TheVHL gene is epigenetically inactivated in pheochromocytomas and abdominal paragangliomas
| Autor: | Fredrika Svahn, Martin Bäckdahl, Nimrod B Kiss, Luqman Sulaiman, C. Christofer Juhlin, Stefano Caramuta, Anders Höög, Adam Andreasson, Catharina Larsson |
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| Rok vydání: | 2013 |
| Předmět: |
DNA promoter methylation
Cancer Research SDHB Molecular Sequence Data Adrenal Gland Neoplasms Down-Regulation Pheochromocytoma Biology Epigenesis Genetic Paraganglioma VHL medicine Humans MEN1 RNA Messenger Epigenetics Promoter Regions Genetic Molecular Biology Base Sequence qRT-PCR Methylation DNA Methylation medicine.disease Gene Expression Regulation Neoplastic pyrosequencing Von Hippel-Lindau Tumor Suppressor Protein Abdominal Neoplasms Case-Control Studies DNA methylation gene expression Cancer research SDHD Research Paper |
| Zdroj: | Epigenetics |
| ISSN: | 1559-2308 1559-2294 |
| DOI: | 10.4161/epi.26686 |
| Popis: | Pheochromocytoma (PCC) and abdominal paraganglioma (PGL) are neuroendocrine tumors that present with clinical symptoms related to increased catecholamine levels. About a third of the cases are associated with constitutional mutations in pre-disposing genes, of which some may also be somatically mutated in sporadic cases. However, little is known about inactivating epigenetic events through promoter methylation in these very genes. Using bisulphite pyrosequencing we assessed the methylation density of 11 PCC/PGL disease genes in 96 tumors (83 PCCs and 13 PGLs) and 34 normal adrenal references. Gene expression levels were determined by quantitative RT-PCR. Both tumors and normal adrenal samples exhibited low methylation index (MetI) in the EGLN1 (PDH2), MAX, MEN1, NF1, SDHB, SDHC, SDHD, SDHAF2 (SDH5), and TMEM127 promoters, not exceeding 10% in any of the samples investigated. Aberrant RET promoter methylation was observed in two cases only. For the VHL gene we found increased MetI in tumors as compared with normal adrenals (57% vs. 27%; P < 0.001), in malignant vs. benign tumors (63% vs. 55%; P < 0.05), and in PGL vs. PCC (66% vs. 55%; P < 0.0005). Decreased expression of the VHL gene was observed in all tumors compared with normal adrenals (P < 0.001). VHL MetI and gene expressions were inversely correlated (R = −0.359, P < 0.0001). Our results show that the VHL gene promoter has increased methylation compared with normal adrenals (MetI > 50%) in approximately 75% of PCCs and PGLs investigated, highlighting the role of VHL in the development of these tumors. |
| Databáze: | OpenAIRE |
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