bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 425: Methylation, copy number, and LOH analysis of Chr1q21.3 for discovery of ovarian and breast cancer biomarkers
Authors: Poulin Matthew L. , Meyer Ann , Alexander Jessica , Xu Jessica , Yan Liying 
Published: May 2015

Abstract
The association of genetic abnormalities and specific cancers is leading to an increasing number of biomarkers that can be used for early detection of cancers, determination of treatment protocols and predicted prognoses. Additionally, the methylation state of an increasing number of genes is also producing possible predictive biomarkers for specific cancers and stages of cancer as well. To this end, we have analyzed both breast and ovarian cancers and their normal adjacent tissue using both DNA methylation analysis and genome wide array screening for LOH and copy number variations. The combination of these two methods has yielded several groupings of markers that are cancer specific as well as showing specificity for the specific tumor type. Specifically, there are increased copies in the chr1q21.3 region in both ovarian and breast tumor DNA and differences in the methylation when one compares breast tumor to ovarian tumor DNA's. Interestingly, in ovarian tumor samples where there is no amplification of the region, the hypomethylation is greater than in tumor samples in which there is amplification in the region. This suggests that a greater degree of demethylation is needed to potentially activate this region of the genome, where this may not be necessary in regions where an increase in gene copy number may cause increased expression.
Citation Format: Matthew L. Poulin, Ann Meyer, Jessica Alexander, Jessica Xu, Liying Yan. Methylation, copy number, and LOH analysis of Chr1q21.3 for discovery of ovarian and breast cancer biomarkers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 425. doi:10.1158/1538-7445.AM2014-425
Abstract 4255: Rational targeting of the Androgen receptor interactome in prostate cancer
Authors: Ravindranathan Preethi , Tilley Wayne , Raj Ganesh V. 
Published: May 2015

Abstract
Background: The Androgen receptor (AR) is the central driver of prostate cancer and AR signaling is intact across all stages of disease. The interaction of AR with protein cofactors is critical for its signaling: targeted disruption of these interactions may enable shutdown of AR signaling.
Methods: Using known crystal structure, modeled structure and imputed structure based models, peptide agents were rationally designed to block the interface between AR and critical cofactors in its interactome and tested for physiologic activity using prostate cancer cell lines, xenografts and primary tumor explants.
Results: Knowledge of the protein cofactors, their interacting motifs and structure of the interface are needed for optimal targeting of protein-protein interactions. Using an iterative rational design approach, we have been able to successfully disrupt three classes of the AR interactome:
1. Interactions where the protein cofactor, the motifs and the structure of the interface is known, (targeting AR-PELP1 interface through a helical LxxLL motif)
2. Interactions where the protein cofactor is known but the motifs and the structure of the interface is not known, (targeting AR-FoxA1 interaction) and
3. Interactions where the motif is known, but neither the protein cofactor nor the structure of the interface are known (only known is a critical motif on AR).
The design of initial compounds targeting the interactions in Class 1 was based on crystal structures, while those for Class 2 and Class 3 were based on either predicted or imputed (motif in different context) structures. The interaction between AR and proteins in each of these classes is disrupted by a targeted agent as evidenced by co-immunoprecipitation of endogenous protein cofactors and AR. The functional utility of these agents blocking the AR interactome on AR driven gene expression and proliferation has been validated for agents in Class 1, but is being validated for agents in Classes 2 and 3. In each case, using significant structural modeling, active agents were synthesized with a minimal use of synthesis of analogues.
Conclusions: The rational targeting of the AR interactome is feasible and may be a useful complement to traditional screening campaigns. We have demonstrated the utility of this approach to blocking the interface in three distinct classes of protein-protein interactions. Further validation/optimization of these drugs is needed prior to their clinical implementation.
Citation Format: Preethi Ravindranathan, Wayne Tilley, Ganesh V. Raj. Rational targeting of the Androgen receptor interactome in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4255. doi:10.1158/1538-7445.AM2014-4255
Abstract 4256: Characterization of the cellular inhibitor of apoptosis 1 (cIAP1) IRES trans-acting factors and their contribution to apoptotic resistance in rhabdomyosarcomas
Authors: Faye Mame Daro , Graber Tyson E. , Beug Shawn , Xiang Xiao , Wild Benjamin , Langlois Stephanie , Cowan Kyle N. , Korneluk Robert G. , Holcik Martin 
Published: May 2015

