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Hypermethylation of the IGF2 differentially methylated region 2 is a specific event in insulinomas leading to loss-of-imprinting and overexpression
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| Zeitschriftentitel: | Endocrine-Related Cancer |
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| Personen und Körperschaften: | , , , , , , |
| In: | Endocrine-Related Cancer, 16, 2009, 3, S. 939-952 |
| Format: | E-Article |
| Sprache: | Unbestimmt |
| veröffentlicht: |
Bioscientifica
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| Schlagwörter: |
| Zusammenfassung: | <jats:p>Prediction of the evolution of endocrine pancreatic tumors remains difficult based on histological criteria alone. We have previously demonstrated that epigenetic changes are an early event in a mouse model developing insulinomas. Particularly, overexpression of the imprinted <jats:italic>IGF2</jats:italic> was caused by the hypermethylation of CpGs in the differentially methylated region 2 (DMR2). Here, we investigated whether <jats:italic>IGF2</jats:italic> hypermethylation is also observed in human insulinomas and whether this alteration is common to other human endocrine tumors of the pancreas and the digestive tract. We analyzed the methylation status of 40 CpGs located in the DMR0 and DMR2 of the <jats:italic>IGF2</jats:italic> as well as in the <jats:italic>H19</jats:italic> DMR by pyrosequencing in a cohort of 62 patients with pancreatic or small intestine endocrine tumors. Altered methylation patterns were observed in all tumor types for the different regions of <jats:italic>IGF2</jats:italic>, but not for <jats:italic>H19</jats:italic>. However, hypermethylation of the <jats:italic>IGF2</jats:italic> DMR2 was specific for insulinomas and did not occur in any of the other types of tumors which were characterized by a loss of methylation in this region. Gain of methylation in the <jats:italic>IGF2</jats:italic> DMR2 in insulinomas correlated with loss-of-imprinting and promoter 4 mediated overexpression of <jats:italic>IGF2</jats:italic> at the RNA and protein level. Furthermore, a decreasing degree of methylation in the different regions of <jats:italic>IGF2</jats:italic> correlated well with increasing degree of malignancy according to the WHO classification of pancreatic endocrine tumors (PETs), suggesting that methylation of <jats:italic>IGF2</jats:italic> might be a useful biomarker for classification and staging of PETs.</jats:p> |
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| Umfang: | 939-952 |
| ISSN: |
1351-0088
1479-6821 |
| DOI: | 10.1677/erc-08-0331 |