Ulcerative colitis-associated colorectal cancer is frequently associated with the microsatellite instability pathway.
OBJECTIVE
Patients with ulcerative colitis have a high risk for the development of colorectal cancer. To understand the molecular mechanisms of the carcinogenesis process of ulcerative colitis-associated colorectal cancer, the genetic alterations in inflamed or neoplastic colon epithelium in ulcerative colitis were analyzed.


METHODS
Fifty-seven patients with ulcerative colitis were enrolled in this study. Specimens were obtained from the patients randomly at six colonic sites. Each patient was histologically classified according to the worst pathologic finding into cancer, dysplasia, indefinite, and normal cases. Microsatellite instability, mutations of target genes, hypermethylation of the hMLH1 promoter region, and mismatch repair protein expression were analyzed.


RESULTS
High-microsatellite instability was found in 4 of 11 cancer cases (36 percent), 5 of 15 dysplasia cases (33 percent), 5 of 11 indefinite cases (45 percent), and none of 20 normal cases (0 percent). A significant correlation was found between the malignant potential and high-microsatellite instability. A frameshift mutation of transforming growth factor beta receptor Type II (TGFbetaRII) was significantly correlated with worsening histologic grade. High-microsatellite instability was significantly associated with hMLH1 hypermethylation and loss of hMSH2 expression.


CONCLUSIONS
The carcinogenesis process in ulcerative colitis-associated colorectal cancer was closely associated with the microsatellite instability pathway through TGFbetaRII mutation by a dysfunction of the mismatch repair system.
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.
Ichiro
I
Fujiwara
Masakazu
M
Yashiro
Naoshi
N
Kubo
Kiyoshi
K
Maeda
Kosei
K
Hirakawa
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D001706:Biopsy; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009687:Nuclear Proteins / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D018125:Receptors, Transforming Growth Factor beta; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein