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Tycko B.,Institute for Cancer Genetics
American Journal of Human Genetics | Year: 2010

In this issue of The Journal, an article by Schalkwyk et al.1 shows the landscape of allele-specific DNA methylation (ASM) in the human genome. ASM has long been studied as a hallmark of imprinted genes, and a chromosome-wide version of this phenomenon occurs, in a random fashion, during X chromosome inactivation in female cells. But the type of ASM motivating the study by Schalkwyk et al. is different. They used a high-resolution, methylation-sensitive SNP array (MSNP) method for genome-wide profiling of ASM in total peripheral-blood leukocytes (PBL) and buccal cells from a series of monozygotic twin pairs. Their data bring a new level of detail to our knowledge of a newly recognized phenomenon-nonimprinted, sequence-dependent ASM. They document the widespread occurrence of this phenomenon among human genes and discuss its basic implications for gene regulation and genetic-epigenetic interactions. But this paper and recent work from other laboratories2,3 raises the possibility of a more immediate and practical application for ASM mapping, namely to help extract maximum information from genome-wide association studies. © 2010 The American Society of Human Genetics. Source

Mungamuri S.K.,Mount Sinai School of Medicine | Wang S.,University of Michigan | Manfredi J.J.,Mount Sinai School of Medicine | Gu W.,Institute for Cancer Genetics | Aaronson S.A.,Mount Sinai School of Medicine
Oncogene | Year: 2015

Chromatin conformation has a major role in all cellular decisions. We showed previously that P53 pro-apoptotic target promoters are enriched with H3K9me3 mark and induction of P53 abrogates this repressive chromatin conformation by downregulating SUV39H1, the writer of this mark present on these promoters. In the present study, we demonstrate that in response to P53 stabilization, its pro-apoptotic target promoters become enriched with the H3K4me3 epigenetic mark as well as its readers, Wdr5, RbBP5 and Ash2L, which were not observed in response to SUV39H1 downregulation alone. Overexpression of Ash2L enhanced P53-dependent apoptosis in response to chemotherapy, associated with increased P53 pro-apoptotic gene promoter occupancy and target gene expression. In contrast, pre-silencing of Ash2L abrogated P53's ability to induce the expression of these transcriptional targets, without affecting P53 or RNAP II recruitment. However, Ash2L pre-silencing, under the same conditions, resulted in reduced RNAP II ser5-CTD phosphorylation on these same pro-apoptotic target promoters, which correlated with reduced promoter occupancy of TFIIB as well as TFIIF (RAP74). Based on these findings, we propose that Ash2L acts in concert with P53 promoter occupancy to activate RNAP II by aiding formation of a stable transcription pre-initiation complex required for its activation. © 2015 Macmillan Publishers Limited. All rights reserved. Source

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A comprehensive analysis of the molecular characteristics of gliomas—the most common malignant brain tumor—explains why some patients diagnosed with slow-growing (low-grade) tumors quickly succumb to the disease while others with more aggressive (high-grade) tumors survive for many years. The multinational study suggests a new way of classifying gliomas that may have a significant impact on patient management and may lead to the development of more targeted therapies. The paper, co-led by researchers from Columbia University Medical Center (CUMC), USA, Ribeirão Preto Medical School (FMRP) at the University of São Paulo (USP), Brazil, and The University of Texas MD Anderson Cancer Center, Houston, Texas, USA, was published in the journal Cell. Currently, pathologists determine if a glioma is low-grade or high-grade based on the tumor tissue’s appearance under the microscope. “While this approach is generally good at distinguishing between gliomas that are clearly very aggressive and those that are relatively slow-growing, it misses the mark in a significant percentage of cases, leading to inappropriate treatment,” said co-senior author Antonio Iavarone, M.D., professor of neurology and pathology and cell biology (in the Institute for Cancer Genetics) at CUMC and a member of the Herbert Irving Comprehensive Cancer Center (HICCC) at NewYork-Presbyterian /Columbia University Medical Center. “Instead, by looking at the molecular makeup of these tumors, we now have a much more precise way of predicting which tumors are more likely to grow rapidly and can prescribe treatments accordingly.” Other researchers have attempted to classify gliomas according to their genetic characteristics. One study found that tumors with mutations in a gene called IDH were significantly less aggressive than those without the mutation, known as IDHwildtype tumors. However, these findings did not fully explain why some patients with IDHmutant tumors fare worse than expected and some with IDHwildtype tumors fare better than expected. Other studies suggested that a glioma’s level of DNA methylation, an epigenetic process that cells use to control gene expression, might explain a tumor’s aggressiveness, but the evidence was inconclusive. In this study, Dr. Iavarone and his colleagues analyzed 1,122 high and low grade glioma samples from the Cancer Genome Atlas, looking for epigenetic changes in the tumors’ DNA. The researchers found that the best predictor of progression in an IDHmutant glioma—the less-aggressive variety—is its level of DNA methylation. Among IDHmutant gliomas, those with a high degree of DNA methylation progressed more slowly. However, tumors with less DNA methylation, about 6 percent of the total, progressed very quickly. “Based on their appearance under the microscope, these aggressive tumors looked very much like the other IDHmutant tumors,” said Dr. Iavarone. “But from a disease prognosis standpoint, they progressed quite similarly to the more lethal subset of IDHwildtype gliomas,” said Dr. Iavarone. Among those with IDHwildtype gliomas—the most aggressive type—a small subset (about 6 percent) had relatively favorable clinical outcomes. The molecular characteristics of this group were similar to those of pilocytic astrocytomas, a childhood brain tumor with a relatively favorable survival rate. “The present study advances the understanding of the glioma division by correlating each subtype of DNA methylation with a distinct clinical outcome,” said co-senior author Houtan Noushmehr, Ph.D., professor of epigenomics and bioinformatics at University of São Paulo and director of the OMICs and Bioinformatics lab at FMRP at Ribeirão Preto, São Paulo. “We discovered low grade and high grade gliomas mixed together within these different epigenetic subtypes. This was an unexpected finding and allowed us to further understand the progression of gliomas within the different subtypes,” said Dr. Noushmehr. “This research has expanded our knowledge of the glioma somatic alteration landscape and emphasized the relevance of DNA methylation profiles as a method for clinical classification,” said senior co-author Roel Verhaak, Ph.D., associate professor of bioinformatics and computational biology MD Anderson. “These findings are an important step forward in our understanding of glioma as discrete disease subsets, and the mechanism driving glioma formation and progression.” The paper also identified several previously unrecognized genetic alterations that may contribute to glioma development, highlighting potential new targets for drug therapy. “This study, which focused on tumor classification, does not point to specific therapies for glioma,” said Dr. Iavarone. “But our findings will help clinicians identify subsets of patients with IDHmutant tumors who need to be treated more aggressively and those with IDHwildtype tumors who can be spared aggressive treatment.”

Fabbri G.,Institute for Cancer Genetics | Khiabanian H.,Columbia University | Holmes A.B.,Institute for Cancer Genetics | Wang J.,Columbia University | And 8 more authors.
Journal of Experimental Medicine | Year: 2013

Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell lymphoma (DLBCL) type. The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ~20 genetic lesions/case. RS lesions are heterogeneous in terms of load and spectrum among patients, and include those involved in CLL progression and chemorefractoriness (TP53 disruption and NOTCH1 activation) as well as some not previously implicated in CLL or RS pathogenesis. In particular, disruption of the CDKN2A/B cell cycle regulator is associated with ~30% of RS cases. Finally, we report that the genomic landscape of RS is significantly different from that of de novo DLBCL, suggesting that they represent distinct disease entities. These results provide insights into RS pathogenesis, and identify dysregulated pathways of potential diagnostic and therapeutic relevance. © 2013 Fabbri et al. Source

Sonabend A.M.,Columbia University | Bansal M.,Center for Computational Biology and Bioinformatics | Guarnieri P.,Center for Computational Biology and Bioinformatics | Lei L.,Columbia University | And 17 more authors.
Cancer Research | Year: 2014

Proneural glioblastoma is defined by an expression pattern resembling that of oligodendrocyte progenitor cells and carries a distinctive set of genetic alterations. Whether there is a functional relationship between the proneural phenotype and the associated genetic alterations is unknown. To evaluate this possible relationship, we performed a longitudinal molecular characterization of tumor progression in a mouse model of proneural glioma. In this setting, the tumors acquired remarkably consistent genetic deletions at late stages of progression, similar to those deleted in human proneural glioblastoma. Further investigations revealed that p53 is a master regulator of the transcriptional network underlying the proneural phenotype. This p53-centric transcriptional network and its associated phenotype were observed at both the early and late stages of progression, and preceded the proneural-specific deletions. Remarkably, deletion of p53 at the time of tumor initiation obviated the acquisition of later deletions, establishing a link between the proneural transcriptional network and the subtype-specific deletions selected during glioma progression. © 2013 American Association for Cancer Research. Source

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