Deregulation of methylation of transcribed-ultra conserved regions in colorectal cancer and their value for detection of adenomas and adenocarcinomas

// Anastasia E. Kottorou 1 , Anna G. Antonacopoulou 1 , Foteinos-Ioannis D. Dimitrakopoulos 1, 3 , Georgia Diamantopoulou 2 , Chaido Sirinian 1 , Melpomeni Kalofonou 1, 6 , Theodoros Theodorakopoulos 2 , Chrysa Oikonomou 3 , Evangelos C. Katsakoulis 2 , Angelos Koutras 1, 3 , Thomas Makatsoris 1, 3 , Nikos Demopoulos 4 , Georgia Stephanou 4 , Michalis Stavropoulos 5 , Konstantinos C. Thomopoulos 2 and Haralabos P. Kalofonos 1, 3 1 Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, Patras, Greece 2 Division of Gastroenterology, University Hospital of Patras, Patras, Greece 3 Division of Oncology, University Hospital of Patras, Patras, Greece 4 Division of Genetics, Cell and Developmental Biology, Department of Biology, University of Patras, Patras, Greece 5 Department of Surgery, Medical School, University of Patras, Patras, Greece 6 Institute of Biomedical Engineering, Imperial College London, London, UK Correspondence to: Haralabos P. Kalofonos, email: kalofonos@upatras.gr Keywords: transcribed-ultra conserved regions; colorectal cancer and adenomas; tissue and plasma methylation; screening biomarker; expression levels Received: January 12, 2017     Accepted: March 02, 2018     Published: April 20, 2018 ABSTRACT Expression of Transcribed Ultraconserved Regions (T-UCRs) is often deregulated in cancer. The present study assesses the expression and methylation of three T-UCRs (Uc160, Uc283 and Uc346) in colorectal cancer (CRC) and explores the potential of T-UCR methylation in circulating DNA for the detection of adenomas and adenocarcinomas. Expression levels of Uc160, Uc283 and Uc346 were lower in neoplastic tissues from 64 CRC patients (statistically significant for Uc160, p <0.001), compared to non-malignant tissues, while methylation levels displayed the inverse pattern ( p <0.001, p =0.001 and p =0.004 respectively). In colon cancer cell lines, overexpression of Uc160 and Uc346 led to increased proliferation and migration rates. Methylation levels of Uc160 in plasma of 50 CRC, 59 adenoma patients, 40 healthy subjects and 12 patients with colon inflammation or diverticulosis predicted the presence of CRC with 35% sensitivity and 89% specificity ( p =0.016), while methylation levels of the combination of all three T-UCRs resulted in 45% sensitivity and 74.3% specificity ( p =0.013). In conclusion, studied T-UCRs’ expression and methylation status are deregulated in CRC while Uc160 and Uc346 appear to have a complicated role in CRC progression. Moreover their methylation status appears a promising non-invasive screening test for CRC, provided that the sensitivity of the assay is improved.