Gene Expression Signature and the Prediction of Ulcerative Colitis–Associated Colorectal Cancer by DNA Microarray

Watanabe, Toshiaki; Kobunai, Takashi; Toda, Etsuko; Kanazawa, Takemichi; Kazama, Yusuke; Tanaka, Junichiro; Tanaka, Toshiaki; Yamamoto, Yasutake; Hata, Keisuke; Kojima, Tetsu; Yokoyama, Tadashi; Konishi, Tsuyoshi; Okayama, Yoshihiro; Sugimoto, Yoshikazu; Oka, Toshinori; Sasaki, Shin; Ajioka, Yohichi; Muto, Tetsuichiro; Nagawa, Hirokazu

doi:10.1158/1078-0432.ccr-06-0753

Cited by 51 publications

(41 citation statements)

References 15 publications

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“…In our previous microarray analysis, RUNX3 was expressed at lower levels in the non-neoplastic mucosa of patients with UC-Ca compared to those without (9). However, microarray analysis is known to lack reproducibility as a means of quantitative analysis of gene expression.…”

Section: Introductionmentioning

confidence: 91%

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RUNX3 copy number predicts the development of UC-associated colorectal cancer

et al. 2010

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Abstract. RUNX3 is a tumour suppressor gene that plays an important role in the development of various cancers. The present study aimed to compare RUNX3 mRNA expression levels and DNA copy numbers in the non-neoplastic rectal mucosa between ulcerative colitis (UC) patients with and without UC-associated colorectal cancer (UC-Ca). We further aimed to build a predictive model of the development of UC-Ca based on the RUNX3 DNA copy number. RUNX3 mRNA expression levels were quantified by RT-PCR. The hypermethylation and DNA copy number of RUNX3 were also determined. Thirty-five UC patients were examined, 17 of whom had UC-Ca (UC-Ca group) and 18 who did not (UCNonCa group). The UC-Ca group had significantly lower mRUNX3 expression levels and smaller DNA copy numbers than the UC-NonCa group (p=0.04, p=0.0016, respectively). RUNX3 expression levels correlated with DNA copy numbers. Classification of the UC-Ca and UC-NonCa group based on DNA copy number gave an accuracy of 82.9%. RUNX3 expression levels in the non-neoplastic rectal mucosa was significantly decreased in the UC-Ca group and it is suggested that this was attributable to the decrease in RUNX3 DNA copy number. The present predictive model may be useful in the selection of high risk UC-Ca patients and to improve the efficacy of surveillance colonoscopy. The present study suggests that RUNX3 might play an important role in the development of UC-Ca. IntroductionPatients with long-standing ulcerative colitis (UC) have an increased risk of developing colorectal cancer. This risk increases with the duration of the disease, and the estimated cumulative risk of UC-associated colorectal cancer (UC-Ca) 30 years after the onset of UC has been reported by metaanalysis to be 18% (1). Therefore, for the early detection of neoplastic lesions, surveillance colonoscopy is recommended for patients whose duration of the disease is 7-8 years or more (2-4). However, to further improve the efficacy of surveillance, new markers to predict the development of UC-Ca are urgently needed.Previous studies have shown that patients with UC-Ca have widespread genetic alterations in the non-neoplastic colonic mucosa, suggesting that such changes might be effective predictors of UC-Ca development (5-8). Indeed, we previously demonstrated this by DNA microarray gene expression analysis (9). However, to date, specific molecular markers that can be used in clinical settings have not been established.RUNX3 belongs to the Runt domain family of transcription factors, and is involved in T-cell differentiation, the TGF-ß-induced tumour suppressor pathway (10,11) and is a known tumour suppressor gene in gastric cancer (12). Previous studies INTERNATIONAL JOURNAL OF ONCOLOGY 38: 201-207, 2011 201 RUNX3 copy number predicts the development of UC-associated colorectal cancer

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Section: Introductionmentioning

confidence: 91%

“…Indeed, we previously demonstrated this by DNA microarray gene expression analysis (9). However, to date, specific molecular markers that can be used in clinical settings have not been established.…”

Section: Introductionmentioning

confidence: 98%

RUNX3 copy number predicts the development of UC-associated colorectal cancer

et al. 2010

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“…However, such a surveillance program has a number of limitations, including its efficacy, high cost, invasiveness, incomplete patient enrollment, sampling variations and poor agreement in histopathological interpretation (3). A number of molecular markers predictive for UC-CRC have been reported (4)(5)(6), but remain unavailable in the practical management of UC patients.…”

Section: Introductionmentioning

confidence: 99%

CD133, OCT4, and NANOG in ulcerative colitis-associated colorectal cancer

et al. 2011

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Abstract. Stem cells are thought to contribute to tissue regeneration as well as carcinogenesis. Ulcerative colitis-associated colorectal cancer (UC-CRC) has shown distinct characteristics compared with those of sporadic CRC. The aim of this study was to evaluate the expression of stem cell markers CD133, OCT4 and NANOG in UC-CRC and the inflamed colonic epithelium of UC patients. Total RNAs of UC-CRC (n=6), inflamed colonic epithelium (n=24), sporadic CRC (n=37) and adjacent normal colonic epithelium (n=37) were isolated from formalin-fixed, paraffin-embedded specimens using microdissection techniques in order to purify colonic epithelial cells. Relative mRNA levels of CD133 (PROM), OCT4 (POU5F1) and NANOG were measured using real-time reverse transcription polymerase chain reaction. Three stem cell markers were also investigated immunohistochemically. PROM, POU5F1 and NANOG levels were found to be significantly lower in UC-CRC than in inflamed colonic epithelium of UC patients. By contrast, sporadic CRC showed a significantly higher expression of PROM, POU5F1 and NANOG compared with adjacent normal colonic epithelium. POU5F1 and NANOG levels were significantly lower in UC-CRC than in sporadic CRC. PROM and NANOG levels in inflamed colonic epithelium were significantly higher among younger UC patients (P<0.05). Longer disease duration was significantly associated with lower PROM expression (P=0.0117). No significant difference was found in PROM levels between UC-CRC and inflamed colonic epithelium in patients with longer disease duration. UC-CRC showed different expression profiles of stem cell markers compared with sporadic CRC. Decreases in PROM expression of inflamed colonic epithelium may identify UC patients at high risk for the development of UC-CRC.

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“…5 Gene expression profiles were determined using Affymetrix HG-U133 Plus2.0 GeneChips (Affymetrix, Santa Clara, Calif) according to the manufacturer's recommendations.…”

Section: Rna Isolation and Microarray Proceduresmentioning

confidence: 99%

“…[4][5][6] In the present study, applying the same method, we examined the gene expression profiles of stage III colorectal cancers and were able to build a predictive model of postoperative recurrence with a high accuracy rate. Among discriminating genes between patients with and without recurrence, we identified calcineurin-binding protein 1 (CABIN1) as showing significantly lower expression among patients with recurrence.…”

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confidence: 99%