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Ulcerative Colitis-Associated Colorectal Cancer is Frequently Associated with the Microsatellite Instability Pathway

  • Original Contribution
  • Published:
Diseases of the Colon & Rectum

Purpose

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 β receptor Type II (TGFβRII) was significantly correlated with worsening histologic grade. High-microsatellite instability was significantly associated with hMLH1 hypermethylation and loss of hMSH2 expression.

Conclusion

The carcinogenesis process in ulcerative colitis-associated colorectal cancer was closely associated with the microsatellite instability pathway through TGFβRII mutation by a dysfunction of the mismatch repair system.

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Authors and Affiliations

  1. Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

    Ichiro Fujiwara M.D., Masakazu Yashiro M.D., Ph.D., Naoshi Kubo M.D., Kiyoshi Maeda M.D., Ph.D. & Kosei Hirakawa M.D., Ph.D.

Authors
  1. Ichiro Fujiwara M.D.
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  2. Masakazu Yashiro M.D., Ph.D.
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  3. Naoshi Kubo M.D.
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  4. Kiyoshi Maeda M.D., Ph.D.
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  5. Kosei Hirakawa M.D., Ph.D.
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Corresponding author

Correspondence to Masakazu Yashiro M.D., Ph.D..

Additional information

Supported in part by a Grant-in Aid for the Osaka City University Medical Research Foundation, a Grant-in Aid for Kobayashi Foundation for Innovative Cancer Chemotherapy, and a Grant-in Aid for the Osaka Medical Research Foundation for Incurable Diseases.

Appendix

Appendix

The genetic alterations detected in representative lesions in each UC patient was provided as the Supplemental Table A.

Supplemental Table A Genetic alterations detected in representative (worst histologic grade) lesions in each UC patient
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Fujiwara, I., Yashiro, M., Kubo, N. et al. Ulcerative Colitis-Associated Colorectal Cancer is Frequently Associated with the Microsatellite Instability Pathway. Dis Colon Rectum 51, 1387–1394 (2008). https://doi.org/10.1007/s10350-008-9212-9

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  • DOI: https://doi.org/10.1007/s10350-008-9212-9

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