Genetic and epigenetic alterations in multistep carcinogenesis of the stomach.
An accumulation of multiple genetic and epigenetic alterations of oncogenes, tumor suppressor genes, DNA repair genes, cell cycle regulators, cell adhesion molecules, and the growth factor/receptor system is involved in the course of multistep conversion of normal epithelial cells to clinical gastric cancer. Some of them differ depending on the histological type, well-differentiated (intestinal) and poorly differentiated (diffuse) types, suggesting the presence of two distinct genetic pathways. Genetic instability, chromosomal instability (telomere reduction), and immortality (activation of telomerase and expression of telomerase reverse transcriptase: TERT) participate in the initial step of stomach carcinogenesis. Because TERT protein expression precedes the telomerase activities in precancerous lesions, TERT expression may be a prerequisite for telomerase activation. The cyclin E gene is amplified in 15%-20% of gastric cancer. Reduced expression of a cyclin-dependent kinase (CDK) inhibitor, p27Kip1, is frequently found in gastric cancer associated with high grade malignancy. E2F-1, an important downstream target of cyclins/CDKs, is overexpressed in about 40% of gastric carcinomas, whereas gene amplification of E2F-1 rarely occurs. Loss of heterozygosity (LOH) of p73, the p53-related new tumor suppressor gene, preferentially occurs in well-differentiated adenocarcinomas of foveolar type expressing pS2, a gastric-specific trefoil factor, indicating the importance of p73 LOH in the genesis.
Yasui
W
W
First Department of Pathology, Hiroshima University School of Medicine, Japan.
Yokozaki
H
H
Fujimoto
J
J
Naka
K
K
Kuniyasu
H
H
Tahara
E
E
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations / Q000235:genetics*; D004268:DNA-Binding Proteins; D005753:Gastric Mucosa / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D012313:RNA; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D019098:Telomerase / Q000235:genetics
D004268:DNA-Binding Proteins; C422952:telomerase RNA; D012313:RNA; C509186:TERT protein, human; D019098:Telomerase