Abstract
The cellular inhibitor of apoptosis protein 1 (cIAP1) is a key regulator of the NFκB signaling pathway and of caspase-8 mediated cell death in mammalian cells. cIAP1 expression is regulated at the translation level via an internal ribosome entry site (IRES). We have previously identified and characterized two IRES trans-acting factors - NF45 and IGF2BP1 - that bind specifically to the cIAP1 IRES and regulates its activity in the context of cell division and apoptosis.
In this study, we characterized the minimal requirement of the cIAP1 IRES for these IRES trans-acting factors as well as other canonical translation factors. We also studied the contribution of cIAP1 expression regulation by these IRES trans-acting factors on the apoptotic resistance of rhabdomyosarcoma cancer cells. In particular, we show that the IRES trans-acting factor IGF2BP1 is overexpressed in a panel of rhabdomyosarcoma primary tumors and cell lines where it drives cIAP1 IRES-mediated translation, contributing to increased resistance to cell death. We also show that targeting cIAP1 by either IGF2BP1 knock-down or IAP antagonists delay RMS tumour growth in the presence of TNFα and improve survival in mice.
Citation Format: Mame Daro Faye, Tyson E. Graber, Shawn Beug, Xiao Xiang, Benjamin Wild, Stephanie Langlois, Kyle N. Cowan, Robert G. Korneluk, Martin Holcik. Characterization of the cellular inhibitor of apoptosis 1 (cIAP1) IRES trans-acting factors and their contribution to apoptotic resistance in rhabdomyosarcomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4256. doi:10.1158/1538-7445.AM2014-4256
Abstract 4270: The use of mutational signatures in identifying carcinogen exposure
Authors: Poon Song Ling , Pang See-Tong , McPherson John R. , Rozen Steven G. , Tan Patrick , Teh Bin Tean 
Published: May 2015

Abstract
Aristolochic acid (AA), a natural product of Aristolochia plants found in herbal remedies and health supplements, is a Group 1 carcinogen that can cause nephrotoxicity and upper urinary tract urothelial cell carcinoma (UCC). Whole genome and exome analysis of 9 AA-associated UCCs revealed a strikingly high somatic mutation rate (150 mutations/Mb), exceeding smoking-associated lung cancer (8 mutations/Mb) and ultraviolet radiation-associated melanoma (111 mutations/Mb). The AA-UCC mutational signature was characterized by A:T to T:A transversions at the sequence motif A[C|T]AGG, located primarily on non-transcribed strands. AA-induced mutations were also significantly enriched at splice sites, suggesting a role for splice site mutations in UCC pathogenesis. RNA sequencing of AA-UCC confirmed a general up-regulation of nonsense-mediated decay machinery components and aberrant splicing events associated with splice site mutations. We observed a high frequency of somatic mutations in chromatin modifiers, particularly KDM6A, in AA-UCC, and demonstrated the sufficiency of AA to induce renal dysplasia in mice and reproduced the AA mutational signature in experimentally treated human renal tubular cells. Finally, exploring other malignancies not previously associated with AA, we screened 93 hepatocellular carcinoma genomes/exomes and identified AA-like mutational signatures in eleven. Our study highlights a unique genome-wide AA mutational signature, and the potential use of mutation signatures as “molecular fingerprints” for interrogating high-throughput cancer genome data, to infer previous carcinogen exposures.
Citation Format: Song Ling Poon, See-Tong Pang, John R. McPherson, Steven G. Rozen, Patrick Tan, Bin Tean Teh. The use of mutational signatures in identifying carcinogen exposure. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4270. doi:10.1158/1538-7445.AM2014-4270
Abstract 4271: The cBioPortal for Cancer Genomics as a clinical decision support tool
Authors: Gao JianJiong , Aksoy B. Arman , Gross Benjamin , Dresdner Gideon , Sun Yichao , Sumer S. Onur , Sander Chris , Schultz Nikolaus 
Published: May 2015

