bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5365: Prospective patient stratification into robust cancer-cell intrinsic subtypes from colorectal cancer biopsies
Authors: Alderdice Matthew , Richman Susan D. , Gollins Simon , Stewart Peter , Hurt Chris , Adams Richard , McCorry Amy M. , Roddy Aideen , Vimalachandran Dale , Isella Claudio , Medico Enzo , Maughan Tim , McArt Darrgh G. , Lawler Mark , Dunne Philip D. 
Published: August 2018

Abstract
Colorectal cancer (CRC) biopsies underpin accurate diagnosis, but are also relevant for patient stratification in molecularly-guided clinical trials. The consensus molecular subtypes (CMS) and colorectal cancer intrinsic subtypes (CRIS) transcriptional signatures have potential clinical utility for improving prognostic/predictive patient assignment. However, their ability to provide robust classification, in pre-treatment biopsies from multiple regions or at different time points remains untested.
In this study, we undertook a comprehensive assessment of the robustness of CRC transcriptional signatures, including CRIS and CMS, using a range of tumour sampling methodologies currently employed in clinical and translational research. These include analyses using (i) laser-capture microdissected CRC tissue, (ii) eight publically available rectal cancer biopsy data sets (n=543), (iii) serial biopsies (from AXEBeam trial, NCT00828672; n=10), (iv) multi-regional biopsies from colon tumours (n=29 biopsies, n=7 tumours) and (v) pre-treatment biopsies from the phase II rectal cancer trial COPERNCIUS (NCT01263171; n=44). Compared to previous results obtained using CRC resection material, we now demonstrate that CMS classification in biopsy tissue is significantly less capable of reliably classifying patient subtype (43% unknown in biopsy versus 13% unknown in resections, p=0.0001). In contrast, there was no significant difference in classification rate between biopsies and resections when using the CRIS classifier. Additionally, we demonstrated that CRIS provides significantly better spatially- and temporally- robust classification of molecular subtypes in CRC primary tumour tissue compared to CMS (p= 0.003 and p=0.02, respectively).
These findings may have potential to inform ongoing biopsy-based patient stratification in CRC, enabling robust and stable assignment of patients into clinically-informative arms of prospective multi-arm, multi-stage clinical trials.
Citation Format: Matthew Alderdice, Susan D. Richman, Simon Gollins, Peter Stewart, Chris Hurt, Richard Adams, Amy M. McCorry, Aideen Roddy, Dale Vimalachandran, Claudio Isella, Enzo Medico, Tim Maughan, Darrgh G. McArt, Mark Lawler, Philip D. Dunne. Prospective patient stratification into robust cancer-cell intrinsic subtypes from colorectal cancer biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5365.
Abstract 5367: Elucidating the factors determining P53 binding and transcriptomic response to DNA damage
Authors: Sundaresan Varsha , Li Ying , DiCiaccio Benedetto , Lin Victor T. , Higaki Adrian A. Acuna , Pelletier Nicole F. , Cheung Jessica T. , Zhou Lei 
Published: August 2018

Abstract
Mutations in tp53 are thought to be one of the most common mechanisms by which cancer cells evade tumor suppression. Yet the exact mechanism of tumor suppression by P53 remains to be fully understood. The transcription factor P53 is activated in response to oncogenic stresses and exerts distinct anti-proliferative functions based on the stressor and cell type. Although numerous mammalian ChIP-Seq studies have identified thousands of P53 binding sites, the functionality of these binding sites remains to be established.
To study how P53 binding following DNA damage differs between cell types, we performed comparisons between P53 ChIP-Seq data from Drosophila embryos at different developmental stages and a Drosophila cell line (Kc167). Differential expression analysis using RNA-Seq indicated that at an early stem cell-like developmental stage of Drosophila embryos there is P53-dependent induction of pro-apoptotic genes in response to irradiation but not in the later differentiated stages. We aim to establish functionally significant P53 binding sites by combining ChIP-Seq and RNA-Seq data from Drosophila embryos as well as Kc167. The functional significance of these binding sites will be identified by CRISPR-Cas9–mediated genome editing. Preliminary genome-wide motif analysis studies also exhibited that homotypic clustering of P53 consensus motifs is associated with P53 binding. We will also perform comparison studies of DNA damage-induced P53 binding in humans, mice and flies to identify analogous patterns.
