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Global profiling of methylation in the cancer genome
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Abstracts / Cancer Genetics and Cytogenetics 203 (2010) 44e65
CHROMOSOMAL TRANSLOCATION ACTIVATES STEM CELL MICRO-RNAS IN THYROID ADENOMA 1
1
1
GLOBAL PROFILING OF METHYLATION IN THE CANCER GENOME Andrew Feber1 1
Volkhard Rippe , Johannes Debler , Lea Dittberner , Verena N. Lorenz , Norbert Drieschner1, Rolf Nimzyk1, Wolfgang Sendt2, Klaus Junker3, Gazanfer Belge1, Jo¨rn Bullerdiek1,4 1. Center for Human Genetics, University of Bremen, Germany 2. Department of General and Visceral Surgery of the St Joseph Stift, Bremen, Germany 3. Department of Pathology, Hospital Bremen-Mitte, Germany 4. Small Animal Clinic and Research Cluster of Excellence “REBIRTH”, University of Veterinary Medicine, Hanover, Germany
Thyroid adenomas are common benign human tumors with a high prevalence even in iodine sufficient areas. Rearrangements of chromosomal band 19q13.4 represent a frequent type of clonal cytogenetic deviation in these tumors, making this rearrangement one of the most frequent chromosomal translocations in human epithelial tumors. Two microRNA (miRNA) gene clusters, i.e., C19MC and miR-371-3, are located in close proximity to the 19q13 breakpoint region. Based on expression analysis of 124 thyroid lesions, we were able to show that by these rearrangements both the C19MC and miR-371-3 cluster become consistently activated, thus allowing the delineation of a distinct molecular subtype of thyroid adenomas. Apparently, the up-regulation is not restricted to cases with 19q13 translocations, but can also be rarely found in thyroid adenomas characterized by an apparently normal karyotype. In-depth molecular characterization of the breakpoint in a cell line from one adenoma of this type revealed the existence of large Pol-II mRNA fragments as the most likely source of up-regulation of the C19MC cluster.
1. University College London Cancer Institute, London, United Kingdom
Aberrant DNA methylation (DNAm) was first linked to cancer over 25 years ago. Since then, many studies have associated hypermethylation of tumour suppressor genes and hypomethylation of oncogenes to the tumourigenic process. Although these studies have given us valuable insight into the role of methylation in disease development and progression, they rely on existing knowledge of methylation within the genome and have typically been limited to the analysis of promoters and CpG islands (CGIs). Recently, new technologies for whole-genome DNAm (methylome) analysis, such as MeDIP-seq, have been developed, enabling unbiased analysis of cancer methylomes. Using MeDIP-seq, we carried out a sequencing-based comparative methylome analysis of malignant peripheral nerve sheath tumours (MPNST), benign neurofibromas, and normal Schwann cells. Analysis of these methylomes revealed a complex landscape of DNAm alterations. Contrary to the current dogma, significant global hypomethylation was not observed in the MPNST methylome. However, a highly significant directional difference in DNAm was found in satellite repeats, suggesting these repeats to be the main target for hypomethylation in MPNST. Comparative analysis of the MPNST and Schwann cell methylomes identified 101,466 cancer-associated differentially methylated regions (cDMRs). Analysis showed these cDMRs to be significantly enriched for two satellite repeat types (SATR1 and ARL) and suggests an association between aberrant DNAm of these sequences and transition from healthy to malignant disease. Significant enrichment of hypermethylated cDMRs in CGI shores, non-CGI-associated promoters (P ! 10 4), and hypomethylated cDMRs in SINE repeats was also identified. Integration of DNAm and gene expression data showed that the expression pattern of genes associated with CGI shore cDMRs was able to discriminate between disease phenotypes. This study establishes MeDIP-seq as an effective method to analyse cancer methylomes.
Abstracts / Cancer Genetics and Cytogenetics 203 (2010) 44e65
CHROMOSOMAL TRANSLOCATION ACTIVATES STEM CELL MICRO-RNAS IN THYROID ADENOMA 1
1
1
GLOBAL PROFILING OF METHYLATION IN THE CANCER GENOME Andrew Feber1 1
Volkhard Rippe , Johannes Debler , Lea Dittberner , Verena N. Lorenz , Norbert Drieschner1, Rolf Nimzyk1, Wolfgang Sendt2, Klaus Junker3, Gazanfer Belge1, Jo¨rn Bullerdiek1,4 1. Center for Human Genetics, University of Bremen, Germany 2. Department of General and Visceral Surgery of the St Joseph Stift, Bremen, Germany 3. Department of Pathology, Hospital Bremen-Mitte, Germany 4. Small Animal Clinic and Research Cluster of Excellence “REBIRTH”, University of Veterinary Medicine, Hanover, Germany
Thyroid adenomas are common benign human tumors with a high prevalence even in iodine sufficient areas. Rearrangements of chromosomal band 19q13.4 represent a frequent type of clonal cytogenetic deviation in these tumors, making this rearrangement one of the most frequent chromosomal translocations in human epithelial tumors. Two microRNA (miRNA) gene clusters, i.e., C19MC and miR-371-3, are located in close proximity to the 19q13 breakpoint region. Based on expression analysis of 124 thyroid lesions, we were able to show that by these rearrangements both the C19MC and miR-371-3 cluster become consistently activated, thus allowing the delineation of a distinct molecular subtype of thyroid adenomas. Apparently, the up-regulation is not restricted to cases with 19q13 translocations, but can also be rarely found in thyroid adenomas characterized by an apparently normal karyotype. In-depth molecular characterization of the breakpoint in a cell line from one adenoma of this type revealed the existence of large Pol-II mRNA fragments as the most likely source of up-regulation of the C19MC cluster.
1. University College London Cancer Institute, London, United Kingdom
Aberrant DNA methylation (DNAm) was first linked to cancer over 25 years ago. Since then, many studies have associated hypermethylation of tumour suppressor genes and hypomethylation of oncogenes to the tumourigenic process. Although these studies have given us valuable insight into the role of methylation in disease development and progression, they rely on existing knowledge of methylation within the genome and have typically been limited to the analysis of promoters and CpG islands (CGIs). Recently, new technologies for whole-genome DNAm (methylome) analysis, such as MeDIP-seq, have been developed, enabling unbiased analysis of cancer methylomes. Using MeDIP-seq, we carried out a sequencing-based comparative methylome analysis of malignant peripheral nerve sheath tumours (MPNST), benign neurofibromas, and normal Schwann cells. Analysis of these methylomes revealed a complex landscape of DNAm alterations. Contrary to the current dogma, significant global hypomethylation was not observed in the MPNST methylome. However, a highly significant directional difference in DNAm was found in satellite repeats, suggesting these repeats to be the main target for hypomethylation in MPNST. Comparative analysis of the MPNST and Schwann cell methylomes identified 101,466 cancer-associated differentially methylated regions (cDMRs). Analysis showed these cDMRs to be significantly enriched for two satellite repeat types (SATR1 and ARL) and suggests an association between aberrant DNAm of these sequences and transition from healthy to malignant disease. Significant enrichment of hypermethylated cDMRs in CGI shores, non-CGI-associated promoters (P ! 10 4), and hypomethylated cDMRs in SINE repeats was also identified. Integration of DNAm and gene expression data showed that the expression pattern of genes associated with CGI shore cDMRs was able to discriminate between disease phenotypes. This study establishes MeDIP-seq as an effective method to analyse cancer methylomes.