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Methylated cyclin D2 gene circulating in the blood as a prognosis predictor of hepatocellular carcinoma
Authors:Masahito Tsutsui  Norio Iizuka  Toyoki Moribe  Toshiaki Miura  Naoki Kimura  Shigeru Tamatsukuri  Hideo Ishitsuka  Yusuke Fujita  Yoshihiko Hamamoto  Ryouichi Tsunedomi  Michihisa Iida  Yoshihiro Tokuhisa  Kazuhiko Sakamoto  Takao Tamesa  Isao Sakaida  Masaaki Oka
Institution:1. Department of Pathology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province 130033, China;2. Department of Nutrition and Food Hygiene, School of Public Health, Jilin University, Changchun, Jilin Province 130021, China;3. Department of Radiological Health, Occupation Disease Prevention and Control Center of Jilin Province, Changchun, Jilin Province 130021, China;4. Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province 130033, China;1. Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea;2. Department of General Surgery, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea;1. Institute of Virology, Vaccines and Sera, “Torlak”, Immunology Research Center “Branislav Jankovi?”, Vojvode Stepe 458, 11152 Belgrade, Serbia;2. Institute of Chemistry in Medicine, School of Medicine, University of Belgrade, Vi?egradska 26, 11000 Belgrade, Serbia;3. Department of Physiology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia;1. Department of Allergology, Medical University of Gdansk, Gdansk, Poland;2. Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland;3. Thoraxklinik, University Hospital Heidelberg, Translational Research Center Heidelberg, Heidelberg, Germany;4. Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain;5. Department of Pathology, Medical University of Gdansk, Gdansk, Poland;6. Radiotherapy and Chemotherapy Clinic, Maria Sk?odowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland;7. Department of Thoracic Surgery, Medical University of Gdansk, Gdansk, Poland;8. Department of Forensic Medicine, Medical University of Gdansk, Gdansk, Poland
Abstract:BackgroundPrognosis of hepatocellular carcinoma (HCC) remains poor because of high recurrence rate. We examined preoperatively the methylated CCND2 gene levels present in the serum following release from HCC cells as a prognosis predictor in patients undergoing curative hepatectomy.MethodsQuantitative real-time RT-PCR and quantitative methylation-specific PCR were used to measure methylated CCND2 gene and its mRNA levels.ResultsThe CCND2 mRNA levels were down-regulated in HCC with early intrahepatic recurrence (IHR) within 1 year of curative hepatectomy. We also identified that this down-regulation was due to promoter hypermethylation. In 70 HCC patients who underwent curative hepatectomy, 39 patients sero-positive for the methylated CCND2 gene (> 70 pg/ml serum) exhibited a significantly shorter disease-free survival (DFS) period (P = 0.02) than the 31 patients who were sero-negative for the methylated CCND2 gene. None of the sero-negative patients demonstrated early IHR, and this method of serum testing did not produce any false-negative predictions for early IHR. Multivariate analysis showed that the serum level of methylated CCND2 was an independent risk factor for DFS (hazard ratio of 1.866, 95% CI: 1.106–3.149).ConclusionMethylated CCND2 gene in the serum serves as a prognosis predictor of HCC after curative hepatectomy.
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