Preliminary studies revealed that a majority of the P53 binding sites are located at the repetitive regions of the Drosophila genome, especially the Long terminal repeats (LTRs) and Long interspersed nuclear elements (LINEs) as seen previously in mammals by other groups including Botcheva et al and Chang et al. P53 has been known to regulate the expression of retrotransposons and maintain genetic stability by keeping the number of repeats in control. We further aim to see if the functions carried out by P53 differ between repetitive vs. non-repetitive binding regions in Drosophila.
This comparative genomics study will help identify the functionally significant P53 binding sites thus further our understanding of tumor suppression by P53. The knowledge obtained from this study will also be valuable in devising novel strategies to restore P53 function in cancers.
Citation Format: Varsha Sundaresan, Ying Li, Benedetto DiCiaccio, Victor T. Lin, Adrian A. Acuna Higaki, Nicole F. Pelletier, Jessica T. Cheung, Lei Zhou. Elucidating the factors determining P53 binding and transcriptomic response to DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5367.
Abstract 5374: Uterine sarcomas: A preliminary study for characterization of a specific molecular signature for Brazilian patients
Authors: Costa Leonardo T. , Torrezan Giovana T. , Paula Claudia A. , Neto Glauco B. , Baracat Edmund C. , Carraro Dirce M. , Carvalho Kátia C. 
Published: August 2018

Abstract
Background: Uterine sarcomas are the most common gynecological sarcomas, comprising around 90% of all of the cases. These tumors can arise either from the endometrial stroma or from the muscle itself. They are genetically heterogeneous tumors and have no specific molecular and radiological diagnosis, or treatment.
Histologically, uterine sarcomas are classified according to their cell of origin and are divided into: carcinosarcomas (CCS), leiomyosarcomas (LMS), endometrial stromal sarcoma (ESS) and adenosarcomas (ADS). There are many factors that can be attributed to uterine sarcomas etiopathogeny such as ethnic, hormonal and hereditary factors. However, few studies were performed searching for specific molecular signature in these tumors, especially concerning a singular population. Objective: To assess the oncogenic profile of Brazilian patients with different histological types of uterine sarcomas. Methods: Until now, we performed the Next Generation Sequencing for 13 samples of uterine sarcomas (comprising: 5 CCS, 3 LMS, 4 SEE and 1 ADS) using the Ion Proton System (ThermoFisher) with the Comprehensive Cancer Panel (containing 409 genes related to carcinogenesis). Results: The genetic sequencing profile analysis showed 140 specific mutations in our samples. Among them, the most common were TP53 (58%), JAK3 (33%), NF1 (33%), KMT2D (33%), MTOR (25%) and PIK3CA (25%). Some findings corroborate the literature on uterine sarcomas, with an exception of the KMT2D gene, that despite of being known and described in other tumors, including the ones of the genital tract, such as vulva, ovary and endometrium, has never been described in uterine sarcomas Conclusion: We found the most frequent mutations in 6 genes in our samples. Only one mutation had not been described before for uterine sarcomas (KMT2D). These are preliminary results, and further analyzes are ongoing.Key words: Uterine Sarcomas, Carcinosarcomas, Next Generation Sequencing
Citation Format: Leonardo T. Costa, Giovana T. Torrezan, Claudia A. Paula, Glauco B. Neto, Edmund C. Baracat, Dirce M. Carraro, Kátia C. Carvalho. Uterine sarcomas: A preliminary study for characterization of a specific molecular signature for Brazilian patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5374.