Abstract
As sequencing of tumor samples is entering clinical practice, there is an urgent need for new tools that facilitate the interpretation of sequence data so that they can effectively inform treatment decisions. To this end, we are evolving the cBioPortal for Cancer Genomics into a clinical decision support tool. The cBioPortal is a web-based visualization and analysis engine that makes complex cancer genomics data accessible to a wide range of cancer researchers and clinicians.
To transition the cBioPortal towards use in clinical practice, we have recently developed the following new functions:
1. Filtering of oncogenic mutations: By using information about the known or likely oncogenic effects of specific mutations, the portal can now filter out passenger events and highlight known and potentially druggable drivers.
2. Clinical timelines: Compact and interactive visualization of a patient's clinical and treatment history
3. Image support: Interactive visualization of histology images
4. Support for multiple tumor samples from a single patient: The portal can display genomic differences and similarities of different samples (e.g. multiple sites of the same tumor, recurrence, metastasis, post-treatment) in the context of a patient's treatment history.
5. Tumor clonality: Assessment of a tumor's purity and clonality / heterogeneity
6. Targeted treatment suggestions: The portal matches drugs to drug targets that are altered in the patient's tumor.
7. Clinical trial matching: Based on a patient's clinical history and the genomic alterations found in the tumor, the cBioPortal will identify relevant clinical trials.
By making complex genomic data easily interpretable and linking it to information about drugs and clinical trials, the system has the potential to facilitate the proper use of genomic data in clinical decision making. We are constantly improving the software and will initially focus most strongly on the matching of patients to clinical trials. We are sharing the software with other hospitals, where it can be used by oncologists and tumor boards.
Citation Format: JianJiong Gao, B. Arman Aksoy, Benjamin Gross, Gideon Dresdner, Yichao Sun, S. Onur Sumer, Chris Sander, Nikolaus Schultz. The cBioPortal for Cancer Genomics as a clinical decision support tool. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4271. doi:10.1158/1538-7445.AM2014-4271
Abstract 428: HIC-1: A gene silenced in cancer stem cells of glioma
Authors: Bhagat Mohita , Sinha Subrata , Chattopadhyay Parthaprasad 
Published: May 2015

Abstract
Background : According to the cancer stem cell hypothesis, tumors contain and are driven by a minority cellular population which has retained or re-established key stem-cell properties. Studies have demonstrated frequent hypermethylation of the HIC-1 locus in human cancers and recent work has demonstrated hypermethylation of HIC-1 in ES cells. Targeted methylation of HIC-1 has been shown to transform mesenchymal stem cells into cancer stem/initiating cells. However, so far no study has established the epigenetic role/status of HIC-1 in cancer stem cells.
Methods and Results: U87MG, a glioblastoma cell line, showed a consistent decrease of HIC-1 expression in gliomaspheres obtained in Stem cell media compared to same tumor cells grown in normal media. To examine for the role of HIC-1 in regulating stemness (Sox-2, Oct-4, Nanog), we established a U87 cell line with dominant negative p53 (dn-U87) expressing low HIC-1 levels. Increase in expression of stemness markers was observed in dn-U87 compared to wt-U87.Moreover,effect of hypoxia in increasing stemness was more pronounced in the dn-U87 cell line.
Knockdown of HIC-1 in U87MG grown in normal or stem cell media exhibited an increase in expression of stemness markers (Sox2, Oct4, Nanog and Nestin) under both conditions compared to Mock and control, further confirming role of HIC-1 in modulating stemness expression . Also, gliomaspheres were obtained much earlier (i.e. on Day 4) in HIC-1 knockdown samples grown in stem cell media compared to both Mock and Control (Day7).
To look for the difference in epigenetic signature of HIC-1 gene between gliomaspheres and tumor cells, we checked for changes in methylation and chromatin accessibility in the two cell populations. MNAse assay ascertained heterochromatization of the HIC-1 promoter in gliomaspheres compared to normal U87 cells, while bisulfite sequencing or High Resolution Melt PCR could not detect any change in methylation pattern of the HIC-1 promoter in the two cell populations studied.
Interpretation and Conclusion: Down-regulation of HIC-1, by i) epigenetic changes or ii) knockdown by siRNA or iii) using mutant p53 cell line, may be responsible for contributing to stem cell-like properties to tumor cells. Since HIC-1 is a tumor suppressor gene silenced in many cancers as a result of promoter hypermethylation, it could by itself be a new target for epigenetic therapy. Moreover, increase in stemness on knockdown of HIC-1 could provide new insights into the behavior of cancer-initiating stem cells.
Citation Format: Mohita Bhagat, Subrata Sinha, Parthaprasad Chattopadhyay. HIC-1: A gene silenced in cancer stem cells of glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 428. doi:10.1158/1538-7445.AM2014-428
Abstract 4280: Integrative analyses of multi-omics sequencing data to guide treatment decisions in a patient with double malignancy
Authors: Zhu Wei , Huang Jiaqi , Higgs Brandon W. , Brohawn Philip , Dai Shujun , Richman Laura , Jallal Bahija , Jiang Liyan , Yao Yihong 
Published: May 2015

