Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Hoadley, Katherine A.; Yau, Christina; Wolf, Denise M.; Cherniack, Andrew D.; Tamborero, David; Ng, Sam; Leiserson, Max D M; Niu, Beifang; McLellan, Michael D.; Uzunangelov, Vladislav; Zhang, Jiashan; Kandoth, Cyriac; Akbani, Rehan; Shen, Hui; Omberg, Larsson; Chu, Andy; Margolin, Adam A.; Veer, Laura J. van’t; López‐Bigas, Núria; Laird, Peter W.; Raphael, Benjamin J.; Li, Ding; Robertson, A. Gordon; Byers, Lauren A.; Mills, Gordon B.; Weinstein, John N.; Waes, Carter Van; Chen, Zhong; Collisson, Eric A.; Benz, Stephen C.; Perou, Charles M.; Stuart, Joshua M.

doi:10.1016/j.cell.2014.06.049

Cited by 1,322 publications

(1,319 citation statements)

References 39 publications

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“…To test this directly, we performed SMS on 14 GBM tumor and seven control biospecimens. As it is difficult to obtain fresh brain tissue samples from healthy individuals, we have followed the example of the TCGA Consortium and used epilepsy samples as a control for GBM (33)(34)(35). We analyzed the RNA sequencing data by testing expression of each annotated transcript in each individual GBM sample compared against all normal samples, rather than grouping all GBM samples together.…”

Section: Resultsmentioning

confidence: 99%

The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation

Pastori

Kapranov

Penas

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

179

146

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Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumorpromoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases.glioblastoma | long noncoding RNAs | epigenetics | BRD4 | I-BET151

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Section: Resultsmentioning

confidence: 99%

The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation

Pastori

Kapranov

Penas

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

179

146

View full text Add to dashboard Cite

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“…88 Cancer subtyping and reclassification can provide custom-designed diagnosis and guide individualized therapy. Hoadley et al, 89 for example, reclassified 3,527 cancer samples (across 12 tissue-of-origin cancer types) into 11 new types based on six kinds of multi-omic data (including exon, copy number variation, DNA methylation, miRNA, mRNA, and protein) and found that these new types are capable of providing independent prognostic power. As stated, L1 activity profiles differ among and within cancer types 32,35 and fluctuate during cancer evolution.…”

Section: Perspectives: Implications Of L1 Activity and Expression Inmentioning

confidence: 99%

LINE-1 in cancer: multifaceted functions and potential clinical implications

Han

et al. 2016

Genetics in Medicine

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ReviewThe human genome is abundant with interspersed repetitive sequences originated from retrotransposons. Until now, three categories of retrotransposons have remained unequivocally active: LINE-1(L1), Alu, and SVA elements. The first one is autonomous-capable of self-propagation through RNA intermediates-and the latter two are nonautonomous and thus rely on L1 for mobilization. There are approximately 500,000 L1 copies in the human genome, composing 17% of human DNA.

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Section: Rna-binding Proteinmentioning

confidence: 99%

“…Meanwhile, the TCGA project generated datasets for over 18 cancer types, which include gene expression, copy number alteration (CNA), DNA methylation, and somatic mutation profiles (10). All of these resources provided a rich base for cancer integrative analysis (11,12).Despite the rapid growth of genomic data, the knowledge on how gene expression programs in tumors are controlled by TFs is still limited. As one challenge, the experimental condition of public ChIP-seq data, such as stem cell line, may not match the physiological condition of a specific cancer type.…”

mentioning

confidence: 99%

Inference of transcriptional regulation in cancers

Jiang

Freedman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Despite the rapid accumulation of tumor-profiling data and transcription factor (TF) ChIP-seq profiles, efforts integrating TF binding with the tumor-profiling data to understand how TFs regulate tumor gene expression are still limited. To systematically search for cancerassociated TFs, we comprehensively integrated 686 ENCODE ChIPseq profiles representing 150 TFs with 7484 TCGA tumor data in 18 cancer types. For efficient and accurate inference on gene regulatory rules across a large number and variety of datasets, we developed an algorithm, RABIT (regression analysis with background integration). In each tumor sample, RABIT tests whether the TF target genes from ChIP-seq show strong differential regulation after controlling for background effect from copy number alteration and DNA methylation. When multiple ChIP-seq profiles are available for a TF, RABIT prioritizes the most relevant ChIP-seq profile in each tumor. In each cancer type, RABIT further tests whether the TF expression and somatic mutation variations are correlated with differential expression patterns of its target genes across tumors. Our predicted TF impact on tumor gene expression is highly consistent with the knowledge from cancer-related gene databases and reveals many previously unidentified aspects of transcriptional regulation in tumor progression. We also applied RABIT on RNAbinding protein motifs and found that some alternative splicing factors could affect tumor-specific gene expression by binding to target gene 3′UTR regions. Thus, RABIT (rabit.dfci.harvard.edu) is a general platform for predicting the oncogenic role of gene expression regulators.regulatory inference | tumor profiling | transcription factor | RNA-binding proteinT umorigenesis is a multistep process requiring alterations in gene expression programs (1, 2). Transcription factors (TFs) are instrumental in driving these gene expression programs, and misregulation of these TFs can result in the acquisition of tumorrelated properties (3). For example, E2F1 is overexpressed in many cancer types and promotes tumor proliferation by regulating expression of genes involved in cell differentiation, metabolism, and development (4). As another example, FOXM1 plays an important role in promoting cell proliferation and cell cycle progression through transcriptional activation of many G2/M-specific genes. Increased FOXM1 gene expression was detected in numerous cancer types, and FOXM1 is a promising therapeutic target for cancer treatment (5). TFs also play critical roles in inducing the tumor microenvironment for metastasis. For example, SNAI1/2, TWIST, and ZEB1/2 orchestrate the expression of genes involved in cell polarity, cell-cell contact, cytoskeleton structure, and extracellular matrix degradation. The joint effect of these TFs promotes cancer cell motility and invasion in the metastatic process (2, 6).With the rapid development of high-throughput technologies, large amounts of datasets have been generated for regulatory proteins. For example, the ENCODE project generated 689 C...

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Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Cited by 1,322 publications

References 39 publications

The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation

The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation

LINE-1 in cancer: multifaceted functions and potential clinical implications

Inference of transcriptional regulation in cancers

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