Evidence of genetic progression in human gastric carcinomas with microsatellite instability.
Mutator phenotype tumors provide unique opportunities to unravel malignant progression because of various gene alterations acquired during clonal tumor evolution. Gastric carcinomas, which have been known to show frequent genetic instability, would be composed of initial gene alterations shared by most tumor areas and subsequent alterations restricted to particular tumor sites. To analyse the timing of genetic events, we examined separate sites of tumor tissue obtained from a given gastric carcinoma patient with microsatellite instability (MSI). Our study included 95 normal/tumor area pairs from 25 patients. Six of the 25 patients (24%) demonstrated various levels of MSI ranging from 7% (two of 30) to 97% (28 of 29) of markers tested in multiple tumor sites. Of the six patients, five manifested frameshift mutations in a tract of ten deoxyadenosines within transforming growth factor beta receptor type II and four demonstrated frameshift mutations in a tract of eight deoxyguanosines within BAX. These mutations were common to all tumor sites regardless of the various level of MSI phenotype, indicating initial events. Two of the six patients exhibited frameshift mutations in mononucleotide repeats of mismatch repair genes, hMSH3 and hMSH6, and the insulin-like growth factor II receptor in restricted tumor areas, indicating additional alterations. Insulin-like growth factor II receptor mutations appear to be caused by hMSH3 and hMSH6 mutations because the former mutations were confined to tumor portions with the latter two mismatch repair lesions. These results provide genetic progression evidence for gastric carcinomas of the mutator pathway. In this pathway, mismatch repair insufficiency initially targets mononucleotide tracts of transforming growth factor beta receptor type II and BAX. During tumorigenesis, primary mismatch repair failure may give rise to the secondary mismatch repair lesions, frameshift mutations of hMSH3 and hMSH6, which result in another tumorigenic mutation in the insulin-like growth factor II receptor.
Chung
Y J
YJ
Department of Microbiology, Catholic University Medical College, Seoul, Korea.
Park
S W
SW
Song
J M
JM
Lee
K Y
KY
Seo
E J
EJ
Choi
S W
SW
Rhyu
M G
MG
D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D016158:Genes, p53; D005819:Genetic Markers; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D013274:Stomach Neoplasms / Q000235:genetics*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics; D019680:Trinucleotide Repeat Expansion; D051028:bcl-2-Associated X Protein
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D007335:Insulin-Like Growth Factor II; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016212:Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C094443:G-T mismatch-binding protein; C078444:MSH3 protein, human; C421109:multidrug resistance-associated protein 1