Abstract 538: ASPM promotes prostate cancer tumorigenesis by bolstering cancer stemness through Wnt-Dvl-3-b-catenin signaling
Authors: Tsai Kelvin K. , Pai Vincent C. , Hsu Chung-Chi , Chan Tze-Sian 
Published: August 2018

Abstract
Metastasis is the major cause of cancer mortality in androgen-independent prostate cancer (PCA) and understanding it is crucial to improving the outcome of patients. Recent evidence suggests that activation of Wnt signaling in cancer stem cells (CSCs) contributes to cancer progression in malignant tumors. Here we report that a novel Wnt activator ASPM (Abnormal spindle-like microcephaly associated) maintains the prostate CSC subpopulation through augmenting the Wnt-β-catenin signaling in PCA. Functional studies showed that downregulation of ASPM expression attenuated the proliferation and invasive of PCA cells and reduced the number of prostate CSCs and inhibited cancer stemness and tumorigenesis. Mechanistically, ASPM interacts with dishevelled-3 (Dvl-3) and inhibits its proteasome-dependent degradation, thereby increasing the protein stability of Dvl-3 and enabling the β-catenin transcriptional activity in PCA cells. The clinical significance of the above findings was credentialed by the profound up-regulation of ASPM in metastatic PCA and the strong correlation of cytoplasmic ASPM expression with poor metastasis-free survival of patients with resected PCA. Collectively, our data points to ASPM as a novel oncoprotein and an essential regulator of cancer stemness in PCA, which has important clinical and therapeutic significance (supported by Ministry of Science and Technology grants MOST 104-2314-B-400-022 and MOST 105-2314-B-400-018 and National Health Research Institutes NHRIs grant CA-106-PP-09 to K.K.T).
Citation Format: Kelvin K. Tsai, Vincent C. Pai, Chung-Chi Hsu, Tze-Sian Chan. ASPM promotes prostate cancer tumorigenesis by bolstering cancer stemness through Wnt-Dvl-3-b-catenin signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 538.
Abstract 5405: Multiplex profiling of miRNA biomarkers for discovery and verification using the FirePlex® platform
Authors: Atabakhsh Elnaz , Kelley Ivona , Tackett Michael , Diwan Izzuddin , Tejada Gensis , Rafferty Conor , Pregibon Daniel 
Published: August 2018

Abstract
To address the needs for microRNA (miRNA) biomarker discovery and verification, we developed the FirePlex® miRNA assay. This assay enables the detection of 5-400 miRNA targets per sample in 96-well format, with readout on standard flow cytometers and analysis with an included bioinformatics software package. The FirePlex miRNA assay combines particle-based multiplexing, using patented FirePlex® hydrogel particles, with single step RT-PCR signal amplification using universal primers. Thus, the FirePlex miRNA assay leverages PCR sensitivity while eliminating the need for separate reverse transcription reactions and mitigating amplification biases introduced by target-specific qPCR. The miRNA assay can reliably detect as few as 1000 miRNA copies per sample with a linear dynamic range of ~5 logs, and without the need of prior RNA purification, making the assay ideally suited for profiling in serum, plasma, exosomes, urine, and directly from FFPE tissues. Furthermore, the ability to multiplex targets in each well eliminates the need to split valuable samples into multiple reactions. Results from the FirePlex miRNA assay are displayed and interpreted using the integrated FirePlex Analysis Workbench, which allows visualization, normalization, and export of experimental data with only a few mouse clicks. To aid biomarker discovery studies, we offer pre-designed panels of 400 miRNAs based on a research-curated list of miRNAs published to be found in circulating biofluids. For studies focused on specific research areas of interest, we offer pre-designed focus panels for Oncology, Cardiology, Neurology, Immunology, and Organ Toxicity. These carefully curated panels include hemolysis markers to assess sample quality, as well as critical normalization factors. Here we present the data from several studies investigating circulating miRNA profiles, as well as miRNA profiles obtained directly from FFPE tissues, using the FirePlex miRNA Assay Panels. Together, this novel combination of bioinformatics tools and multiplexed, high-sensitivity assays enables rapid discovery and verification of miRNA biomarker signatures from biofluid samples.
