p53 mutations and microsatellite instability in sporadic gastric cancer: when guardians fail.
Genetic instability may underlie the etiology of multistep gastric carcinogenesis. The altered microsatellites observed in tumors with the ubiquitous somatic mutation (USM) phenotype may represent the expression of such instability. Similarly, p53 mutations may allow the accumulation of genetic alterations caused by multiple mechanisms. In 40 sporadic gastric adenocarcinomas, nine tumors (22.5%) with p53 mutations in exons 5-8, and six tumors (15%) with the USM+ phenotype, were detected. None of the tumors had both alterations. The tumors with p53 mutations were predominantly in the proximal stomach whereas the USM+ tumors were predominantly in the distal stomach. The mutant p53 alleles were homogeneously distributed throughout the primary tumors, but usually absent from adjacent normal or dysplastic epithelium, indicating that p53 mutations are typically acquired before the bulk of clonal expansion. The loss of mutant p53 alleles during progression was also rarely observed in metastatic foci. Altered microsatellites were homogeneously present in the USM+ primary and metastatic tumors and one synchronous tubular adenoma, but were not detected in adjacent normal and metaplastic epithelium. These findings also demonstrate that the USM+ phenotype is expressed before the bulk of clonal expansion. In most (5 of 6) USM+ tumors, the sizes of the altered microsatellites differed between regions, indicating that the instability usually persists during clonal expansion. These findings indicate that both p53 mutations and the USM+ phenotype are present prior to the bulk of tumor growth and therefore may contribute to, rather than be a late consequence of, malignant transformation.
Strickler
J G
JG
Department of Anatomical Pathology, Mayo Clinic, Rochester, Minnesota 55905.
Zheng
J
J
Shu
Q
Q
Burgart
L J
LJ
Alberts
S R
SR
Shibata
D
D
D000368:Aged; D001483:Base Sequence; D003062:Codon / Q000235:genetics; D004276:DNA, Satellite / Q000235:genetics*; D005091:Exons / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
D003062:Codon; D004276:DNA, Satellite