Comparing the DNA Hypermethylome with Gene Mutations in Human Colorectal Cancer

Schuebel, Kornel E.; Chen, Wei; Cope, Leslie; Glöckner, Sabine C.; Suzuki, Hiromu; Yi, Joo Mi; Chan, Timothy A.; Neste, Leander Van; Criekinge, Wim Van; Bosch, Sandra van den; Engeland, Manon van; Ting, Angela H.; Jair, Kamwing; Yu, Wayne; Toyota, Minoru; Imai, Kohzoh; Ahuja, Nita; Herman, James G.; Baylin, Stephen B.

doi:10.1371/journal.pgen.0030157

Cited by 315 publications

(339 citation statements)

References 47 publications

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“…Recent evidence indicates that inappropriate epigenetic silencing of tumor suppressor genes is as common as mutation-induced disruption in human cancer (Baylin, 2005;Chen and Baylin, 2005;Curtin et al, 2005;Dahl and Guldberg, 2007;Gronbaek et al, 2007;Schuebel et al, 2007). In GBM, both promoter hypermethylation and histone modifications have been shown to modulate the local chromatin environment and mediate expression of several genes critical for cell proliferation, response to therapy, tumor progression, apoptosis, angiogenesis and migration (Hegi et al, 2005;Foltz et al, 2006;Wang et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

DNA methyltransferase-mediated transcriptional silencing in malignant glioma: a combined whole-genome microarray and promoter array analysis

et al. 2009

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Epigenetic inactivation of tumor suppressor genes is a common feature in human cancer. Promoter hypermethylation and histone deacetylation are reversible epigenetic mechanisms associated with transcriptional regulation. DNA methyltransferases (DNMT1 and DNMT3b) regulate and maintain promoter methylation and are overexpressed in human cancer. We performed whole-genome microarray analysis to identify genes with altered expression after RNAi-induced suppression of DNMT in a glioblastoma multiforme (GBM) cell line. We then identified genes with both decreased expression and evidence of promoter CpG island hypermethylation in GBM tissue samples using a combined whole-genome microarray transcriptome analysis in conjunction with a promoter array analysis after DNA immunoprecipitation with anti-5-methylcytidine. DNMT1 and 3b knockdown resulted in the restored expression of 308 genes that also contained promoter region hypermethylation. Of these, 43 were also found to be downregulated in GBM tissue samples. Three downregulated genes with hypermethylated promoters and restored expression in response to acute DNMT suppression were assayed for methylation changes using bisulfite sequence analysis of the promoter region after chronic DNMT suppression. Restoration of gene expression was not associated with changes in promoter region methylation, but rather with changes in histone methylation and chromatin conformation. Two of the identified genes exhibited growth suppressive activity in in vitro assays. Combining targeted genetic manipulations with comprehensive genomic and expression analyses provides a potentially powerful new approach for identifying epigenetically regulated genes in GBM.

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Section: Discussionmentioning

confidence: 99%

DNA methyltransferase-mediated transcriptional silencing in malignant glioma: a combined whole-genome microarray and promoter array analysis

et al. 2009

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“…In point of fact, this epigenetic event affects more genes than do mutations [5,31]. The alteration is associated with very stable states of transcriptional silencing, and for many tumor suppressor genes such as the von Hippel-Lindau (VHL) gene [32], cyclin-dependent kinase inhibitors 2A (CDKN2A) [33,34] and 2B (CDKN2B) [35][36][37][38], and others, this change can serve as an alternative mechanism to mutation for tumor suppressor gene inactivation.…”

Section: Dna Methylationmentioning

confidence: 99%

Cancer epigenetics: linking basic biology to clinical medicine

2011

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Cancer evolution at all stages is driven by both epigenetic abnormalities as well as genetic alterations. Dysregulation of epigenetic control events may lead to abnormal patterns of DNA methylation and chromatin configurations, both of which are critical contributors to the pathogenesis of cancer. These epigenetic abnormalities are set and maintained by multiple protein complexes and the interplay between their individual components including DNA methylation machinery, histone modifiers, particularly, polycomb (PcG) proteins, and chromatin remodeling proteins. Recent advances in genome-wide technology have revealed that the involvement of these dysregulated epigenetic components appears to be extensive. Moreover, there is a growing connection between epigenetic abnormalities in cancer and concepts concerning stem-like cell subpopulations as a driving force for cancer. Emerging data suggest that aspects of the epigenetic landscape inherent to normal embryonic and adult stem/ progenitor cells may help foster, under the stress of chronic inflammation or accumulating reactive oxygen species, evolution of malignant subpopulations. Finally, understanding molecular mechanisms involved in initiation and maintenance of epigenetic abnormalities in all types of cancer has great potential for translational purposes. This is already evident for epigenetic biomarker development, and for pharmacological targeting aimed at reversing cancerspecific epigenetic alterations.

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“…Recently, encouraging results were obtained with an HDAC (histone deacetylase) inhibitor, which seems to target only JAK2 V617F-positive cells among primary myeloid progenitors from PV patients. 149 Thus, like other cancers, 150 MPNs might also show restriction of fate options through hypermethylation. This notion is supported by the different effects of sequential treatment with the DNA methyltransferase inhibitor, decitabine, followed by the histone deacetylase inhibitor, trichostatin A (TSA), on normal CD34( þ ) versus PMF CD34( þ ) cells.…”

Section: Jak2 V617f and Chromatinmentioning

confidence: 99%

Aberrant signal transduction pathways in myeloproliferative neoplasms

2008

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The BCR-ABL-negative myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), entered the spotlight in 2005 when the unique somatic acquired JAK2 V617F mutation was described in 495% of PV and in 50% of ET and PMF patients. For the very rare PV patients who do not harbor the JAK2 V617F mutation, exon 12 JAK2 mutants were discovered also to result in activated forms of JAK2. A minority of ET and PMF patients harbor mutations that constitutively activate the thrombopoietin receptor (TpoR). In bone marrow reconstitution models based on retroviral transduction, the phenotype induced by JAK2 V617F is less severe and different from the rapid fatal myelofibrosis induced by TpoR W515L. The reasons for these differences are unknown. Exactly by which mechanism(s) one acquired somatic mutation, JAK2 V617F, can promote three different diseases remains a mystery, although gene dosage and host genetic variation might have important functions. We review the recent progress made in deciphering signaling anomalies in PV, ET and PMF, with an emphasis on the relationship between JAK2 V617F and cytokine receptor signaling and on cross-talk with several other signaling pathways.

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Comparing the DNA Hypermethylome with Gene Mutations in Human Colorectal Cancer

Cited by 315 publications

References 47 publications

DNA methyltransferase-mediated transcriptional silencing in malignant glioma: a combined whole-genome microarray and promoter array analysis

DNA methyltransferase-mediated transcriptional silencing in malignant glioma: a combined whole-genome microarray and promoter array analysis

Cancer epigenetics: linking basic biology to clinical medicine

Aberrant signal transduction pathways in myeloproliferative neoplasms

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