Citation Format: Elnaz Atabakhsh, Ivona Kelley, Michael Tackett, Izzuddin Diwan, Gensis Tejada, Conor Rafferty, Daniel Pregibon. Multiplex profiling of miRNA biomarkers for discovery and verification using the FirePlex® platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5405.
Abstract 5411: Micro-RNA expression in cemento-ossifying fibroma
Authors: Pereira Thais S. , Guimarães André Luiz S. , Gomes Carolina C. , Gomez Ricardo S. , Diniz Marina G. 
Published: August 2018

Abstract
Cemento-ossifying fibroma (COF) is a benign fibro-osseous neoplasm of uncertain pathogenesis and its treatment is associated with significant morbidity. MicroRNAs (miRNA) are small non-coding RNAs that regulate gene expression and may represent therapeutic targets. The purpose of the study was to generate a comprehensive miRNA profile of COF compared to normal bone. Additionally, the most relevant pathways and target genes of differentially expressed miRNA were investigated by in silico analysis. Nine COF and ten normal bone samples were included in the study. miRNA profiling was carried out by using TaqMan® OpenArray® Human MicroRNA panel containing 754 validated human miRNAs. We identified the most relevant miRNAs target genes through the leader gene approach, using STRING and Cytoscape software. Pathways enrichment analysis was performed using DIANA-miRPath. Eleven miRNAs were downregulated (hsa-miR-95-3p, hsa-miR-141-3p, hsa-miR-205-5p, hsa-miR-223-3p, hsa-miR-31-5p, hsa-miR-944, hsa-miR-200b-3p, hsa-miR-135b-5p, hsa-miR-31-3p, hsa-miR-223-5p, hsa-miR-200c-3p) and five were upregulated (hsa-miR-181a-5p, hsa-miR-181c-5p, hsa-miR-149-5p, hsa-miR-138-5p, hsa-miR-199a-3p) in COF compared to normal bone. Eighteen common target genes were predicted, and the leader genes approach identified the following genes involved in human COF: EZH2, XIAP, MET and TGFBR1. According to the biology of bone and COF, the most relevant Kegg-pathways revealed by enrichment analysis were Proteoglycans in cancer, miRNAs in cancer, Pathways in cancer, p53, PI3K-Akt, FoxO, and TGF-beta signalling pathways, which were previously found to be differentially regulated in bone neoplasms, odontogenic tumours and osteogenesis. Dysregulation of miRNAs occurs in COF and EZH2, XIAP, MET and TGFBR1 are potential targets for functional analysis validation. Supported by: CNPq, CAPES and FAPEMIG (Brazil).
Citation Format: Thais S. Pereira, André Luiz S. Guimarães, Carolina C. Gomes, Ricardo S. Gomez, Marina G. Diniz. Micro-RNA expression in cemento-ossifying fibroma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5411.
