Abstract A37: Aberrant DNA methylation of HTATIP2 and UCH-L1 as prognostic and predictive biomarkers for cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is a malignancy of bile duct epithelial cell lining. In the past decade, the incidence and mortality rates of CCA have been increasing worldwide. The effective treatment modality for CCA is surgical resection. Adjuvant chemotherapy and/or radiotherapy are optional therapy for unresectable and postoperative CCA. Unfortunately, the responsiveness of CCA patients to chemotherapy was relatively low and 5-year survival rate was poor. We have analyzed data which were obtained from our previous study on methylation microarray based on chemotherapeutic drug resistance and found aberrant DNA methylation of genes related to chemotherapy. This present study aimed to quantitate DNA methylation levels of 10 candidate genes related to chemotherapy in 54 CCA and 19 normal adjacent tissues using methylation-sensitive high resolution melting (MS-HRM) analysis. The methylation level of each gene was statistically analyzed with clinical parameters. Genes with high methylation level were UCH-L1 and IRF4, and genes with moderate methylation were CCND2, HTATIP2 and TP53I3. We found significant difference in methylation levels of HTATIP2 (P=0.036) and UCH-L1 (P=0.012) between short and long survival groups. Patients with high methylation level of HTATIP2 and low methylation of UCH-L1 showed longer overall survival (P=0.03 and P=0.044, respectively). Interestingly, chemotherapeutic responders showed higher methylation level of HTATIP2 than non-responders (P=0.020), whereas no significant difference in UCH-L1 methylation level was observed between these two groups. The methylation levels of HTATIP2 and UCH-L1 were low in normal adjacent tissues. In patients who received chemotherapy, patients who had high methylation of HTATIP2 and low methylation of UCH-L1 showed longer overall survival (P<0.001 and P=0.041, respectively). Moreover, HTATIP2 methylation was associated with tumor progression in which lower methylation level was found in CCA patients with positive lymph node metastasis (P=0.029). In conclusion, our finding indicates the great value of DNA methylation levels of HTATIP2 and UCH-L1 as prognostic and predictive markers for CCA patients. Citation Format: Temduang Limpaiboon, Chaiyachet Nanok, Siriporn Proungvitaya, Patcharee Jearanaikoon, Ake Pugkhem, Anucha Puapairoj. Aberrant DNA methylation of HTATIP2 and UCH-L1 as prognostic and predictive biomarkers for cholangiocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A37.