Abstract 3367: The clinical significance of epigenetic microRNA-137 silencing in patients with ulcerative colitis
Authors: Toiyama Yuji , Okugawa Yoshinaga , Tanaka Koji , Araki Toshimitsu , Uchida Keiichi , Kusunoki Masato , Boland C.Richard , Goel Ajay 
Published: July 2017

Background: Although present guidelines recommend periodic colonoscopy with multistep biopsies for surveillance of ulcerative colitis (UC)-associated colorectal cancer (CRC), it remains unclear about the effectively. To improve the surveillance, more effective markers are needed to identify patients at high risk for UC-CRC. MicroRNA (miRNA)-137 is often methylated in sporadic CRC. Methylation of this miRNA also occurs in an age-dependent manner, suggesting a potential “field defect”, and possibly an early event in colitis-associated carcinogenesis. The objective of this study was to determine whether a methylation-related “field defect” of miR-137 could be exploited clinically to identify individuals with UC who are at increased risk for developing neoplasia.

Materials & Methods: We conducted four-step analysis using 387 samples from 238 UC patients of two independent cohorts, which included 152 patients without neoplasia (matched specimens obtained from cecum, transverse colon and rectum for each patient), 17 with dysplasia, and 69 with cancers (neoplasms and corresponding rectal mucosa). We performed bisulfite pyrosequencing to quantify miR-137 promoter methylation levels of these samples.

Results: In non-neoplastic UC patients, methylation levels of miR-137 were significantly higher in rectal mucosa than in proximal cecum mucosa (7.0 ± 2.8% vs. 4.9 ± 2.0%, P&lt;0.0001), and were associated with age at diagnosis (P=0.0009), age at operation (P=0.0004) and disease duration (P=0.009) in rectal mucosa. In addition, methylation levels of miR-137 were significantly higher in dysplasia (P&lt;0.0001) and CRC (P&lt;0.0001) compared to non-neoplastic UC mucosa. In addition, miR-137 methylation levels in rectal mucosa from patients with neoplasia (dysplasia or cancer) were significantly higher compared to methylation in patients without neoplasia, suggesting the existence of ‘field defect’ in rectal mucosa from patients with neoplasia. Receiver operating characteristic (ROC) analysis revealed that methylation levels of miR-137 in rectal mucosa successfully differentiated patients with CRC from those without (AUC: 0.8). Furthermore, multivariate logistic regression analysis revealed that miR-137 methylation in rectal mucosa emerged as an independent predictor of UC-CRC (OR: 5.55; P=0.0148). Finally, ROC analysis was performed to validate the findings and revealed that methylation levels of miR-137 could discriminate UC patients with vs. without neoplasia, with almost same AUC value (0.76).

Conclusions: Methylation of miR-137 occurs in an age- and cancer-dependent manner in UC patients. Analysis of miR-137 methylation levels in rectum may be a biomarker for identification of UC patients at greatest risk for UC-CRC.

Citation Format: Yuji Toiyama, Yoshinaga Okugawa, Koji Tanaka, Toshimitsu Araki, Keiichi Uchida, Masato Kusunoki, C.Richard Boland, Ajay Goel. The clinical significance of epigenetic microRNA-137 silencing in patients with ulcerative colitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3367. doi:10.1158/1538-7445.AM2017-3367