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Frequent and Distinct Aberrations of DNA Methylation Patterns in Fibrolamellar Carcinoma of the Liver
BACKGROUND: Gene silencing due to aberrant DNA methylation is a frequent event in hepatocellular carcinoma (HCC) and also in hepatocellular adenoma (HCA). However, very little is known about epigenetic defects in fibrolamellar carcinoma (FLC), a rare variant of hepatocellular carcinoma that displays...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2966398/ https://www.ncbi.nlm.nih.gov/pubmed/21060828 http://dx.doi.org/10.1371/journal.pone.0013688 |
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author | Tränkenschuh, Wolfgang Puls, Florian Christgen, Matthias Albat, Cord Heim, Albert Poczkaj, Jeanette Fleming, Peer Kreipe, Hans Lehmann, Ulrich |
author_facet | Tränkenschuh, Wolfgang Puls, Florian Christgen, Matthias Albat, Cord Heim, Albert Poczkaj, Jeanette Fleming, Peer Kreipe, Hans Lehmann, Ulrich |
author_sort | Tränkenschuh, Wolfgang |
collection | PubMed |
description | BACKGROUND: Gene silencing due to aberrant DNA methylation is a frequent event in hepatocellular carcinoma (HCC) and also in hepatocellular adenoma (HCA). However, very little is known about epigenetic defects in fibrolamellar carcinoma (FLC), a rare variant of hepatocellular carcinoma that displays distinct clinical and morphological features. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the methylation status of the APC, CDH1, cyclinD2, GSTπ1, hsa-mir-9-1, hsa-mir-9-2, and RASSF1A gene in a series of 15 FLC and paired normal liver tissue specimens by quantitative high-resolution pyrosequencing. Results were compared with common HCC arising in non-cirrhotic liver (n = 10). Frequent aberrant hypermethylation was found for the cyclinD2 (19%) and the RASSF1A (38%) gene as well as for the microRNA genes mir-9-1 (13%) and mir-9-2 (33%). In contrast to common HCC the APC and CDH1 (E-cadherin) genes were found devoid of any DNA methylation in FLC, whereas the GSTπ1 gene showed comparable DNA methylation in tumor and surrounding tissue at a moderate level. Changes in global DNA methylation level were measured by analyzing methylation status of the highly repetitive LINE-1 sequences. No evidence of global hypomethylation could be found in FLCs, whereas HCCs without cirrhosis showed a significant reduction in global methylation level as described previously. CONCLUSIONS: FLCs display frequent and distinct gene-specific hypermethylation in the absence of significant global hypomethylation indicating that these two epigenetic aberrations are induced by different pathways and that full-blown malignancy can develop in the absence of global loss of DNA methylation. Only quantitative DNA methylation detection methodology was able to identify these differences. |
format | Text |
id | pubmed-2966398 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29663982010-11-08 Frequent and Distinct Aberrations of DNA Methylation Patterns in Fibrolamellar Carcinoma of the Liver Tränkenschuh, Wolfgang Puls, Florian Christgen, Matthias Albat, Cord Heim, Albert Poczkaj, Jeanette Fleming, Peer Kreipe, Hans Lehmann, Ulrich PLoS One Research Article BACKGROUND: Gene silencing due to aberrant DNA methylation is a frequent event in hepatocellular carcinoma (HCC) and also in hepatocellular adenoma (HCA). However, very little is known about epigenetic defects in fibrolamellar carcinoma (FLC), a rare variant of hepatocellular carcinoma that displays distinct clinical and morphological features. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the methylation status of the APC, CDH1, cyclinD2, GSTπ1, hsa-mir-9-1, hsa-mir-9-2, and RASSF1A gene in a series of 15 FLC and paired normal liver tissue specimens by quantitative high-resolution pyrosequencing. Results were compared with common HCC arising in non-cirrhotic liver (n = 10). Frequent aberrant hypermethylation was found for the cyclinD2 (19%) and the RASSF1A (38%) gene as well as for the microRNA genes mir-9-1 (13%) and mir-9-2 (33%). In contrast to common HCC the APC and CDH1 (E-cadherin) genes were found devoid of any DNA methylation in FLC, whereas the GSTπ1 gene showed comparable DNA methylation in tumor and surrounding tissue at a moderate level. Changes in global DNA methylation level were measured by analyzing methylation status of the highly repetitive LINE-1 sequences. No evidence of global hypomethylation could be found in FLCs, whereas HCCs without cirrhosis showed a significant reduction in global methylation level as described previously. CONCLUSIONS: FLCs display frequent and distinct gene-specific hypermethylation in the absence of significant global hypomethylation indicating that these two epigenetic aberrations are induced by different pathways and that full-blown malignancy can develop in the absence of global loss of DNA methylation. Only quantitative DNA methylation detection methodology was able to identify these differences. Public Library of Science 2010-10-29 /pmc/articles/PMC2966398/ /pubmed/21060828 http://dx.doi.org/10.1371/journal.pone.0013688 Text en Tränkenschuh et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Tränkenschuh, Wolfgang Puls, Florian Christgen, Matthias Albat, Cord Heim, Albert Poczkaj, Jeanette Fleming, Peer Kreipe, Hans Lehmann, Ulrich Frequent and Distinct Aberrations of DNA Methylation Patterns in Fibrolamellar Carcinoma of the Liver |
title | Frequent and Distinct Aberrations of DNA Methylation Patterns in Fibrolamellar Carcinoma of the Liver |
title_full | Frequent and Distinct Aberrations of DNA Methylation Patterns in Fibrolamellar Carcinoma of the Liver |
title_fullStr | Frequent and Distinct Aberrations of DNA Methylation Patterns in Fibrolamellar Carcinoma of the Liver |
title_full_unstemmed | Frequent and Distinct Aberrations of DNA Methylation Patterns in Fibrolamellar Carcinoma of the Liver |
title_short | Frequent and Distinct Aberrations of DNA Methylation Patterns in Fibrolamellar Carcinoma of the Liver |
title_sort | frequent and distinct aberrations of dna methylation patterns in fibrolamellar carcinoma of the liver |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2966398/ https://www.ncbi.nlm.nih.gov/pubmed/21060828 http://dx.doi.org/10.1371/journal.pone.0013688 |
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