bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 236: Identification of novel cancer target genes by combining data from the cancer genome-wide association studies (GWAS), regulatory DNA elements and The Cancer Genome Atlas (TCGA)
Authors: Kulkarni Diptee A. , Guo Karl , Jing Junping , Khaladkar Mugdha , Song Kijoung , Dong Coco , Cooper David , Schwartz Benjamin 
Published: August 2018

Abstract
Unlike tumors that develop because of somatic genetic alterations such as frequent coding mutations or chromosomal deletions, amplifications or translocations, some tumors are addicted to expression of certain genes for their sustained proliferation and survival - for example, LIM domain only 1 (LMO1) expression in neuroblastoma (NB). Numerous genome-wide association studies (GWAS) have identified significant associations between germline single-nucleotide polymorphisms (SNPs), many in the non-coding genome, and cancer. A robust genome-wide association has been reported previously between an intronic LMO1 SNP and NB susceptibility. By further sequencing and epigenetic fine mapping of the SNP locus, it was demonstrated that the causal SNP is part of a transcription factor binding site within an enhancer element, regulates expression of LMO1 and in turn increases the tumorigenic potential. To identify additional examples of regulatory SNPs as cancer drivers, we overlaid published genome-wide significant cancer associations with active chromatin marks from Encyclopedia of DNA Elements and searched for SNPs that resided within gene regulatory elements. To map these SNPs to candidate genes and determine direction of effect, we co-localized GWAS signals with expression quantitative trait (eQTL) signals from the Genotype-Tissue Expression (GTEx) Consortium database. Lastly, we checked for gene amplification and/or overexpression of the mapped genes in the Cancer Genome Atlas (TCGA) data to identify a set of target genes that not only exhibit significant cancer association in GWAS, but also have evidence for epigenetic regulation and propensity for amplification and/or overexpression in tumors. We identified more than 25 novel cancer-target pairs with strong germline, regulatory and somatic evidence. A look up through synthetic lethality screen data available in-house suggested that several of these targets are self-lethal, further underscoring their importance for cancer cell proliferation and survival. Additional in vitro experiments are being planned to further validate the targets.
Citation Format: Diptee A. Kulkarni, Karl Guo, Junping Jing, Mugdha Khaladkar, Kijoung Song, Coco Dong, David Cooper, Benjamin Schwartz. Identification of novel cancer target genes by combining data from the cancer genome-wide association studies (GWAS), regulatory DNA elements and The Cancer Genome Atlas (TCGA) [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 236.
Abstract 2360: Deregulated APA and cancer specific APA isoforms
Authors: Begik Oguzhan , Ercan Melda , Cingoz Harun , Can Tolga , Oyken Merve , Erson-Bensan Ayse Elif 
Published: August 2018

Abstract
Certain aspects of diagnosis, prognosis, and treatment of cancer patients are still important challenges to be addressed. We developed a pipeline to uncover patterns of alternative polyadenylation (APA), a hidden complexity in cancer transcriptomes, to further accelerate efforts to discover novel cancer genes and pathways. Here, we found a significant shift in usage of poly(A) signals in six common tumor types compared to normal tissues. We further defined specific subsets of APA events to efficiently classify cancer types/subtypes. Triple negative breast cancers, for example, have specific 3'UTR length alterations where the significant majority are shortening events (70%, 113 of 165) of mostly proliferation-related transcripts compared with normal breast tissue. Such shortening events correlate with increased protein levels and relapse free survival of patients, suggesting functional significance of isoform variability. In line with this isoform diversity, we also detected deregulated expression of mRNA polyadenylation complex proteins in breast cancer cells. Of note, APA proteins are responsive to proliferative signals including estrogen and epidermal growth factor, suggesting a potential explanation to 3'-end isoform diversity in cancer cells. Overall, our study offers a computational and experimental approach for use of APA in novel gene discovery and classification in common tumor types, with important implications in basic research, biomarker discovery, and precision medicine approaches.
Citation Format: Oguzhan Begik, Melda Ercan, Harun Cingoz, Tolga Can, Merve Oyken, Ayse Elif Erson-Bensan. Deregulated APA and cancer specific APA isoforms [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 2360.
Abstract 2361: Big data analysis allows the identification of long non-coding RNAs with therapeutic potential against hepatocellular carcinoma
Authors: Unfried Juan P. , Serrano Guillermo , Suárez Beatriz , Ferretti Valeria , Sangro Paloma , Prior Celia , Boix Loreto , Bruix Jordi , Sangro Bruno , Segura Victor , Fortes Puri 
Published: August 2018

Abstract
Hepatocellular carcinoma (HCC) is a disease associated with high morbidity and mortality for which there is currently no curative treatment and therapeutic targeting remains ineffective. To search for new therapeutic targets, we have evaluated the coding and non-coding transcriptome of all RNA-Seq data from TCGA, comprising over 10000 patients and 34 different tumors with HCC among them. To this, we have added the transcriptomes of additional 10000 samples from 53 human tissues from the GTEx project. Using neural networks and bioinformatics analyses we have identified coding and non-coding genes with preferential and differential expression and obtained a more precise location of HCC in the human transcriptional landscape. The analyses of tumor-deregulated gene expression indicated that coding genes have a high tumor promiscuity. Non-coding genes, on the contrary, showed higher tissue specificity and their expression was altered in a more tumor-specific manner, predictive of a therapeutic target with fewer secondary effects. We have identified 7321 long non-coding RNAs (lncRNAs) deregulated in at least one tumor type. In HCC, we found 1128 deregulated lncRNAs of which 138 were specific of HCC. Bioinformatic functional predictions indicated a positive relationship of deregulated lncRNAs with cell proliferation and motility while immune response was negatively associated. Ten lncRNAs with oncogenic potential were selected and their expression was validated in two independent cohorts of HCC patients. Most tumor samples showed high expression levels of these lncRNAs when compared to their paired peritumoral sample. Furthermore, several candidates were found to be expressed at very low levels in healthy liver. When expression of 2 of them was inhibited with antisense drugs in HCC cells, a drastic stall in proliferation was observed. Proliferation was recovered after restoring lncRNA expression. We think these candidates may play a key role in the proliferation and motility of cancer cells and show great potential as therapeutic targets. Our studies suggest that big data analyses can give a much-needed boost to HCC target search and to personalized medicine against cancer and other diseases.
Citation Format: Juan P. Unfried, Guillermo Serrano, Beatriz Suárez, Valeria Ferretti, Paloma Sangro, Celia Prior, Loreto Boix, Jordi Bruix, Bruno Sangro, Victor Segura, Puri Fortes. Big data analysis allows the identification of long non-coding RNAs with therapeutic potential against hepatocellular carcinoma [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 2361.
Abstract 2365: A chemical genetics approach identifies PTP4A3 as a regulator of colon cancer cell adhesion
Authors: McQueeney Kelley E. , Salamoun Joseph M. , Ahn Jennifer , Pekic Paula , Blanco Isabella K. , Struckman Heather , Sharlow Elizabeth R. , Wipf Peter , Lazo John S. 
Published: August 2018

Abstract
Dysregulation of the tightly controlled protein phosphorylation networks that govern cellular behavior causes cancer. The membrane-associated, intracellular protein tyrosine phosphatase PTP4A3 is overexpressed in human colorectal cancer and contributes to cell migration and invasion. To interrogate further the role of PTP4A3 in colorectal cancer cell migration and invasion, we deleted the Ptp4a3 gene from murine colorectal tumor cells. The resulting PTP4A3-/- cells exhibited impaired colony formation, spheroid formation, migration, and adherence compared to the isogenic PTP4A3fl/fl cells. We replicated these phenotypic changes using the new small molecule allosteric PTP4A3 inhibitor, JMS-053. A related structure, JMS-038, which lacked phosphatase inhibition, displayed no cellular activity. Reduction in cell viability and colony formation by JMS-053 occurred in both mouse and human colorectal cell lines and required PTP4A3 expression. Ptp4a3 deletion increased the expression of extracellular matrix and adhesion genes, including the tumor suppressor Emilin 1. JMS-053 also increased Emilin 1 gene expression. Moreover, the human TCGA genomic database revealed colorectal tumors with high Ptp4a3 expression had low Emilin1 expression. These chemical and biological reagents reveal a previously unknown communication between the intracellular PTP4A3 phosphatase and the extracellular matrix and support efforts to pharmacologically target PTP4A3.
Citation Format: Kelley E. McQueeney, Joseph M. Salamoun, Jennifer Ahn, Paula Pekic, Isabella K. Blanco, Heather Struckman, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo. A chemical genetics approach identifies PTP4A3 as a regulator of colon cancer cell adhesion [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 2365.
Abstract 2382: In silico/in vitro studies of novel hot spot mutations in BCR-ABL1: A multidisciplinary approach to shed a new light on TKI resistance
Authors: Laurini Erik , Aulic Suzana , Skoko Natasa , Polez Sulena , Baralle Marco , Romano Maurizio , Pricl Sabrina 
Published: August 2018

Abstract
Acquisition of mutations in the BCR-ABL1 kinase domain (KD) is frequently associated with tyrosine kinase inhibitor (TKI) failure in CML. Recently, we revealed a novel mutation “hot- spot” in the BCR-ABL1 KD region (residues 295 - 312), associated with high resistance and poor clinical outcomes [1]. Some of these new BCR-ABL1 variants locate in a protein region, which might not be directly involved in TKI interaction. Therefore, we hypothesized that some of these mutations might be linked to TKI resistance via a direct mechanism while others might exert an indirect effect on drug resistance. The present contribution integrates molecular, computational, and structural biology techniques to understand the eventual role of the newly reported hot-spot mutations of the BCR-ABL1 KD in TKI resistance observed in CML patients using a "two-tier level" investigation: isolated KDs and SH2-linker-SH3-KD BCR- ABL1 constructs. Molecular Modeling will assess in silico whether the clinically observed “hot-spot” BCR-ABL1 mutations might be directly related to a change in the thermodynamic stability and/or protein structure and how these modifications could be involved in the BCR-ABL1 binding profile to specific TKIs (e.g., imatinib, dasatinib, and ponatinib) compared with wild-type (WT) systems and “prototypical” BCR-ABL1 mutations (e.g. T315I). In parallel, in vitro analysis will evaluate the effects exerted by the selected mutations on the intrinsic activity of the kinase and to determine the inhibition activity of the selected drugs on these BCR-ABL1 variants. Specifically, direct drug binding to both KD and SSK constructs will be measured using isothermal titration calorimetry and in vitro kinase assays will monitor the ability of these mutant isoforms to auto-phosphorylate and to phosphorylate a substrate peptide. Finally, structural biology (e.g., SAXS and far-UV CD) evidences of WT and mutant isolated KDs and SH2-linker-SH3-KD (SSK) constructs (per se and in complex with TKIs) will be discussed to support in silico predictions. [1] Gibbons DL, Pricl S et al., Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy. Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3550-5. doi: 10.1073/pnas.1321173111.
Citation Format: Erik Laurini, Suzana Aulic, Natasa Skoko, Sulena Polez, Marco Baralle, Maurizio Romano, Sabrina Pricl. In silico/in vitro studies of novel hot spot mutations in BCR-ABL1: A multidisciplinary approach to shed a new light on TKI resistance [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 2382.
Abstract 2388: IC50 profiling against 320 protein kinases: Improving the accuracy of kinase inhibitor selectivity testing
Authors: Mueller Daniel , Totzke Frank , Weber Thomas , Pathe Marcel , Schaechtele Christoph , Kubbutat Michael H. 
Published: August 2018

