Abstract 651: The clinical significance of tissue miR-124 methylation in sporadic and ulcerative colitis-associated colorectal cancer.

Abstract

Abstract Background: Growing evidence indicates that the expression of several miRNAs can be epigenetically regulated through methylation of their promoter CpG sequences. MiR-124 is one such tumor suppressive miRNA, which is expressed at lower levels in various human cancers due to methylation of its promoter region. The present study aimed to determine miR-124 methylation status and determine its clinical significance in sporadic and ulcerative colitis-associated colorectal cancer (CRC). Materials & Methods: We analyzed 579 colorectal tissues, which included 176 sporadic CRC and the corresponding adjacent normal colonic mucosa (NC), 57 colorectal adenomas and 20 normal colonic mucosae from non-cancer patients (NN). In addition, we also examined 135 normal mucosae (N-UC), 12 dysplasia(D-UC) and 12 colitic cancers (C-UC) from UC patients. We performed quantitative bisulfite pyrosequencing analysis to determine miR-124 promoter methylation levels. Results: MiR-124 methylation rate was significantly higher in CRCs and adenomas compared to NC or NN (P<0.0001, CRC vs. NC; P<0.0001, CRC vs. NN). Receiver operating characteristic (ROC) analysis revealed that methylation levels of miR-124 can robustly discriminate patients with CRC (AUC=0.977) and adenomas (AUC=0.985) from healthy controls. Kaplan-Meier survival analysis showed that patients with high miR-124 methylation demonstrated poor overall survival (p=0.001), and high miR-124 methylation was an independent prognostic factor of sporadic CRC (p=0.028). Similarly, miR-124 methylation was significantly higher in C-UC and D-UC compared to N-UC (p<0.0001). ROC analysis showed that miR-124 methylation can successfully discriminate C-UC (AUC=0.978) and D-UC (AUC=0.884) from N-UC. Interestingly, high levels of miR-124 methylation in rectal specimens were an independent predictor for the development of UC-associated CRC. Conclusions: miR-124 methylation is an early event in sporadic, as well as ulcerative colitis-associated CRC. Since miR-124 methylation could robustly identify patients with colorectal adenomas and cancers, this miRNA has the potential to serve as a diagnostic marker in colorectal neoplasia. Citation Format: Yuji Toiyama, Keun Hur, Koji Tanaka, Yasuhiro Inoue, Takeshi Nagasaka, Masato Kusunoki, C. Richard Boland, Ajay Goel. The clinical significance of tissue miR-124 methylation in sporadic and ulcerative colitis-associated colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 651. doi:10.1158/1538-7445.AM2013-651