Microsatellite instability in precancerous lesions and adenocarcinomas of the stomach.
BACKGROUND
It is generally known that replication errors (RERs) at microsatellite loci detected in human malignancies reflect a genetic instability that is caused by abnormalities of DNA mismatch repair system and underlie human carcinogenesis. The authors analyzed RERs in precancerous lesions and adenocarcinomas of the stomach to learn when genetic instability occurs in stomach carcinogenesis. In addition, the authors examined genetic instability occurs in stomach carcinogenesis. In addition, the authors examined genetic alterations of the p53 and adenomatous polyposis coli (APC) genes to investigate the correlation between genetic instability and genetic alterations in these tumor suppressor genes.


METHODS
The authors examined microsatellite assay at 9 microsatellite loci in 24 sporadic gastric cancers, 12 gastric adenomas, and 9 intestinal metaplasia mucosae of the stomach from patients with gastric cancers using fresh frozen or formalin fixed and paraffin embedded samples paired with normal mucosae. They also screened loss of heterozygosity (LOH) of the p53 and APC genes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.


RESULTS
In total, the RER(+) phenotypes were observed in 8 of 24 (33%) gastric cancers, 5 of 12 (42%) gastric adenomas, and 3 of 9 (33%) intestinal metaplasia mucosae of the stomach. Histology, RERs were detected in 3 of 9 (33%) well differentiated adenocarcinomas, 2 of 11 (18%) poorly differentiated adenocarcinomas, and 3 of 4 (75%) scirrhous type gastric cancers respectively. Several cases showed RERs at many microsatellite loci simultaneously. Some RER(+) phenotypes had genetic alterations of the p53 or APC genes detected by LOH using PCR-RFLP analysis. However, no significant correlation was found between RER(+) phenotypes and LOH in these genes.


CONCLUSIONS
The frequency of RERs in detected gastric cancers were almost the same when compared with previously reported data. Interestingly, RERs were detected in greater than 30% of precancerous lesions, suggesting that genetic instability is an early somatic event of multistep stomach carcinogenesis. It also suggests that the adenoma-carcinoma sequence does exist in stomach carcinogenesis, especially in well differentiated adenocarcinomas. Moreover, alterations in the p53 and APC genes detected by PCR-RFLP analysis did not correlate with RER(+) phenotypes.
Semba
S
S
First Department of Pathology, Hiroshima University, School of Medicine, Japan.
Yokozaki
H
H
Yamamoto
S
S
Yasui
W
W
Tahara
E
E
D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000235:genetics*; D004276:DNA, Satellite / Q000235:genetics*; D005260:Female; D017491:Genes, APC; D016158:Genes, p53; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011230:Precancerous Conditions / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics*
D004273:DNA, Neoplasm; D004276:DNA, Satellite