Abstract
Protein kinases belong to one of the largest families of evolutionary related proteins. More than 500 distinct kinases are encoded by approximately 2% of all human genes. Over the past decades, numerous protein kinases have been described of which deregulation contributes to many human diseases. Today, more than 30 protein kinase inhibitors have been approved for the treatment of cancer emphasizing the significance of kinases as one of the most versatile drug targets.
Due to the structural similarity especially within the ATP-binding site, many kinase inhibitors show limited selectivity. Still, sufficient selectivity within the human kinases is of critical importance e.g. to reduce the risk of adverse side effects during treatment.
Therefore, measuring and improving selectivity of a compound within the kinome is of pivotal importance during drug discovery and optimization phase in the development of therapeutically relevant kinase inhibitors.
Broad profiling of kinase inhibitors in biochemical activity assays of several hundred kinases is nowadays well established. Commonly, kinase profiling is done using one or two concentrations of a test compound and measurement of the relative inhibition of the kinase activity compared to a high and low control.
However, due to the limited dynamic range of this approach, and the challenge to select the most appropriate compound concentration, this profiling approach gives often limited information with respect to the differences in the potency of compounds against On-target- and Off-target kinases.
We set up an IC50 kinase profiling approach that consists of measuring the effect of a compound on the activity of 320 human protein kinases at six different concentrations. We will present data showing the effect of compound concentration on the selectivity score in traditional profiling setting. IC50 kinase profiles of different approved and clinical stage kinase inhibitors will be presented demonstrating that an IC50 based profiling allows the accurate determination of selectivity of a compound based on the comparison of the IC50 values against the On-target- in relation to the IC50 values of the Off-target kinases providing significantly improved guidance in the further optimization of the test compound.
Citation Format: Daniel Mueller, Frank Totzke, Thomas Weber, Marcel Pathe, Christoph Schaechtele, Michael H. Kubbutat. IC50 profiling against 320 protein kinases: Improving the accuracy of kinase inhibitor selectivity testing [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 2388.
Abstract 239: Development of DNA chip for detection of predictive SNPs for gemcitabine-induced adverse events
Authors: Nakamura Noriaki , Hirayama Koichi , Yamano Hirofumi , Okamura Hiroshi , Zembutsu Hitoshi 
Published: August 2018

Abstract
[Introduction] Anticancer agent gemcitabine is one of the effective chemotherapies and has been widely used for the treatment of patients with various tumors. However, 13-35% of patients receiving gemcitabine experience severe leukopenia/neutropenia. In our previous studies, we identified four novel SNPs (rs11141915, rs1901440, rs11719165 and rs12046844) associated with this toxicity. To predict the risk of gemcitabine-induced myelosuppression, we developed a high accuracy DNA chip system for genotyping of these four SNPs.
[Methods] We used 17 and 170 germline DNA samples of patients who received gemcitabine therapy in the first stage and second stage respectively. For SNP genotyping using the DNA chip, we amplified target regions by PCR with 10 ng of DNA extracted from blood samples. The PCR product was hybridized with the probe on the DNA chip. Genotype was detected by genotyping score, which was calculated the ratio of risk allele fluorescence intensity to total fluorescence intensity. To confirm the accuracy and reliability of this method, TaqMan genotyping assay was performed for 187 samples.
[Results and Discussion] In the first stage, genotypes of 17 samples were clearly divided into 3 types (non-risk type homo, hetero type, risk type homo). We defined an appropriate cut off value of genotyping score for detection of genotype according to the results of first stage. In the second stage, 170 samples, whose genotype were unknown, were genotyped using the DNA chip. The genotype results were completely concordant (100%) with those using TaqMan genotyping assay. Our DNA chip system is extremely useful as a simple method that is capable of genotyping using DNAs extracted from small amount of blood samples in general hospitals. The development of our DNA chip system provides new insights into personalized anti-cancer drug therapy including gemcitabine for the patients with cancer.
Citation Format: Noriaki Nakamura, Koichi Hirayama, Hirofumi Yamano, Hiroshi Okamura, Hitoshi Zembutsu. Development of DNA chip for detection of predictive SNPs for gemcitabine-induced adverse events [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 239.
Abstract 240: SNP-mediated repression of DCBLD1 by YY1 may explain a GWAS finding on lung cancer
Authors: Wang Yu , Ma Rongna , Lin Hongyan , Yu Xiao , Yu Herbert , Qian Biyun 
Published: August 2018

