bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3415: Cytogenetics of renal oncocytomas identify three distinct and mutually exclusive diagnostic classes of chromosome aberrations
Authors: Anderson Christopher B. , Lipsky Michael , Nandula Subhadra V. , Christopher Freeman E. , Thomas Matthews , Walsh Caitlin E. , Li Gen , Szabolcs Matthias , Mansukhani Mahesh M. , McKiernan James M. , Vundavalli Murty V. 
Published: August 2018

Abstract
Christopher B. Anderson1, Michael Lipsky1, Subhadra V. Nandula2,3, Christopher E. Freeman2, Thomas Matthews2, Catlin Walsh2, Gen Li1, Matthias Szabolcs2, Mahesh M. Mansukhani 2, James M. McKiernan1, Vundavalli V. Murty 2 1Departments of Urology, 2Pathology and Cell Biology, Columbia University Medical Center, New York, New York; 3Cancer Genetics Inc, Rutherford, New Jersey
The cytogenetic alterations in renal oncocytoma (RO) are poorly understood. We analyzed 130 consecutive RO for karyotypic alterations. Clonal chromosome abnormalities were identified in 63 (48.5%) cases, which could be categorized into 3 classes of mutually exclusive cytogenetic categories. Class 1 RO had diploid karyotypes with 11q13 rearrangement in balanced translocations with ten or more different chromosome partners in all 20 (31.7%) cases. We identified recurrent translocation partners at 5q35, 6p21, 9p24, 11p13-14 and 11q23, and confirmed that CCND1 gene rearrangement at 11q13 utilizing fluorescence in situ hybridization (FISH). Class 2 RO exhibited hypodiploid karyotypes with loss of chromosome 1 and concurrent losses of Y in males and X in females in 25 (39.7%) cases. The class 3 tumors comprising of 18 (30.2%) cases showed diverse types of abnormalities with the involvement of 2 or more chromosomes exclusive of abnormalities seen in Class 1 and 2 tumors. Furthermore, karyotypically uninformative cases were subjected to FISH analysis to identify class 1 and 2 abnormalities. In this group we found similar frequencies of CCND1 rearrangement, loss of 1 or Y as with karyotypically abnormal cases. We validated our results against 91 tumors from the Mittleman database. Correlation of clinical data with all the 3 classes of RO showed no clear evidence of overall patient survival. Our findings support the hypothesis that RO exhibit 3 principal cytogenetic categories, which may have different roles in initiation and/or progression. These cytogenetic markers provide a key tool in the diagnostic evaluation of RO.
Citation Format: Christopher B. Anderson, Michael Lipsky, Subhadra V. Nandula, Freeman E. Christopher, Matthews Thomas, Caitlin E. Walsh, Gen Li, Matthias Szabolcs, Mahesh M. Mansukhani, James M. McKiernan, Murty V. Vundavalli. Cytogenetics of renal oncocytomas identify three distinct and mutually exclusive diagnostic classes of chromosome aberrations [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 3415.
Abstract 3416: Customizable gene panels overcome challenges associated with targeted resequencing
Authors: Barry Andrew John , Patel Kruti M. , Emerman Amy B. , Adams Scott , Bowman Sarah , Mauceli Evan , Stewart Fiona , Dimalanta Eileen , Russello Salvatore , Elfe Charles , Davis Theodore , Hendrickson Cynthia 
Published: August 2018

Abstract
Efficient utilization of targeted gene panels for clinical research is challenged by the wide variation in gene constituents specific to a given study. While focused gene panels efficiently provide the necessary depth of coverage for low-frequency variant detection, the high costs and technical requirements associated with panel design present obstacles to delivering assays that are focused on the specific targets of interest. The NEBNext DirectTM technology utilizes a novel approach to selectively enrich nucleic acid targets ranging from a single gene to several hundred genes, without sacrificing specificity. The approach rapidly hybridizes both strands of genomic DNA with biotinylated probes prior to streptavidin bead capture, enzymatic removal of off-target sequences, and conversion of captured molecules into sequence-ready libraries. This results in an exceptionally uniform coverage profile for a given target. Unlike alternative hybridization methods, this 1-day workflow does not necessitate upfront library preparation, and instead converts the captured molecules into libraries compatible with Illumina sequencing. We have designed and optimized baits specific to the full exonic content of &gt;800 genes associated with cancer as well as a variety of other disease areas. These are designed, balanced, and pooled on a per gene basis, and can be readily combined into customized panels, allowing rapid turnaround of specific custom gene subsets. Here, we present the ability to rapidly deploy custom gene panels across a variety of panel sizes and content, while maintaining high specificity, uniformity of coverage across target content, and sensitivity to detect nucleic acid variants from clinically relevant samples.
Citation Format: Andrew John Barry, Kruti M. Patel, Amy B. Emerman, Scott Adams, Sarah Bowman, Evan Mauceli, Fiona Stewart, Eileen Dimalanta, Salvatore Russello, Charles Elfe, Theodore Davis, Cynthia Hendrickson. Customizable gene panels overcome challenges associated with targeted resequencing [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 3416.
Abstract 3424: Genomic alterations in clonal hematopoiesis
Authors: Huang Kuan-Lin , Xie Mingchao , Wu Yige , Jayasinghe Reyka , Varghese Rajees , Mashl R. Jay , Cao Song , Wyczalkowski Matthew , Liang Wen-wei , Wendel Michael C. , Fields Ryan , McLellan Michael D. , Link Daniel C. , Chen Feng , Ding Li 
Published: August 2018

Abstract
Cancer development is an incremental process. Mutations that initiate clonal hematopoiesis often arise in individuals many years before disease symptoms are apparent. We discovered blood somatic mutations in 8,612 germline blood samples in The Cancer Genome Atlas, drawing fundamental distinctions between these events and germline variants. In a preliminary scan of 5,949 samples, 13,345 blood-specific mutations were identified, preferentially distributed across 26 genes, including ones frequently mutated in hematologic malignancies (e.g., DNMT3A, ASXL1, TET2, JAK2, IDH2, SF3B1, MLL3, and KDM6A) and genes rarely mutated in primary hematologic tumors, including EGFR, PIK3CA, NOTCH2, and PPM1D. Further, we utilized both exome sequencing and SNP array data to conduct the first large-scale survey of blood somatic copy number variation, discovering potentially oncogenic events such as JAK2 amplification. Finally, elderly individuals and smokers have increased likelihoods of undergoing clonal expansion. Our analysis of genomic alterations reveals the origins of hematologic malignancies and can facilitate advancement in early detection and prevention.
Citation Format: Kuan-Lin Huang, Mingchao Xie, Yige Wu, Reyka Jayasinghe, Rajees Varghese, R. Jay Mashl, Song Cao, Matthew Wyczalkowski, Wen-wei Liang, Michael C. Wendel, Ryan Fields, Michael D. McLellan, Daniel C. Link, Feng Chen, Li Ding. Genomic alterations in clonal hematopoiesis [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 3424.
Abstract 3429: Genome and epigenome profiling of high stage neuroblastoma
Authors: Ohira-Ichikawa Miki , Sugino Ryuichi P. , Takenobu Hisanori , Li Zhenghao , Haruta Masayuki , Nagae Genta , Renard-Guillet Claire , Nakagawara Akira , Aburatani Hiroyuki , Kamijo Takehiko 
Published: August 2018

Abstract
Neuroblastoma (NB) is the most common pediatric extracranial solid tumor with a wide range of clinical phenotypes from spontaneous regression to highly resistant to chemotherapy. Loss of 1p and 11q and genomic alterations of MYCN, ALK, ATRX and TERT have been known to be involved in oncogenesis and unfavorable phenotype of NB, however, only small numbers of recurrent driver mutations have been observed by NGS-based studies. This implies epigenetic alterations also influence the pathogenesis of NB. In this study, to elucidate the molecular basis of malignant subtype of NB, we conducted methylome analysis for 145 primary NBs (stage 1:3; stage 2:8; stage 3:16; stage 4:105; stage 4s:13) by Infinium Human Methylation 450 BeadChip. By hierarchical clustering of methylome signature, the tumors were classified into four clusters. Cluster-1 shows good similarity with nerve cell controls and, together with cluster-3 (very young, early tumor stage), exhibited favorable prognosis. Unfavorable cluster-2 and -4 exhibited hyper-methylation phenotypes in CpG islands (CGI) and the former was enriched by MYCN-amplified tumors. These two clusters (n=73) showed strong correlation with poor patient prognosis (p=0.0055). 1400 hyper-methylated CGI locus which corresponded 550 genes were picked up and annotated by GO database. The term “cell adhesion”, “cell-cell signaling”, “transmission of nerve impulse” and “cellular component morphogenesis” were enriched. No 1p or 11q genes were enriched in hyper-methylated genes but several genes such as ANKK1 on chr11q whose lower expression levels are strongly correlated with unfavorable prognosis of the patient (p=4.0e-07) were included. Further analyses by comparing the influences in gene expression profiles by methylation and by histone modification of PRC2 are ongoing. Our recent data indicated that NTRK1, whose higher expression is a strong favorable marker, is transcriptionally downregulated in MYCN-amplified tumors by both methylation and H3K27me3 on distinct promoter regions (Li Z et al). Since application of epigenetic drugs are one of the possible therapeutic choices for NB, transcriptional regulation by the epigenetic alterations are needed to be intensively studied.
Citation Format: Miki Ohira-Ichikawa, Ryuichi P. Sugino, Hisanori Takenobu, Zhenghao Li, Masayuki Haruta, Genta Nagae, Claire Renard-Guillet, Akira Nakagawara, Hiroyuki Aburatani, Takehiko Kamijo. Genome and epigenome profiling of high stage neuroblastoma [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 3429.
Abstract 3435: Differential genomics and transcriptomics between tyrosine kinase inhibitor sensitive versus resistant BCR-ABL dependent chronic myeloid leukemia
Authors: Singh Neetu , Tripathi Anil Kumar , Sahu Dinesh Kumar , Mishra Archana , Linan Margaret , Argente Bianca , Varkey Julia , Chowdhry Rebecca , Agarwal Avinash , Yoo Chris , Kant Ravi , Bhatt Madan Lal 
Published: August 2018

Abstract
Previously it has been stated that BCR-ABL1 fusion protein is sufficient to induce CML, but additional genomic changes are required for disease progression. Based on this notion, we profiled control and Tyrosine Kinase Inhibitors (TKI)-treated-CML-samples in different-phases supported by copies of BCR-ABL-transcripts. Molecular-profiling was done through Molecular Inversion Probe (MIP) based array, Human Transcriptomics Array2.0, and Axiom Biobank genotyping-arrays. Transcriptionally, clusters of control, TKI-resistant and -sensitive cases were identified which showed correlation with BCR-ABL transcript-levels with the involvement of 228 pathways. On a comparison between TKI-sensitive versus resistant cases, at the exonic level Cassette Exon splicing event was observed in LAPTM4B (0.46), PIEZO2 (0.32), ANGPT1 (0.29), CFH (0.28), HLTF (0.28), SPTLC3 (0.26); Alternative 3' Acceptor Site splicing (0.22); and Junctional splicing in CD109 and ZNF711. These splicing events led to up-regulation of these transcripts. On further processing through Reactome Pathway, we identified over-expression of Hemostasis pathway in CML-resistant cases with specific involvement of Tie2 and Basigin signalling pathway. Based on CNV profiling, we identified low CNVs in CP-new and CP-UT-TKIs-sensitive cases with undetectable or &lt;10% BCR-ABL copies. While, high CNVs (previously reported gain of 9q34) was observed in BCR-ABL-independent and -dependent TKIs-non-sensitive-CP-UT/AP-UT/B-UT and B-new samples. Further, genotyping CML-CP-UT cases with BCR-ABL 10 to 77.02% copies, we identified and validated rsIDs, rsID239798 and rsID9475077 in linkage with FAM83B which may act as potential therapeutic resistance candidate. BCR-ABL1, additional genetic events, over-expression of Tie-2 and Basigin signalling pathway and rsIDs in linkage with FAM83B in TKI resistant cases can be used for developing a signature profile which may help in monitoring therapy.
Citation Format: Neetu Singh, Anil Kumar Tripathi, Dinesh Kumar Sahu, Archana Mishra, Margaret Linan, Bianca Argente, Julia Varkey, Rebecca Chowdhry, Avinash Agarwal, Chris Yoo, Ravi Kant, Madan Lal Bhatt. Differential genomics and transcriptomics between tyrosine kinase inhibitor sensitive versus resistant BCR-ABL dependent chronic myeloid leukemia [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 3435.
Abstract 344: A high-throughput functional screen reveals synthetic lethal interactions associated with replication stress in HORMAD1-expressing triple-negative breast cancers
Authors: Tarantino Dalia , Walker Callum , Weekes Daniel , Pemberton Helen , Frankum Jessica , Brough Rachel , Lord Christopher J. , Grigoriadis Anita , Tutt Andrew 
Published: August 2018

