Predicting ulcerative colitis-associated colorectal cancer using reverse-transcription polymerase chain reaction analysis.

BACKGROUND: Widespread genetic alterations are present not only in ulcerative colitis (UC)-associated neoplastic lesions but also in the adjacent normal colonic mucosa. This suggests that genetic changes in nonneoplastic mucosa might be effective markers for predicting the development of UC-associated cancer (UC-Ca). This study aimed to build a predictive model for the development of UC-Ca based on gene expression levels measured by reverse-transcription polymerase chain reaction (RT-PCR) analysis in nonneoplastic rectal mucosa. PATIENTS AND METHODS: Fifty-three UC patients were examined, of which 10 had UC-Ca and 43 did not (UC-NonCa). In addition to the 40 genes and transcripts previously shown to be predictive for developing UC-Ca in our microarray studies, 149 new genes, reported to be important in carcinogenesis, were selected for low density array (LDA) analysis. The expression of a total of 189 genes was examined by RT-PCR in nonneoplastic rectal mucosa. RESULTS: We identified 20 genes showing differential expression in UC-Ca and UC-NonCa patients, including cancer-related genes such as CYP27B1, RUNX3, SAMSN1, EDIL3, NOL3, CXCL9, ITGB2, and LYN. Using these 20 genes, we were able to build a predictive model that distinguished patients with and without UC-Ca with a high accuracy rate of 83% and a negative predictive value of 100%. CONCLUSION: This predictive model suggests that it is possible to identify UC patients at a high risk of developing cancer. These results have important implications for improving the efficacy of surveillance by colonoscopy and suggest directions for future research into the molecular mechanisms of UC-associated cancer.

Gene expression signature and the prediction of ulcerative colitis-associated colorectal cancer by DNA microarray.

PURPOSE: Ulcerative colitis (UC) is associated with a high risk of colorectal cancer. To identify genes that could predict the development of cancer in UC, we conducted a DNA microarray analysis using nonneoplastic rectal mucosa of UC patients. EXPERIMENTAL DESIGN: Gene expression in nonneoplastic mucosa of 53 UC patients were examined. Gene expression profiles were examined using human Genome U133 Plus 2.0 gene chip array (Affymetrix). Among 53 UC patients, 10 had UC-associated cancer (UC-Ca group) whereas 43 did not (UC-NonCa group). RESULTS: By comparing gene expression profiles of nonneoplastic rectal mucosae between the UC-Ca and UC-NonCa groups, we could identify 40 genes that were differentially expressed between two groups. The list of discriminating genes included low-density lipoprotein receptor-related protein (LRP5 and LRP6). Previous studies suggested that LRP5 and LRP6 expression promotes cancer cell proliferation and tumorigenesis and are considered as candidate oncogenes. In the present study, both LRP5 and LRP6 showed significantly higher expression in the UC-Ca group, which suggests the importance of these genes in the development of UC-associated colorectal cancers. With the 40 selected discriminating genes, we did class prediction of the development of colorectal neoplasms in UC patients. Using the k-nearest neighbor method and the support vector machine, we could predict the development of UC-associated neoplasms with an accuracy of 86.8% and 98.1%, respectively. CONCLUSIONS: These findings have important implications for the early detection of malignant lesions in UC and may provide directions for future research into the molecular mechanisms of UC-associated cancer.