bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-174: A DNA hypermethylation module for the stem/progenitor cell signature of cancer
Authors: Easwaran Hariharan , Johnstone Sarah E. , Van Neste Leander , Ohm Joyce E. , Mosbruger Tim , Aryee Martin , Yegnasubramanian Srinivasan , Matsui William , Baylin Stephen B. 
Published: July 2012

Abstract
It has been firmly established that cancer gene expression partly mimics the gene expression signature in embryonic stem cells (ESC). Since most cancers arise in adult stem or progenitor cells, rather than ESC, we now compare cancer chromatin to both embryonic and adult cell renewal systems to understand the relationships between DNA hypermethylation, gene expression, and chromatin states. DNA hypermethylation at CpG island promoters of hundreds of genes, including classic tumor suppressors, is a major modulator of gene expression in human cancers. Past studies suggest ∼ 50% of these are frequently marked by polycomb complex (PcG) transcriptional repressors, but not DNA methylation, in embryonic stem cells (ESC). In ESC, PcG occupancy is predominantly in the context of “bivalent chromatin”, wherein the active transcription mark H3K4me3 and the repressive PcG mark H3K27me3 are simultaneously present. Genes so marked are in a low, but poised, transcription state important for stemness and self-renewal, characteristics shared with tumor cells. Using whole genome ChIP-seq and DNA methylation arrays, we find between 70 to 80% of genes with DNA hypermethylation in cancer have bivalent chromatin not only in ESC, but also in adult stem cells. For these genes, there appears to be an epigenetic switch in cancer wherein bivalent chromatin is replaced by DNA hypermethylation resulting in tighter repression of gene expression. Many of these DNA methylated cancer genes are constituents of the recently proposed “PRC module” of the “ESC cancer signature.” Our data suggest a “DNA methylation module” that recapitulates the “stem cell signature” and that DNA hypermethylation may be a key mechanism that confers cell-renewal and stemness to tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-174. doi:10.1158/1538-7445.AM2011-LB-174
Abstract LB-176: A novel high density DNA methylation array with single CpG site resolution
Authors: Bibikova Marina , Barnes Bret , Tsan Chan , Ho Vincent , Klotzle Brandy , Le Jennie M. , Delano David , Gunderson Kevin L. , Fan Jian-Bing , Shen Richard 
Published: July 2012

Abstract
Aberrations in DNA methylation patterns are widely recognized as a hallmark of the cancer cell. DNA methylation has emerged as a promising biomarker for the detection and classification of various types of cancer, and ability to accurately assess the DNA methylation changes plays an important role in understanding of disease onset and progression.
We developed a new generation of genome-wide DNA methylation BeadChip which allows high-throughput methylation profiling of human genome. The new high density BeadChip can assay over 480K CpG sites and analyze twelve samples in parallel. The innovative content includes coverage of 99% of RefSeq genes with multiple probes per gene, 96% of CpG islands from the UCSC database, CpG island shores and additional content selected from whole-genome bisulfite sequencing data and input from DNA methylation experts. The well-characterized Infinium® assay is used for analysis of CpG methylation using bisulfite-converted genomic DNA. In this assay, unmethylated cytosines (C) are converted to uracil (U) when treated with bisulfite, while methylated cytosines remain unchanged. The assay design is using single probe assays for CpG loci with up to two underlying CpG dinucleotides, and two-probe assays for CpG loci with multiple underlying CpG sites, with one probe querying the “unmethylated” allele and the other probe querying the “methylated” allele. The assays are designed under the assumption that methylation is regionally correlated (within 50 base pairs) and that all CpG sites underlying the probe are assumed to be “in phase” with the queried CpG site.
For the BeadChip development, we used methylation standards created by de-methylating gDNA with Phi29 whole genome amplification, methylating the amplified DNA with SssI methylase and mixing the unmethylated and methylated DNA in a 1:1 ratio to create a 50% methylation state. 500 ng gDNA input is used for bisulfite conversion and is sufficient for two assays. Reproducible DNA methylation profiles were obtained between replicates (an average R2 of 0.98).
We applied this technology to DNA methylation analyses in cancer cell lines of different tissue of origin and normal DNA samples derived from multiple tissues. Highly specific methylation signatures were obtained for each sample type.
The ability to determine genome-wide methylation patterns will rapidly advance methylation research and ultimately lead to the development of powerful tools for diagnosis, prognosis, and treatment of human diseases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-176. doi:10.1158/1538-7445.AM2011-LB-176
Abstract LB-329: Copy number variations associated with hereditary breast and colorectal carcinomas
Authors: Abreu Francine B. , Santos Erika Maria Monteiro , Rossi Benedito Mauro , Achatz Maria Isabel , Cristina Ana , Krepischi Victorino , Kowalski Luiz Paulo , Brentani Ricardo Renzo , Rogatto Silvia Regina 
Published: July 2012

Abstract
Breast and colorectal cancer are the most common malignant neoplasia in the world. In Brazil, breast cancer is the first malignant neoplasia and colorectal cancer, the third. It is estimated that among 5–10% of all cancer cases are hereditary. Copy number alterations (CNVs) may affect genes associated to cancer, providing an explanation for high risk cancer families. In this study, 57 individuals with Hereditary Breast and Colorectal Carcinoma were screened for BRCA1, BRCA2, CHEK2, TP53, MLH1 and MSH2 mutations by Sanger's sequencing method. In addition, copy number alterations were evaluated by array comparative genomic hybridization (aCGH) using a platform of 4×180K (Agilent). The data were compared with the Database of Genomic Variations (DGV;http://projects.tcag.ca/variation/) and with a reference dataset obtained from 82 healthy Brazilian individuals. Genomic data were extracted and flagged with Feature Extraction software and analyzed using Genomic Workbench Standard 5.0.14, statistical algorithm ADM2 and sensitivity threshold of 6.7. Alterations identified in more than 5% of the control women were excluded from both groups. The patients were divided into two groups: 28 patients with breast or colorectal cancer (group 1) and 29 women with breast and colorectal carcinoma (group 2). Sixteen relatives from seven patients were also evaluated by aCGH. All patients were negative for BRCA1, BRCA2, CHEK2, TP53, MLH1 and MSH2 pathogenetic mutations. However, the aCGH analysis detected a total of 569 chromosomal alterations in healthy Brazilian dataset (in average 6.8/individual), 170 CNVs (in average 6.1/individual) in group 1, and 232 (in average 8.0/individual) in group 2 patients. Forty-five and 63 chromosomal regions altered were detected in group 1 and 2, respectively. Nineteen chromosomal alterations were common to both groups. Mapped on these regions altered, it was identified 28 microRNAs. Ten specific chromosomal alterations were found in patients and their relatives; seven of them were losses involving genes not previously described in breast and colorectal carcinomas patients. Our results suggest that these chromosomal regions harbor genes associated with Hereditary Breast and Colorectal Carcinomas.
Financial Support: FAPESP (2008/57887–9) and CNPq (57589/2008–9)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-329. doi:10.1158/1538-7445.AM2011-LB-329
Abstract LB-332: High-throughput proteomic analysis identifies protein S as a potential modulator of androgen-independent prostate cancer
Authors: Saraon Punit , Jarvi Keith , Diamandis Eleftherios P. 
Published: July 2012

Abstract
Prostate cancer is the most commonly diagnosed and second leading cause of death due to cancer in men. Androgen deprivation remains the mainstay therapy, which is efficient in shrinking androgen-dependent tumors. However, many men eventually stop responding to this treatment, progressing to a more lethal androgen-independent prostate cancer. The mechanisms mediating these transitions remain unknown, and as a result, there are no effective treatments. We hypothesize the presence of specific modulators, important for the progression to androgen-independency. To test this, we performed high-throughput proteomic analysis on the conditioned media of the androgen-dependent cell lines LNCaP and VCaP, androgen-independent cell lines LNCaP-SF, DU-145, PC3, PPC1, 22Rv1, as well as a normal prostate cell line (RWPE). This allowed us to compile a comprehensive data set, permitting us to mine for differentially secreted proteins that could serve as potential markers for androgen-independent cancers. We utilized quantitative real-time PCR, as well as in vitro wound healing assays to corroborate our proteomic analysis results. We were able to identify the anti-coagulant factor, Protein S (PROS1), as a potential modulator and marker of androgen-independence. Based on spectral counts, PROS1 was found highly secreted in all the androgen-independent cell lines, with no detectable secretion in the normal or androgen-dependent cell lines. The gene expression profile of the androgen-independent cell lines also maintained the over-expression of PROS1, when compared to the normal and androgen-dependent cell lines, while only prostate cancer tissue samples showed an upregulation of PROS1. Furthermore, recombinant PROS1-treated LNCaP cells demonstrated an increase in wound repair and invasive growth potential, implying that PROS1 may have functional roles outside of the coagulation pathway. Our results suggest that PROS1 is involved in the progression of androgen-independent prostate cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-332. doi:10.1158/1538-7445.AM2011-LB-332
Abstract LB-337: Post-transcriptional regulators of microRNA biogenesis drive glioblastoma-specific expression
Authors: Chung Wei-Jen , Sumazin Pavel , Yang Xuerui , Bansal Mukesh , Califano Andrea 
Published: July 2012

Abstract
MicroRNAs have emerged as key regulators of both normal and pathologic phenotypes, including cancer. Fine grain regulation of their biogenesis, however, is still a poorly understood process and only a relatively small repertoire of proteins controlling its key steps has been characterized. In order to understand the extent and specificity of microRNA biogenesis control, as well as its role in glioblastoma tumorigenesis and progression, we developed and experimentally validated miRage, an algorithm for genome-wide inference of microRNA biogenesis regulators. MiRage identifies biogenesis-regulator candidates using the conditional mutual information between the candidates, mature microRNAs precursors, and abundance to identify those proteins that are required for the maturation of microRNAs.
miRage predicted hundreds of potential biogenesis regulators that are either specific to individual microRNAs or to microRNA families. Several of the inferred regulators that are differentially expressed across glioblastoma prognosis were validated in the SNB19 cell line. Differential expression of mature microRNAs, their host genes, and their precursors were measured before and after ectopic expression or RNAi mediated silencing of predicted regulators. ACSM3, which is predicted to regulate 70% of the differentially expressed microRNAs in glioblastoma, was shown to post-transcriptionally inhibit miR-155. This microRNA is an experimentally validated regulator of CEBPβ, a master regulator of the mesenchymal signature of GBM; indeed siRNA-mediated silencing of ACSM3 dramatically activated miR-155 and down-regulated CEBPβ. In addition, several members of the DDX RNA-binding protein family were inferred as specific regulators of microRNA biogenesis. For instance, we show that DDX10 activates miR-218 and inhibits miR-9; up regulation of DDX10 may account for miR-218 overexpression in poor-prognosis tumors. We showed that RBBP4 inhibits miR-23b, WDR8 inhibits miR-18b, ACTA2 inhibits miR-218, and PRIC285 inhibits miR-196a and miR-25.
Taken together, these results suggest that microRNA biogenesis is a much more complex and finely regulated process than previously thought, and that microRNA biogenesis regulators may play a key role in tumor initiation and progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-337. doi:10.1158/1538-7445.AM2011-LB-337
Abstract LB-339: MicroRNA modulators regulate oncogenes and tumor suppressors in glioblastoma
Authors: Sumazin Pavel , Yang Xuerui , Chung Wei-Jen , Bansal Mukesh , Califano Andrea 
Published: July 2012

Abstract
MicroRNAs, including miR-21, MiR-26a and miR-221/2, are potential key regulators of gene expression in glioblastoma, the most common and the most aggressive type of primary human brain tumor. Their activity is modulated by post-transcriptional factors that regulate mRNA processing pathways and by the abundance of their targets. Despite recent efforts to identify microRNA modulators, this mode of regulation is still poorly understood, and the repertoire and extent that microRNA modulators regulate gene expression in tumors and affect tumorigenesis remain unknown.
We developed a genome-wide approach to identify glioblastoma-specific microRNA modulators. We identified hundreds of candidate modulators, including modulators that either activate or suppress miRISC-mediated regulation, and mRNAs that act as decoys and compete for microRNA binding in glioblastoma. Validation experiments were done in SNB19 cell line by measuring differential expression of mature microRNAs and their targets after ectopic expression or inhibition of predicted regulator proteins. 3′ UTR luciferase assays were used to establish the post-transcriptional nature of the regulation. Focusing on two known drivers of gliomagenesis and progression, we showed that PTEN is post-transcriptionally up regulated by WNT7A through miR-21 and down regulated by PALB2 through miR-106a, and that RUNX1 is post-transcriptionally down regulated by WIPF2 through miR-17–5p. Further, we showed that PTEN and RUNX1, which are widely considered functionally unrelated, act as decoys for one another by competing for a common microRNA-regulatory program: they post-transcriptionally regulate one another through their microRNA regulators. In addition, other modulators with prognosis-predictive genetic alterations act through common microRNA-regulatory programs to regulate PTEN and RUNX1 expression. For example, prognosis-predictive genetic alterations at the CTBP2 locus significantly alter both CTBP2 and PTEN expression in glioblastoma; siRNA-mediated silencing of CTBP2 resulted in a 30% reduction in the expression of PTEN 3′ UTR luciferase reporters.
Our results demonstrate that microRNA modulators regulate the expression of key glioblastoma drivers, and that genetic alterations at microRNA modulators lead to aberrant post-transcriptional regulation of these drivers. Taken together, these results suggest that microRNA modulation plays a significant role in tumorigenesis and progression of gliobalstoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-339. doi:10.1158/1538-7445.AM2011-LB-339
Abstract LB-342: MicroRNA-130b contributes to mesenchymal differentiation and leiomyosarcomagenesis
Authors: Danielson Laura , Guijarro Maria , Zavadil Jiri , Wei Jianjun , Levine Douglas , Hernando Eva 
Published: July 2012

Abstract
Leiomyosarcoma (LMS) is a highly aggressive cancer of smooth muscle origin for which the molecular bases of transformation and progression are poorly defined. MicroRNAs (miRNAs) are small non-coding RNAs that have been implicated in tumor development by acting as tumor suppressors or oncogenes. Therefore, identifying a mechanistic role for miRNAs in the biology of LMS will result in better understanding of this complex disease. Moreover, investigation of miRNAs that may also play a role in smooth muscle cell (SMC) differentiation might enhance our understanding of this highly undifferentiated neoplasia. MiRNA microarrays previously performed in our lab identified miR130b as upregulated in uterine LMS compared to normal myometrium. The objective of the current study is to investigate the role of this miRNA in SMC differentiation and LMS genesis and progression.
Preliminary studies have demonstrated increased proliferation, invasion, and colony formation in LMS cell lines overexpressing miR130b indicating that it may be pro-oncogenic. Moreover, miR130b overexpression in human mesenchymal stem cells (hMSCs) induced to differentiate into SMCs inhibited their maturation. Target analysis thus far has revealed that miR130b reduces the levels of its predicted targets Tuberous sclerosis 1, Dicer1, and Connexin 43.
Ongoing overexpression and knockdown studies will determine the necessity and sufficiency of miR130b on in vitro tumorigenic properties of LMS cell lines and SMC differentiation of hMSCs. Microarray expression studies and direct target analysis are being used to elucidate the molecules through which miR130b exerts its functions. Additionally, patient samples will be analyzed to determine the relevance of miR130b overexpression in LMS. Genomic amplification will be assessed as a potential mechanism for the increased levels of miR130b in LMS tissues. Human specimens will also be used to investigate correlations between miRNA expression and its direct targets.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-342. doi:10.1158/1538-7445.AM2011-LB-342
Abstract LB-343: Ultraviolet radiation modulates distinct mouse epidermal miRNAs expression profile
Authors: Jamal Mohammad S. , Verma Ajit K. 
Published: July 2012

Abstract
Chronic exposure to ultraviolet radiation (UVR) is the most common etiologic factor linked to the development of squamous cell carcinoma (SCC), a non-melanoma form of skin cancer that can metastasize. To find clues about the mechanism of UVR-induced development of SCC in FVB/N mice, we found that chronic UVR exposures lead to aberrant expression of several microRNAs (miRNAs). In the present experiment, mice were exposed to four (Monday, Wednesday, Friday and Monday) UVR (2 kJ/m2) treatments, emitted by Kodacel-filtered FS-40 sun lamps (approximately 60% UVB and 40% UVA). At 3 hrs post last UVR exposure, mice were sacrificed. RNAs were prepared from the scraped epidermis of these mice. To screen for unknown miRNAs, we performed the 1040 miRNAs microarray analysis. UVR treatment resulted in modulation of 15 miRNAs: six miRNAs (miR-145, miR-1937a, miR-1937b, miR-341*, miR-451, miR-720) were up-regulated while nine miRNAs (let-7g, miR-125–5p, miR-195, miR-200b, miR-29a, miR-30c, miR-429, miR-92a) were down-regulated. The microarray results were further validated by qRT-PCR. These UVR-induced over-expressed (e.g; miR-451) and down-regulated (e.g; let-7g, miR-195) miRNAs have been observed to be oncogene and tumor suppressor, respectively in various types of cancers. To determine the downstream target genes (DTG) of these miRNAs, insilico analysis was performed. We employed the DIANA LAB DNA Intelligent and Target-Scan program to reveal the various pathways and genes regulated by these miRNAs. Finally we did the IPA to decipher the existing network between these target genes. Among all the miRNAs modulated by UVR treatment, only miR-429 and miR-195 shown to have significant network. MiR-429 network consist of few important hubs. Those were TARDBP, PCBP (Poly (rC) Binding Protein) and PUF60. TARDBP is reported to bind to chromosomally integrated TAR DNA and repress HIV transcription. PCBP1 and PCBP2 are multifunctional protein reported to be translational coactivator. PUF60 is known as a transcriptional repressor. The network obtained by miR-195 DTG revealed that various cytokines exist in the downstream network. Among them, IL-10, IFN-γ and TNF-α are the most significant hub of the network. We also found ZFP36 as an important hub, which is known for recruiting the miRNA at the 3′UTR of mRNA. IPA analysis suggests that all of the above hub molecules play major roles in cell cycle and cancer initiation and progression. UVR-induced deregulated miRNAs (miR-145, miR-1937a, miR-1937b, miR-341*, miR-451, miR-720 – let-7g, miR-125–5p, miR-195, miR-200b, miR-29a, miR-30c, miR-429, miR-92a) may constitute important components of UVR carcinogenesis (Support: NIH grant CA35368).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-343. doi:10.1158/1538-7445.AM2011-LB-343