Gastric cancers of the microsatellite mutator phenotype display characteristic genetic and clinical features.
OBJECTIVE
Colon cancer of the microsatellite mutator phenotype (MMP) exhibits significant genotype differences from cancer without the MMP. Twenty-nine MMP-positive gastric cancers were analyzed to clarify if these genotype differences were also associated with distinctive clinicopathologic features.


METHODS
Alterations of p53, beta2-microglobulin (beta2M ), hMLH1, and hMSH2 genes were analyzed by using polymerase chain reaction, single-strand conformational polymorphism, sequencing, microallelotyping, hypermethylation assays, and immunostaining. The results were contrasted with mutations in BAX, hMSH3, and hMSH6, genes target for the MMP.


RESULTS
Tumors with the MMP had a significantly lower incidence of p53 gene mutations than the other tumors and often contained beta2M gene somatic mutations. Many tumors contained concomitant genetic and epigenetic alterations in DNA mismatch repair genes, hMLH1, hMSH2, hMSH3, and hMSH6. Gastric cancer of the MMP was associated with well/moderate differentiation, distal location, and better survival.


CONCLUSIONS
Analysis of somatic alterations in microsatellite sequences and in cancer genes target for the MMP is useful for the classification of groups of gastric cancers with different prognosis. The results further support the concept that (gastric) cancer of the MMP represents a distinctive oncogenic pathway because the mutated cancer genes are usually different from those found in tumors without the MMP.
Yamamoto
H
H
Oncogene and Tumor Suppressor Gene Program, La Jolla Cancer Research Center, The Burnham Institute, La Jolla, California.
Perez-Piteira
J
J
Yoshida
T
T
Terada
M
M
Itoh
F
F
Imai
K
K
Perucho
M
M
D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence / Q000235:genetics; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006801:Humans; D019656:Loss of Heterozygosity; D008745:Methylation; D018895:Microsatellite Repeats / Q000235:genetics; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001613:beta 2-Microglobulin / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D001613:beta 2-Microglobulin; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein