bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-173: Genome-scale analysis of aberrant DNA methylation in colorectal cancer
Authors: Hinoue Toshinori , Weisenberger Daniel J. , Lange Christopher P.E. , Noushmehr Houtan , Byun Hyang-Min , van Dijk Cornelis M. , Pan Fei , Malik Simeen , Van Den Berg David J. , Shen Hui , Tollenaar Rob A.E.M. , Laird Peter W. 
Published: July 2012

Abstract
Colorectal cancer (CRC) is a heterogeneous disease in which unique subtypes are characterized by distinct genetic and epigenetic alterations. Here we performed comprehensive genome-scale DNA methylation profiling of 125 colorectal tumors and 29 adjacent normal tissues. We identified four DNA methylation-based subgroups of CRC using model-based cluster analyses. Each subtype shows characteristic genetic and clinical features, indicating that they represent biologically distinct subgroups. A CIMP-high (CIMP-H) subgroup includes all CIMP-positive tumors characterized by the MethyLight five-marker panel, and is strongly associated with MLH1 DNA hypermethylation and the BRAFV600E mutation. A CIMP-low subgroup is enriched for KRAS mutations and characterized by DNA hypermethylation of a subset of CIMP-associated markers rather than a unique group of CpG islands. Non-CIMP tumors are separated into two distinct clusters. One non-CIMP subgroup is distinguished by a significantly higher frequency of TP53 mutations and frequent occurrence in the distal colon, while the tumors that belong to the fourth group exhibit a low frequency of both cancer-specific DNA hypermethylation and gene mutations and are significantly enriched for rectal tumors. Furthermore, we identified 114 genes that were downregulated more than 2-fold in CIMP-H tumors together with promoter DNA hypermethylation. These represent approximately 7% of genes that acquired promoter DNA methylation in CIMP-H tumors. Intriguingly, 48/114 genes were also transcriptionally silent in non-CIMP subgroups, but this was not attributable to promoter DNA hypermethylation. Together, we identified four distinct DNA methylation subgroups of CRC and provided novel insight regarding the role of CIMP-specific DNA hypermethylation in gene silencing.
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-173. doi:10.1158/1538-7445.AM2011-LB-173
Abstract LB-312: Methylated RASSF1a is the first specific DNA marker for minimal residual disease testing in neuroblastoma
Authors: Stutterheim Janine , Ichou Fatima Ait , den Ouden Emmy , Versteeg Rogier , Caron Huib N. , Tytgat Godelieve A.M. , Ellen van der Schoot C. 
Published: July 2012

Abstract
Purpose
PCR-based detection of minimal residual disease (MRD) in neuroblastoma is presently based on neuroblastoma-specific transcripts. However, the expression of these targets varies between patients and upon treatment, and only PHOX2B is truly specific. RASSF1a is methylated (RASSF1aM) in neuroblastoma and we investigated whether it can serve as a specific and stable DNA MRD marker.
Patients and methods
The RASSF1aM specific real-time quantitative (RQ)-PCR was tested on control bone marrow (BM) (n=50), on 71 neuroblastoma tumors and on 159 clinical BM samples at diagnosis and at follow up of 77 patients. Results were compared to a panel of RNA markers and correlated with prognosis.
Results
RASSF1aM was present in all stage 4 and 4s tumors (n=50) and in 86% stage 1–3 tumors (n=21). The level of methylation in stage 4 neuroblastoma was correlated with overall survival (p=0.02). RASSF1aM-PCR was highly specific (only one amplification in 50 control samples tested in triplicate) and had a similar sensitivity as the RNA-based PCRs as shown on clinical samples. Moreover, RASSF1aM enabled accurate quantification without need for the original tumor.
Conclusion
RASSF1aM is a novel, highly specific DNA marker for MRD detection in neuroblastoma, equal to PHOX2B in specificity and sensitivity, and better suitable for MRD quantification. We propose to include RASSF1aM in further prospective MRD studies in neuroblastoma alongside RNA MRD markers. In addition, this assay can be used for sensitive detection and quantification of circulating cells in all cancers with hypermethylated RASSF1a.
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-312. doi:10.1158/1538-7445.AM2011-LB-312
Abstract LB-328: Highly sensitive detection of miRNA and mRNA from frozen, FFPE tissue and body fluid samples by expression microarray
Authors: Takizawa Satoko , Sudo Hiroko , Ueda Yoji , Kuroda Toshihiko , Ichikawa Makiko , Nomura Osamu , Akiyama Hideo 
Published: July 2012

Abstract
The RNA profiling from clinical samples readily obtainable in the routine care, such as blood or FFPE samples, is a promising method to find the unknown high-value diagnostic markers. However, as RNA is subjected to degradation even in properly-collected, and immediately frozen tissue, it is more difficult to obtain intact RNA from FFPE or body fluid samples for diagnostic analysis. “3D-Gene” is a highly sensitive gene expression microarray, featuring the unique pillar structure on the substrate and the beads agitation system during the hybridization reaction. Using “3D-Gene”, we achieved highly sensitive detection of mRNA or miRNA from diagnostically important clinical samples.
Total RNA was extracted from human serum, plasma and frozen or FFPE tissue samples, with the recommended protocol for each sample. For mRNA detection, total RNA was reverse-transcribed to cDNA and labeled with fluorescent dye directly or after the amplification. For miRNA detection, total RNA was labeled with fluorescent dye directly. These pretreated target nucleotides were hybridized to “3D-Gene” while the hybridized buffer containing target nucleotides was agitated by beads during hybridization. The hybridized microarrays were washed and scanned for image acquisition.
(1) With “3D-Gene”, we could detect the mRNA expression profile from FFPE samples with high reproducibility. We also showed high correlation of the expression profiles between FFPE and frozen tissue samples. With 500 ng total RNA obtained from frozen as well as FFPE tissue samples, miRNA was reproducibly detected at attomolar level. Some miRNA biomarkers for various cancers were found from FFPE samples.
(2) Serum and plasma are suggested to contain microsomes in which miRNA is enclosed. miRNA from serum and plasma samples were detected with high sensitivity and reproducibility with “3D-Gene”. Some miRNA biomarkers for various cancers were found from patients' serum.
“3D-Gene” is a potential tool for detecting transcriptome with high sensitivity and useful for quest and validation of diagnostic biomarkers from clinical samples.
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-328. doi:10.1158/1538-7445.AM2011-LB-328
Abstract LB-333: Metabolic imaging of cancer using nanostructure-initiator mass spectrometry
Authors: Greving Matthew P. , Zhang Cathy , Yan Zhengming , Spilker Mary E. , Li Wenlin , Siuzdak Gary , O'Brien Peter J. 
Published: July 2012

Abstract
Metabolic adaptation is critical for the development and progression of cancer, and may influence the sensitivity of tumor cells to chemotherapy. Tumor metabolic profiling provides insights into those processes, but most quantitative methods are relatively limited in terms of assay sensitivity and spatial resolution, and by necessity focus on cultured cells, explanted tumors, or tissue extracts. Nanostructure-initiator Mass Spectrometry (NIMS) is a mass-based imaging technique that requires no sample preparation or extraction, and provides unbiased characterization of tissue metabolites in situ at low micron resolution. Seeking mechanistic insights and biomarkers of drug response, we used NIMS to profile xenobiotic- and cell-intrinsic metabolism in cultured Burkitt's lymphoma cells and breast cancer xenograft tumors treated with Rapamycin (RAPA) and Docetaxel (DOC), respectively. In both systems, non-radioactive fluorothymidine (FLT) metabolism was monitored as an indicator of cell proliferation, since FLT phosphorylation by thymidine kinase occurs mainly in G1-S phase cells. Rapamycin, FLT, and phosphorylated FLT metabolites were readily detected in Raji cells. RAPA, a starvation mimetic, induced dramatic alterations in metabolome of Raji cells 30, 60, and 90 minutes after treatment. Significant changes in cellular energetic- and biosynthetic intermediates were seen, including elevations in D-glucose (p=0.071); stearic acid (p=0.089); uridine monophosphate (p=0.002); N-Acetyl-L-glutamic acid (p=0.033); tiglyglycine (p=0.011); and isobutyryl carnitine (p=0.037). NIMS analysis of tumor tissues and normal liver from SCID-Beige mice implanted with MDA-MB-231 tumors showed FLT metabolite distribution consistent with that expected for proliferating cells. DOC induced derangement in that distribution and in endogenous metabolite profiles when compared to vehicle treatment. NIMS metabolomics thus allows simultaneous quantification of drug exposure, drug metabolism, and broad metabolic responses to treatment with single cell resolution. Metabolic discrimination of tissues, as with NIMS, is increasingly used to inform our understanding of pathology and to identify endogenous biomarkers. The approach described here, where differences in xenobiotic metabolism are used as landmarks of proliferating tumor cells in situ, offers novel tools for translating in vitro findings into a deeper understanding of tumor responses to therapy.
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-333. doi:10.1158/1538-7445.AM2011-LB-333
Abstract LB-345: Amplification of miR-26a-2 in human liposarcoma is correlated with poor patient survival
Authors: Lee Dhong Hyun Tony , Goff Catherine , Cutter Suzanne , Amanat Soroosh , Doan Ngan , Said Jonathan , Forscher Charles , Koeffler H. Phillip 
Published: July 2012

Abstract
Human liposarcoma (LPS) is one of the most common soft tissue sarcomas in adults. However, its molecular mechanism is poorly understood. For better understanding of the disease, we examined 54 human liposarcoma samples including 51 primary tumors and 3 cell lines (SW872, LP6, LP141) using Affymetrix 250K single nucleotide polymorphism (SNP) array. Allele-specific copy number (CN) analysis using anonymous references revealed that CN gain was dominant event over CN loss and loss of heterozygosity (LOH) in human LPS. Recurrent CN gain at 1q21–24 (43% of the samples), 5p13-p15 (46%), and 8q24 (41%) were identified. The most prominent CN gain was found in the 12q13-q15 region. 88% of the samples, mostly well-differentiated / de-differentiated subtype (WDLPS / DDLPS), showed various levels of CN gains centered at MDM2 gene.
In addition to MDM2 amplicon, we also identified an MDM2-independent amplicon in the 12q13-q15 region centered at miR-26a-2 gene at the same frequency (88%). MDM2 amplicon almost always accompanied miR-26a-2 amplicon. Likewise, samples without MDM2 amplicon did not have a miR-26a-2 amplicon. Quantitative reverse transcription real-time PCR (qRT-PCR) analysis showed that this CN gain of miR-26a-2 was strongly correlated with high mRNA expression of the gene in the WDLPS / DDLPS subtype. Furthermore, high mRNA expression of miR-26a-2 significantly correlated with a worse patient survival (p=0.05). Interestingly, some samples in myxoid / round-cell subtype (MRC) also showed high expression of miR-26a-2 without any prominent CN changes. High expression in the MRC subtype was also correlated with poor patient survival (p=0.0029). Western blot analysis using LPS cell lines revealed that cells with high miR-26a-2 expression showed decreased levels of RB1 and PTEN, which are two verified targets of miR-26a-2.
In conclusion, our analysis demonstrated the clinical importance of miR-26a-2 gene in human LPS. This finding may contribute to the discovery of prognostic markers as well as novel therapeutic targets for human LPS.
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-345. doi:10.1158/1538-7445.AM2011-LB-345
Abstract LB-350: Tissue and serum miRNA profiling for detection of bladder, breast and prostate cancer
Authors: Porter-Gill Patricia A. , Fu Yi-Ping , Kaushiva Alpana , Price Douglas , Dahut William , Figg William , Prokunina-Olsson Ludmila 
Published: July 2012

Abstract
Biomarkers that can differentiate between normal and tumor state, and can be measured in easily accessible body fluids such as blood and urine, can be very important for cancer diagnostics and disease monitoring. MicroRNAs (miRNAs), short non-coding regulatory RNA molecules, are attractive as biomarkers because they are stable in different conditions and are easy to measure with quantitative PCR (qPCR) methods. In this study we aimed to identify a universal panel of miRNAs for cancer screening that can be easily tested in the serum of healthy individuals and patients with different types of cancer. First, we measured expression of ∼800 miRNAs in 40 controls and 60 patients with bladder, breast or prostate cancer using the low density TaqMan expression arrays (Applied Biosystems) and starting from 250 ul of serum. Based on these results we selected a panel of 24 miRNAs that showed best discrimination between normal and cancer samples. These miRNAs were then re-tested as a custom-designed mini-panel in serum samples of 44 healthy controls and cancer patients (31 bladder, 25 breast and 28 prostate) and in relevant normal and tumor tissue samples (42 normal bladder and 43 bladder tumors, 44 normal breast and 42 breast tumors and in 50 normal prostate and 20 prostate tumors). Only miRNAs that expressed in the same direction in serum and tissue samples and showed significant association with cancer in both sample types were used for further analysis.
The current panel consists of 16 miRNAs – 14 targets, one positive control and one negative control. Using this panel on serum samples from 44 controls, 31 bladder cancer patients, 25 breast cancer patients and 28 prostate cancer patients we performed ROC analysis and achieved complete discrimination (AUC ∼1.0) between all types of cancers and controls and good discrimination between different types of cancers (minimal AUC 0.89 for breast and bladder samples). Our results prove that miRNA detection from serum might be a promising method of cancer detection. Currently, we are performing validation studies in independent sets of samples. A combination of information on genetic susceptibility factors identified by genome-wide association studies (GWAS), other cancer-specific factors such as PSA for prostate cancer and miRNA expression profiling, might provide additional tools for early disease diagnostics and help to guide treatment options.
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-350. doi:10.1158/1538-7445.AM2011-LB-350
Abstract LB-420: Intratumoral de novo steroid synthesis mediates prostate cancer resistance to androgen deprivation and CYP17a1 inhibition
Authors: Cai Changmeng , Balk Steven P. 
Published: July 2012

Abstract
Prostate cancer (PCa) that relapses after androgen deprivation therapy (ADT, medical or surgical castration), termed castration resistant prostate cancer (CRPC), has increased expression of enzymes that convert adrenal dehydroepiandrosterone (DHEA) and androstenedione to testosterone and dihydrotestosterone (DHT). DHEA and androstenedione are synthesized at high levels by the adrenals through the sequential actions of CYP11A1 and CYP17A1; hence CYP17A1 inhibitors such as abiraterone are effective therapies for CRPC. However, mechanisms contributing to CYP17A1 inhibitor relapse remain to be determined. We show that castration resistant VCaP PCa xenografts synthesize androgens de novo at levels that fully restore androgen receptor (AR) activity and respond to abiratrone, and that development of abiraterone resistance is associated with markedly increased intratumoral CYP17A1 expression. Consistent with these results, we find that tumor expression of CYP17A1 is markedly increased in patients after CYP17A1 inhibitor therapy. We further show that CRPC cells expressing a T877A mutant AR are not CYP17A1 dependent, and that AR activity in these cells is instead mediated by upstream CYP11A1 dependent pregnenolone/progesterone synthesis. These findings indicate that CYP17A1 inhibitor resistant tumors are still steroid dependent and may respond to dose escalation, alternative CYP17A1 inhibitors, or agents blocking other steps in steroid synthesis.
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-420. doi:10.1158/1538-7445.AM2011-LB-420
Abstract LB-438: Proteomic analysis of aristolochic acid-induced nephrotoxicity in rats
Authors: Yu Li-Rong , Li Zhiguang , Gao Yuan , Chen Tao 
Published: July 2012

Abstract
Aristolochic acids (AA) are a family of structurally related nitrophenanthrene carboxylic acids, mainly consisting of aristolochic acid I (AAI) and aristolochic acid II (AAII), and are the active component of some herbal medicines. Use of dietary supplements and other botanical products containing AA have resulted in severe nephrotoxicity and consequent renal replacement therapy. Aristolochic acids are potent carcinogens as well, inducing urothelial cancers in humans and kidney tumors in rats. Previous studies have shown that the tumorigenicity of AA could result from AA-induced DNA adduct formation and mutation induction. To further understand the molecular mechanisms underlying AA-induced nephrotoxicity (e.g., carcinogenesis) and identify disease biomarkers, a quantitative proteomic analysis was conducted on kidneys from AA-treated rats. Animal treatment was conducted according to the approved protocol and followed the recommendations of the NCTR Institutional Animal Care and Use Committee. Six-week-old Big Blue rats were treated with AA as its sodium salt at concentrations of 0.1, 1.0, and 10.0 mg/kg body weight by gavage five times/week for 12 weeks or with 0.9% sodium chloride as the control using the same schedule. Six rats from each treatment group were sacrificed 1 day after the last treatment. The kidneys were isolated, frozen quickly in liquid nitrogen, and stored at −80 °C. Kidney tissues from the control and the highest AA dose treatment (10 mg/kg body weight) were selected for proteomic analysis. Proteins were extracted and digested into peptides. Trypsin-catalyzed 16O/18O stable isotope labeling was performed for each pair of control/treatment samples, which were then analyzed using two-dimensional liquid chromatography coupled online with tandem mass spectrometry (LC-MS/MS). Approximately 3000 proteins were quantified from each pair of samples, and more than 150 proteins were concordantly over expressed or under expressed across all the AA-treated samples. Pathway analysis indicated that significant changes include proteins involving xenobiotic metabolism, response to stimulus including DNA damage, cell proliferation and neoplasm, etc. Intriguingly, proteins indicating kidney pathological changes such as nephron degeneration were identified as well. Although further verification is needed, the quantitative proteomic study identified proteins related to potential toxicity and oncogenic pathways and proteins that could serve as urinary biomarkers of renal damage inflicted by aristolochic acid exposure.
The views presented do not necessarily reflect those of the U. S. Food and Drug Administration.
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-438. doi:10.1158/1538-7445.AM2011-LB-438
Abstract LB-441: The genome wide gene-environment interaction analysis for asbestos exposure on lung cancer susceptibility
Authors: Wei Sheng , Wang Li-e , McHugh Michelle K. , Han Younghun , Amos Christopher I. , Spitz Margaret R. , Xiong Momiao , Wei Qingyi 
Published: July 2012

Abstract
Asbestos exposure is a known risk factor for lung cancer. Although recent genome wide association studies (GWAS) have identified a few novel loci for lung cancer risk, little is known about genome wide gene-environment interactions and lung cancer risk. To determine genetic variations involved in the interactions of gene-asbestos exposure on lung cancer risk, we conducted genome wide gene-environment interaction analyses at levels of single nucleotide polymorphisms (SNPs), genes and pathways, using the Texas lung cancer GWAS dataset. This dataset included 307,870 SNPs from 1,154 lung cancer cases and 1,137 cancer-free controls. The initial SNP-level p values for interactions between genetic variants and self-reported asbestos exposure were estimated by unconditional logistic regression models adjusted for age, sex, smoking status and pack-years. The p value for the most significant SNP rs12706823 was 1.37 × 10–4 and did not reach the genome-wide statistical significance. Using a versatile gene-based test approach to estimate the interactions at the gene level, we found the top significant gene was RNF121and was located on 11q13.4 (p value = 4 × 10–4). Interestingly, most of the genes with top significant p values were located in 11q13. When we used an improved gene set enrichment analysis approach (i-GSEA), however, we found a total of 249 pathways containing 16,079 genes, of which the Fas signaling pathway was the most significant pathway, significantly involved in the interactions between genetic variations and self-reported asbestos exposure (nominal p value &lt; 0.001; false discovery rate (FDR) &lt; 0.05). We believe our analysis is the first to comprehensively describe the genome wide gene-asbestos exposure interaction on lung cancer risk at the levels of SNPs, genes and pathways. Our findings suggested that the current designed GWAS may have a limited power to detect gene-environment interactions at the SNP or gene levels, but the pathway-based approach may be more powerful in performing genome wide gene-environment analyses. (This study was supported by NIH grants R01 ES 11740, R01CA 131274, R01CA055769, R01CA127219, R01CA121197 and P30CA016672)
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-441. doi:10.1158/1538-7445.AM2011-LB-441