frequent promoter hypermethylation of the apc and rassf1a tumour suppressors in parathyroid tumours频繁的启动子甲基化的apc和rassf1a基因在肿瘤抑制甲状旁腺肿瘤.pdfVIP

Frequent Promoter Hypermethylation of the APC and RASSF1A Tumour Suppressors in Parathyroid Tumours 1,2 1 1 1 ¨ ¨ 1 C. Christofer Juhlin *, Nimrod B. Kiss , Andrea Villablanca , Felix Haglund , Jorgen Nordenstrom , ¨ ¨ 2, Catharina Larsson1 Anders Hoog 1 Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden, 2 Department of Oncology-Pathology, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden Abstract Background: Parathyroid adenomas constitute the most common entity in primary hyperparathyroidism, and although recent advances have been made regarding the underlying genetic cause of these lesions, very little data on epigenetic alterations in this tumour type exists. In this study, we have determined the levels of promoter methylation regarding the four tumour suppressor genes APC, RASSF1A, p16INK4A and RAR-b in parathyroid adenomas. In addition, the levels of global methylation were assessed by analyzing LINE-1 repeats. Methodology/Principal Findings: The sample collection consisted of 55 parathyroid tumours with known HRPT2 and/or MEN1 genotypes. Using Pyrosequencing analysis, we demonstrate APC promoter 1A and RASSF1A promoter hypermethylation in the majority of parathyroid tumours (71% and 98%, respectively). Using TaqMan qRT-PCR, all tumours analyzed displayed lower RASSF1A mRNA expression and higher levels of total APC mRNA than normal parathyroid, the latter of which was largely conferred by augmented APC 1B transcription levels. Hype