Abstract
Genome-wide association studies (GWAS) have identified many cancer-associated single nucleotide polymorphisms (SNP) with limited understanding of their real implication in cancer. To study the biological relevance of a GWAS-discovered SNP, we performed linkage disequilibrium (LD) analysis on rs9387478 and identified four potentially functional SNPs. We found that SNP rs17079281 C&gt;T was associated with lung cancer in 766 Chinese cases and 773 matched controls, and the association was validated by another independent study (558 cases and 534 controls). Luciferase assay and CRISP/Cas9-generated genotype experiments showed that transcription factor YY1 suppressed DCBLD1 expression in an allele-specific manner, higher inhibition to T than to C alleles. In vitro and in vivo experiments on gain and loss of function further demonstrated that DCBLD1 behaved like an oncogene for lung cancer. These findings suggest that rs17079281 genotype may differentially affect YY1's suppression on DCBLD1 which influences the risk of lung cancer as an oncogene.
Citation Format: Yu Wang, Rongna Ma, Hongyan Lin, Xiao Yu, Herbert Yu, Biyun Qian. SNP-mediated repression of DCBLD1 by YY1 may explain a GWAS finding on lung 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 240.
Abstract 2405: P53-dependent mitophagy controls glycolytic shift in radioresistant head and neck cancer cells
Authors: Chang Hyo Won , Kim Ji Won , Kim Mi Ra , Nam Hae Yun , Lee Myungjin , Lee Won Hyeok , Kim Song Hee , Seong Da Seul , Han Myung Woul , Lee Jong Cheol , Park Jung Je , Seo Ji-hyun , Kim Seong Who , Kim Sang Yoon 
Published: August 2018

Abstract
P53 is an important biomarker in response to genotoxic stress, but it is also known to plays a key role in the regulation of metabolic homeostasis. The loss of p53 is a well-established contributor to the malignant transformation and glycolytic phenotype acquisition of cells during cancer development. However, the role of p53 in genotoxic therapy-induced metabolic shift in cancers remains unclear. Here, we attempted to elucidate how p53 participates in the glycolytic shift of head and neck cancer cell lines following irradiation. We established a stable radioresistant head and neck cancer cells (HN30-R; p53 wild type and UMSCC1-R; p53 null type) through cumulative irradiation and then analyzed their glucose metabolic profiles and mitochondria respiration. As a result, the metabolic analysis revealed no changes glycolysis of HN30-R cells, but UMSCC1-R cells exhibited increased glycolysis through increased glucose uptake and lactate production and glycolytic intermediates as well as related glycolytic enzymes, compared to UMSCC1 cells. Also, we confirmed that the mitochondrial respiration was reduced by the maximal respiration parameters of oxygen consumption rate (OCR) and that abnormal mitochondria were accumulated by electron microscopy in UMSCC1-R cells. Thus, UMSCC1-R cells exhibited an increased sensitivity to glycolysis-targeting drugs such a hexokinases inhibitor (2-deoxy-D-glucoes; 2-DG) and a lactate dehydrogenase-A inhibitor (AT101), but HN30-R cells did not shown any changes. Moreover, we identified that mitophagy limits glycolytic shift through the p53-dependent clearance of abnormal mitochondria. Taken together, these results suggest that p53 null type cells increased aerobic glycolysis to overcome the accumulation of abnormal mitochondria in radioresistnat cells. Conversely, p53 wild type cells inhibited the glycolytic shift by regulating a integrity through p53-dependent mitophagy. Thus, glycolysis-targeted drugs could be an alternative strategy for overcoming recurrent cancers after radiotherapy, and p53 status could be a biomarker for selecting participants for clinical trials.
Citation Format: Hyo Won Chang, Ji Won Kim, Mi Ra Kim, Hae Yun Nam, Myungjin Lee, Won Hyeok Lee, Song Hee Kim, Da Seul Seong, Myung Woul Han, Jong Cheol Lee, Jung Je Park, Ji-hyun Seo, Seong Who Kim, Sang Yoon Kim. P53-dependent mitophagy controls glycolytic shift in radioresistant head and neck cancer cells [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 2405.