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Integrative Analysis Reveals Relationships of Genetic and Epigenetic Alterations in Osteosarcoma
BACKGROUND: Osteosarcomas are the most common non-haematological primary malignant tumours of bone, and all conventional osteosarcomas are high-grade tumours showing complex genomic aberrations. We have integrated genome-wide genetic and epigenetic profiles from the EuroBoNeT panel of 19 human osteo...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492335/ https://www.ncbi.nlm.nih.gov/pubmed/23144859 http://dx.doi.org/10.1371/journal.pone.0048262 |
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author | Kresse, Stine H. Rydbeck, Halfdan Skårn, Magne Namløs, Heidi M. Barragan-Polania, Ana H. Cleton-Jansen, Anne-Marie Serra, Massimo Liestøl, Knut Hogendoorn, Pancras C. W. Hovig, Eivind Myklebost, Ola Meza-Zepeda, Leonardo A. |
author_facet | Kresse, Stine H. Rydbeck, Halfdan Skårn, Magne Namløs, Heidi M. Barragan-Polania, Ana H. Cleton-Jansen, Anne-Marie Serra, Massimo Liestøl, Knut Hogendoorn, Pancras C. W. Hovig, Eivind Myklebost, Ola Meza-Zepeda, Leonardo A. |
author_sort | Kresse, Stine H. |
collection | PubMed |
description | BACKGROUND: Osteosarcomas are the most common non-haematological primary malignant tumours of bone, and all conventional osteosarcomas are high-grade tumours showing complex genomic aberrations. We have integrated genome-wide genetic and epigenetic profiles from the EuroBoNeT panel of 19 human osteosarcoma cell lines based on microarray technologies. PRINCIPAL FINDINGS: The cell lines showed complex patterns of DNA copy number changes, where genomic copy number gains were significantly associated with gene-rich regions and losses with gene-poor regions. By integrating the datasets, 350 genes were identified as having two types of aberrations (gain/over-expression, hypo-methylation/over-expression, loss/under-expression or hyper-methylation/under-expression) using a recurrence threshold of 6/19 (>30%) cell lines. The genes showed in general alterations in either DNA copy number or DNA methylation, both within individual samples and across the sample panel. These 350 genes are involved in embryonic skeletal system development and morphogenesis, as well as remodelling of extracellular matrix. The aberrations of three selected genes, CXCL5, DLX5 and RUNX2, were validated in five cell lines and five tumour samples using PCR techniques. Several genes were hyper-methylated and under-expressed compared to normal osteoblasts, and expression could be reactivated by demethylation using 5-Aza-2′-deoxycytidine treatment for four genes tested; AKAP12, CXCL5, EFEMP1 and IL11RA. Globally, there was as expected a significant positive association between gain and over-expression, loss and under-expression as well as hyper-methylation and under-expression, but gain was also associated with hyper-methylation and under-expression, suggesting that hyper-methylation may oppose the effects of increased copy number for detrimental genes. CONCLUSIONS: Integrative analysis of genome-wide genetic and epigenetic alterations identified dependencies and relationships between DNA copy number, DNA methylation and mRNA expression in osteosarcomas, contributing to better understanding of osteosarcoma biology. |
format | Online Article Text |
id | pubmed-3492335 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34923352012-11-09 Integrative Analysis Reveals Relationships of Genetic and Epigenetic Alterations in Osteosarcoma Kresse, Stine H. Rydbeck, Halfdan Skårn, Magne Namløs, Heidi M. Barragan-Polania, Ana H. Cleton-Jansen, Anne-Marie Serra, Massimo Liestøl, Knut Hogendoorn, Pancras C. W. Hovig, Eivind Myklebost, Ola Meza-Zepeda, Leonardo A. PLoS One Research Article BACKGROUND: Osteosarcomas are the most common non-haematological primary malignant tumours of bone, and all conventional osteosarcomas are high-grade tumours showing complex genomic aberrations. We have integrated genome-wide genetic and epigenetic profiles from the EuroBoNeT panel of 19 human osteosarcoma cell lines based on microarray technologies. PRINCIPAL FINDINGS: The cell lines showed complex patterns of DNA copy number changes, where genomic copy number gains were significantly associated with gene-rich regions and losses with gene-poor regions. By integrating the datasets, 350 genes were identified as having two types of aberrations (gain/over-expression, hypo-methylation/over-expression, loss/under-expression or hyper-methylation/under-expression) using a recurrence threshold of 6/19 (>30%) cell lines. The genes showed in general alterations in either DNA copy number or DNA methylation, both within individual samples and across the sample panel. These 350 genes are involved in embryonic skeletal system development and morphogenesis, as well as remodelling of extracellular matrix. The aberrations of three selected genes, CXCL5, DLX5 and RUNX2, were validated in five cell lines and five tumour samples using PCR techniques. Several genes were hyper-methylated and under-expressed compared to normal osteoblasts, and expression could be reactivated by demethylation using 5-Aza-2′-deoxycytidine treatment for four genes tested; AKAP12, CXCL5, EFEMP1 and IL11RA. Globally, there was as expected a significant positive association between gain and over-expression, loss and under-expression as well as hyper-methylation and under-expression, but gain was also associated with hyper-methylation and under-expression, suggesting that hyper-methylation may oppose the effects of increased copy number for detrimental genes. CONCLUSIONS: Integrative analysis of genome-wide genetic and epigenetic alterations identified dependencies and relationships between DNA copy number, DNA methylation and mRNA expression in osteosarcomas, contributing to better understanding of osteosarcoma biology. Public Library of Science 2012-11-07 /pmc/articles/PMC3492335/ /pubmed/23144859 http://dx.doi.org/10.1371/journal.pone.0048262 Text en © 2012 Kresse 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 Kresse, Stine H. Rydbeck, Halfdan Skårn, Magne Namløs, Heidi M. Barragan-Polania, Ana H. Cleton-Jansen, Anne-Marie Serra, Massimo Liestøl, Knut Hogendoorn, Pancras C. W. Hovig, Eivind Myklebost, Ola Meza-Zepeda, Leonardo A. Integrative Analysis Reveals Relationships of Genetic and Epigenetic Alterations in Osteosarcoma |
title | Integrative Analysis Reveals Relationships of Genetic and Epigenetic Alterations in Osteosarcoma |
title_full | Integrative Analysis Reveals Relationships of Genetic and Epigenetic Alterations in Osteosarcoma |
title_fullStr | Integrative Analysis Reveals Relationships of Genetic and Epigenetic Alterations in Osteosarcoma |
title_full_unstemmed | Integrative Analysis Reveals Relationships of Genetic and Epigenetic Alterations in Osteosarcoma |
title_short | Integrative Analysis Reveals Relationships of Genetic and Epigenetic Alterations in Osteosarcoma |
title_sort | integrative analysis reveals relationships of genetic and epigenetic alterations in osteosarcoma |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492335/ https://www.ncbi.nlm.nih.gov/pubmed/23144859 http://dx.doi.org/10.1371/journal.pone.0048262 |
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