Abstract
Multiple primary malignancies are becoming common. The number of second or higher-order cancers is burgeoning and accounted for about 16% of incident cancers. Double malignancy cases pose the problem of finding the best treatment for the patient. Next generation sequencing (NGS) was used in this study to characterize the genetic and genomic composition in a patient with multiple cancer syndromes. A lung adenocarcinoma brain metastasis sample (FFPE) naïve to any tumor therapy, and relapsed primary lung adenocarcinoma and ovarian serous carcinoma tumor biopsies (fresh frozen) were procured from a 51-year old Chinese female never-smoker. The primary lung and ovarian cancer samples were post to the treatments with both first line and EGFR-TKI targeted therapy. Multiple NGS approaches were conducted on the patient biopsies, including DNA whole genome/exome sequencing, RNA sequencing, and microRNA sequencing. Integrative analyses of the comprehensive NGS data indicated EGFR exon 19 deletions in-frame, which encode part of the kinase domain presented in both primary lung cancer and its brain metastases. EGFR T790M mutation which accounts for the resistance of lung tumor to the EGFR-TKI therapy was identified in the relapsed lung sample but not in the brain malignancy. These results were well aligned with the clinical response to EGFR-TKI treatment in the patient. Furthermore, we uncovered frequent occurrences of somatic copy number variations in both lung and ovarian tumors. A somatic non-sense mutation (COSMIC ID: 307331) in TP53 was uniquely identified in the ovarian tumor biopsy, suggesting a different mechanism driving tumorigenesis than that in the lung. Besides, we also identified a heterozygous insertion in DUSP16 and a stop code gained mutation in MAP3K15 in the patient's germline DNA, a potential predisposition of multiple cancer syndromes and early onset of tumor in this patient. Finally, structural variation and gene fusion, gene interaction, pathway analysis of the affected genes were integrated and evaluated. Overall, NGS approaches shed insights into the molecular phenotypes of tumors and thus have the potential to provide the physician key scientific rationale to design targeted therapeutic approaches in the treatment course.
Citation Format: Wei Zhu, Jiaqi Huang, Brandon W. Higgs, Philip Brohawn, Shujun Dai, Laura Richman, Bahija Jallal, Liyan Jiang, Yihong Yao. Integrative analyses of multi-omics sequencing data to guide treatment decisions in a patient with double malignancy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4280. doi:10.1158/1538-7445.AM2014-4280
Abstract 4281: Targeted or whole genome sequencing of formalin-fixed tissue samples
Authors: Munchel Sarah , Hoang Yen , Zhao Yue , Cottrell Joseph , Klotzle Brandy , Godwin Andrew , Noel Janelle , Fridley Brooke , Beyerlein Peter , Fan Jian-Bing , Bibikova Marina , Chien Jeremy R. 
Published: May 2015

Abstract
Background: To provide a systematic analysis of formalin fixation artifacts on Illumina sequencing libraries and results, we generated two complementary sequencing libraries (target enrichment sequencing and whole exome sequencing) from 11 pairs of matched formalin-fixed paraffin-embedded (FFPE) and fresh-frozen (FF) tumor samples and two pairs of matched FFPE and FF germline samples. We also generated whole genome sequencing data from a single pair of FF/FFPE tumor samples.
Results: The results indicate minimal variations in library fragment size, coverage, and PCR duplicates within FF/FFPE paired samples that are less than 1 year old; whereas, a large variation in these parameters were observed in FF/FFPE pairs in samples that are approximately 2 years old. No significant increase in global mismatch rates and C•G&gt;T•A substitutions were observed in FFPE samples from the former group; whereas, a discernible increase in mismatch rates and C•G&gt;T•A substitutions were observed in FFPE samples from the latter group. However, over 99.7% and 99.5% of concordant calls were observed between matched FF and FFPE pairs at reference and non-reference positions within the targeted regions, respectively. Although an increased rate of global mismatches and C•G&gt;T•A substitutions were observed in some FFPE samples, discordant rates were low (&lt;0.26) in all samples because most of the FFPE artifacts were filtered out using GATK workflow. Consistent with this analysis, C•G&gt;T•A substitutions are comparable in non-reference positions in paired FF and FFPE samples.
Conclusions: We developed upfront quality assessment and library preparation method that use low input DNA from FFPE samples to perform next-generation sequencing. The results from our studies indicate the suitability of FFPE samples in sequencing studies.
Citation Format: Sarah Munchel, Yen Hoang, Yue Zhao, Joseph Cottrell, Brandy Klotzle, Andrew Godwin, Janelle Noel, Brooke Fridley, Peter Beyerlein, Jian-Bing Fan, Marina Bibikova, Jeremy R. Chien. Targeted or whole genome sequencing of formalin-fixed tissue samples. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4281. doi:10.1158/1538-7445.AM2014-4281
Abstract 4282: High content multiparametric functional screen for regulators of epithelial-mesenchymal transition identifies genes associated with chemoresistance
Authors: Williams Elizabeth D. , Said Nur Akmarina , Gould Cathryn M. , Thompson Erik W. , Simpson Kaylene J. 
Published: May 2015

Abstract
Metastasis accounts for the majority of treatment-refractory cancers and poor prognosis of the disease. The phenotypic transition of non-motile epithelial tumor cells to migratory and invasive ‘mesenchymal’ cells enables the escape of cancer cells from the primary tumor into the circulation. Morphological changes from cobblestone epithelial cells to elongated and spindle-shaped cells is a key feature of this process. This transition is also marked by upregulation of vimentin, an intermediate filament found in mesenchymal cells. We have previously developed a bladder cancer model with a step-wise enhancement in the metastatic cascade that we have used to interrogate the role of tumor cell plasticity in metastasis (1). Given the need to elucidate pathways and assign functions to particular genes involved in this process, we conducted a high content screening assay across genome wide siRNA, miRNA and kinase inhibitor (131 compounds) libraries to systematically identify modulators of EMT/MET. We identified candidate gene regulators of EMT in TSU-Pr1-B1 bladder cancer cells using the readouts of morphological change (cells stained with CMFDA) and a vimentin promoter activity (dsRed reporter construct). Following integration of the predicted target genes for miRNA hits and kinase inhibitors with siRNA hits, initial validation using a siRNA deconvolution strategy was performed for 400 targets. 221 siRNAs were classified as inducing statistically significant effects on cell shape and/or vimentin promoter reporter activity (defined as at least 2/4 duplexes inducing the effect for a given target). Gene ontology and pathway analyses feature cell cycle and various developmental pathways. Furthermore, the validated gene list was associated with bladder cancer histology and drug sensitivity in clinical specimens in multiple cancer types (Oncomine). Molecules identified in this assay will be further analysed using functional assays to determine their role in maintaining the epithelial phenotype and as regulators of chemoresistance.
(1) Chaffer et al. (2005) Clin Exp Metastasis 22: 115-25.
Citation Format: Elizabeth D. Williams, Nur Akmarina Said, Cathryn M. Gould, Erik W. Thompson, Kaylene J. Simpson. High content multiparametric functional screen for regulators of epithelial-mesenchymal transition identifies genes associated with chemoresistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4282. doi:10.1158/1538-7445.AM2014-4282