title: Relationship between intratumor histological heterogeneity and genetic abnormalities in gastric carcinoma with microsatellite instability.
abstract: Microsatellite instability (MSI)-mutator phenotype variably targets microsatellite-like sequences in coding regions of cancer-related genes. Intratumor histological heterogeneity of gastric carcinoma with MSI was evaluated and found to be linked with the topographical distribution of MSI-associated mutations. One hundred fifty tumor sites derived from 51 gastric cancer patients were microdissected with respect to histological and topographical clonality. We found 11 gastric carcinomas with a high frequency of MSI, which were characterized by marked intratumor genetic heterogeneity arising from the progressive MSI-phenotype that was associated with frameshift mutations on multiple cancer-related genes. The 11 MSI-tumor cases manifested the MSI-phenotype in 34 of 36 tumor sites tested, but not in the remaining 2 sites. Most (88.2%, 30 of 34) MSI-positive sites and most (96.2%, 25 of 26) tumor sites harboring the frameshift mutations in transforming growth factor-beta receptor type II gene exhibited intestinal-type histology, whereas the 2 MSI-negative sites were found to be of diffuse-type histology without accompanying frameshift mutations. In 2 of 5 cases harboring E2F-4 frameshift mutations, glandular structures of intestinal-type tumor were likely to be variably differentiated in relation to the extent of the mutation, i.e., the number of mutated alleles and the size of deleted or inserted base pairs. Overall, the intratumor histological heterogeneity of gastric carcinoma with MSI was associated with the progressive frameshift mutations in transforming growth factor-beta receptor type II and E2F-4 genes.
authors.affiliation: Department of Microbiology, College of Medicine, Catholic University of Korea, Seoul, Korea.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Chung
authors.forename: K M
authors.initials: KM
authors.lastname: Kim
authors.forename: J R
authors.initials: JR
authors.lastname: Choi
authors.forename: S W
authors.initials: SW
authors.lastname: Choi
authors.forename: M G
authors.initials: MG
authors.lastname: Rhyu
mesh_terms: D020137:Base Pair Mismatch; D004268:DNA-Binding Proteins / Q000235:genetics; D005091:Exons; D016368:Frameshift Mutation; D016158:Genes, p53; D005819:Genetic Markers; D006801:Humans; D007438:Introns; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D018598:Minisatellite Repeats; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D009154:Mutation; D012150:Polymorphism, Restriction Fragment Length; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D017527:Receptor, IGF Type 2 / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D051028:bcl-2-Associated X Protein
chemical_list: D004268:DNA-Binding Proteins; D005819:Genetic Markers; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017527:Receptor, IGF Type 2; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein; C094443:G-T mismatch-binding protein; C078444:MSH3 protein, human; C421109:multidrug resistance-associated protein 1