Abstract 5416: Isolation of the PAX8 transcriptional complex to identify novel therapeutic vulnerabilities for ovarian cancer
Authors: Chaves-Moreira Daniele , Mitchell Marilyn , Sidoli Simone , Garcia Benjamin , Drapkin Ronny 
Published: August 2018

Abstract
A central problem in the treatment of ovarian cancer remains the heterogeneity among ovarian tumors. DNA and RNA sequencing studies have demonstrated both intertumoral and intratumoral genetic variation. Despite efforts to elucidate common signaling pathways among various ovarian cancer subtypes, few have led to meaningful patient stratification or to truly individualized targeted molecular therapies. Our proposed set of experiments is a radical departure from the conventional approach to treating ovarian cancer. PAX8, a transcription factor that identifies nearly all high-grade serous ovarian cancers (HGSOCs), is also the master regulator of fallopian tube development. Building off observations pointing to the fallopian tube epithelium as a major site of origin for HGSOCs, we propose targeting the fallopian tube developmental program as the basis for new therapies. This possibility is supported by the observation that knockdown of PAX8 leads to apoptosis in ovarian cancer cells. We hypothesize that blocking the ability of PAX8 to influence its gene targets, either by interrupting PAX8 protein-protein interactions or by inhibiting the products of PAX8-driven signaling, has the potential to eliminate the primary growth stimulus for high-grade serous tumors. In order to achieve that goal, we have identified candidate PAX8-interacting partners using gel filtration chromatography and tandem-affinity immunopurification coupled with mass spectrometry analyses. Interactions have been validated by Western blot, immunofluorescence, and proximity ligation assay. We used ovarian cancer (KURAMOCHI, OVSAHO and OVCAR4) and fallopian tube (FT189, FT194 and FT246) cell lines to determine whether PAX8 protein partners changed between benign and malignant cells. Our preliminary results suggest that PAX8 interacts with other transcription factors such as TEAD4 and components of chromatin-remodeling complexes (RUVBL1, RUVBL2 and CHD4). Many of these factors are known to mediate the effects of oncogenes such as YAP, β-catenin and c-Myc. Further studies will be done in order to decipher the functional contribution of each candidate PAX8-interacting protein. Our ultimate goal is to determine how PAX8 regulates expression of its target genes and how PAX8-interacting proteins influence that function. Inhibition of certain protein-protein interactions may provide novel avenues to abrogate PAX8 function in ovarian cancer cells.
Citation Format: Daniele Chaves-Moreira, Marilyn Mitchell, Simone Sidoli, Benjamin Garcia, Ronny Drapkin. Isolation of the PAX8 transcriptional complex to identify novel therapeutic vulnerabilities for ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5416.
Abstract 5418: GATA3 zinc-finger mutation induces transcriptional reprogramming in breast cancer through gain and loss of function
Authors: Takaku Motoki , Grimm Sara A. , Roberts John D. , Chrysovergis Kaliopi , Myers Page , Perou Charles M. , Wade Paul A. 
Published: August 2018

Abstract
Recent large-scale breast cancer genomic profiling identified frequent mutations in a pioneer transcription factor, GATA3. The expression of GATA3 is a prominent marker of luminal breast tumors, and loss of GATA3 expression is associated with aggressive tumor phenotypes. In addition, GATA3 mutations are frequently found in these luminal tumors. However, the clinical and molecular outcomes of GATA3 mutations are poorly understood. Our novel classification scheme of GATA3 mutations defines distinct clinical features of breast tumors with mutations in the second GATA3 zinc-finger (ZnFn2): frequent observation in luminal B subtype and worse prognosis than other GATA3 mutant cases. To dissect the molecular impacts of these ZnFn2 mutations, we generated a GATA3 mutant breast cancer cell clone by CRISPR-Cas9 gene editing. An engineered ZnFn2 mutant cell line manifested increased tumor growth as xenografts and more aggressive phenotypes in vitro. The ZnFn2 mutation led to loss of GATA3 binding and decreased expression at a subset of genes, including progesterone receptor (PR). The mutant cells also exhibited gain of GATA3 binding at other loci, correlated with increased expression of mesenchymal marker genes. Decreased expression of PR and impaired response to progesterone were crucial for cancer-promoting functions in GATA3 ZnFn2 mutant cells. Downregulation of PR and its downstream genes was also observed in the clinical gene expression data. These results illuminate tumor-promoting functions of GATA3 ZnFn2 mutations in breast cancer.
Citation Format: Motoki Takaku, Sara A. Grimm, John D. Roberts, Kaliopi Chrysovergis, Page Myers, Charles M. Perou, Paul A. Wade. GATA3 zinc-finger mutation induces transcriptional reprogramming in breast cancer through gain and loss of function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5418.