title: Genetic instability on chromosome 17 in the epithelium of non-polypoid colorectal carcinomas compared to polypoid lesions.
abstract: Early colorectal carcinomas (submucosal invasive adenocarcinomas) can be classified into polypoid growth carcinoma (PG-Ca) and non-polypoid growth carcinoma (NPG-Ca) types, the latter transforming more rapidly to advanced carcinoma. Previously, we indicated that stromal genetic instability might contribute to tumorigenesis of both sporadic and ulcerative colitis-associated colorectal adenocarcinomas. In the present study, we analyzed genetic instability of both epithelial and surrounding stromal components in PG-Ca and NPG-Ca. In 99 colorectal submucosal invasive adenocarcinomas, epithelial and stromal genetic instability was analyzed with National Cancer Institute standard microsatellite markers, chromosome 17 (Chr.17) markers and tumor suppressor gene-related markers, using a combination of the laser-captured microdissection and GeneScan approaches. Immunohistochemical analysis was carried out for hMLH1, hMSH2, MGMT and p53. In addition, we investigated methylation of the hMLH1 and MGMT promoters. The frequencies of epithelial microsatellite instability (MSI) with Chr.17 markers were significantly higher in NPG-Ca (33.3%) compared to PG-Ca (10.4%), particularly with D17S579 and D17S796. For loss of heterozygosity, only D17S786 showed a significant difference. The frequencies of stromal MSI with all markers were 31.7% and 25.9% in NPG-Ca and PG-Ca, respectively, but D17S579 and TP53 showed higher MSI in NPG-Ca than PG-Ca. Immunohistochemically, p53 protein expression in PG-Ca was significantly higher in loss of heterozygosity-positive cases with altered Chr.17 markers overall, especially the D17S796 marker, compared to cases without genetic instability. These results suggest that epithelial and stromal MSI of Chr.17 markers contributes more to carcinogenesis in NPG-Ca, whereas stromal genetic instability might be necessary for the development of both types of colorectal carcinoma.
authors.affiliation: Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan. dm03008a@st.kitasato-u.ac.jp
authors.forename: Taishi
authors.initials: T
authors.lastname: Ogawa
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshida
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tsuruta
authors.forename: Katsunori
authors.initials: K
authors.lastname: Saigenji
authors.forename: Isao
authors.initials: I
authors.lastname: Okayasu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D002454:Cell Differentiation; D043171:Chromosomal Instability; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D016133:Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D019853:O(6)-Methylguanine-DNA Methyltransferase; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein