.11.2005; Springer Nature B.V
• Subjects: Adaptor Proteins, Signal Transducing; Adult; Age of Onset; Antineoplastic agents; Apoptosis Regulatory Proteins; beta Catenin - genetics; Biological and medical sciences; Biomarkers, Tumor - genetics; Cadherins - genetics; Calcium-Calmodulin-Dependent Protein Kinases - genetics; Cancer; Carrier Proteins - genetics; CpG Islands; Death-Associated Protein Kinases; Digestive system; DNA Methylation; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genes; Genes, APC; Glutathione S-Transferase pi - genetics; Humans; Loss of Heterozygosity; Male; Medical sciences; Microsatellite Repeats; Middle Aged; Mutation; Mutation, Missense; MutL Protein Homolog 1; Nerve Tissue Proteins - genetics; Nuclear Proteins - genetics; Pharmacology. Drug treatments; Phenotype; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Promoter Regions, Genetic; Stomach Neoplasms - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Thrombospondin 1 - genetics; Tissue Inhibitor of Metalloproteinase-3 - genetics; Tissues; Tumors; Sporadic; Malignant tumor; Microsatellite instability; Carcinogenesis; Stomach neoplasms; Stomach carcinoma; Age of onset; GC rich sequence; APC; Microsatellite DNA; Digestive diseases; Instability; Methylation; Gastric disease; Tumor suppressor gene
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-005-0017-0

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. 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. 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. 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.