Abstract
HORMAD1, expression of which is usually restricted to germline cells, is expressed in ~60% of triple-negative breast cancers (TNBCs) where it is associated with higher levels of allelic imbalance. In experimental systems, HORMAD1 also drives Homologous Recombination (HR) deficiency, PARP inhibitor and cisplatin sensitivity. To provide further insights into the role of HORMAD1 in TNBC, we generated a doxycycline-inducible HORMAD1 expression system in the copy number stable, HORMAD1-negative, TNBC cell line SUM159. Clonal, HORMAD1-positive, populations were established which displayed increased levels of genomic instability and reduced levels of homologous recombination. To identify synthetic lethal therapeutic targets associated with HORMAD1 expression in TNBC, we performed an RNAi library screen, in which the viability of HORMAD1-expressing SUM159 clonal cell populations was assessed following the targeted depletion of 1743 genes. Candidate synthetic lethal (SL) genes were validated in a secondary screen using 3 additional HORMAD1-expressing SUM159 clones. The primary siRNA screen identified 63 genes which were SL with elevated HORMAD1 expression, including XRCC1, TDP1, Pol η, BRIP1 and ATR - genes with a known function in mitigating replication stress. DNA polymerase η (POLH) is a Y-family DNA polymerase involved in translesion synthesis (TLS), a DNA damage tolerance pathway employed by proliferating cells to bypass replication fork stalling DNA lesions and to prevent replication fork collapse. We hypothesised that HORMAD1 expression leads to Pol η localisation to replication factories, to mediate lesion bypass. Consistent with this, we found an enrichment in Pol η and monoubiquitylated-PCNA in the chromatin fraction of HORMAD1-expressing SUM159 cells, suggesting that Pol η and TLS might buffer the effect of elevated HORMAD1 expression in TNBC. Our data suggest that HORMAD1 expression in mitotic cells leads to a dependency on pathways implicated in preventing or resolving replication stress, such as TLS, and suggests that vulnerabilities associated with specific DNA repair processes could be used to target HORMAD1-positive TNBCs.
Citation Format: Dalia Tarantino, Callum Walker, Daniel Weekes, Helen Pemberton, Jessica Frankum, Rachel Brough, Christopher J. Lord, Anita Grigoriadis, Andrew Tutt. A high-throughput functional screen reveals synthetic lethal interactions associated with replication stress in HORMAD1-expressing triple-negative breast cancers [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 344.
Abstract 3444: EGFR-dependent matriptase activation in ErbB2-amplified breast cancer
Authors: Gaymon Darius 
Published: August 2018

Abstract
Of the nearly 250,000 new breast cancer cases expected annually, nearly 25% will have ErbB2 (HER2) gene amplification, which is associated with increased growth signaling, more aggressive disease, and poor patient prognosis. Matriptase is a type II transmembrane serine protease that plays a role in normal epithelial cell biology. The expression and activation of matriptase are tightly regulated in normal cells partly through co-expression with endogenous inhibitor, HAI-1, which rapidly inhibits the protease, once activated, by the formation of a high affinity complex. Matriptase has oncogenic potential when its regulation is deranged and it activates downstream substrates known to play a role in tumor progression such as pro-HGF. ErbB2 activity can regulate matriptase activity in prostate cancer and so we set out to elucidate the relationship between ErbB2 and matriptase in ErbB2-amplified breast cancer. SKBR3, AU565, and ErbB2 transfected MCF7 cells (MB7) were used to explore the relationship between ErbB2 levels and matriptase activation as they express higher levels of ErbB2 compared with MCF7 cells. Under standard growth conditions, high level of ErbB2 activation was associated with extensive matriptase activation. Activation of ErbB2 by stimulating EGFR with EGF resulted in increased matriptase activation. Inhibition of ErbB2 activity by serum deprivation or Lapatinib (a dual ErbB2 and EGFR kinase inhibitor) treatment resulted in decreased matriptase activation. Treatment with Lapatinib or the EGFR-specific inhibitor, Gefitinib, blocked matriptase activation whereas the ErbB2 inhibitor, AG825, has no effect. Using inhibitors of downstream signaling pathways, EGFR-induced matriptase activation was shown to be mediated by PI3K signaling. Further elucidation of the pathway is ongoing. In summary, our data suggest that EGFR signaling in this context modulates matriptase activation, which may also contribute to breast cancer progression.
Citation Format: Darius Gaymon. EGFR-dependent matriptase activation in ErbB2-amplified breast 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 3444.
Abstract 3449: AGL loss promotes anchorage independent growth of non-small cell lung cancer by activating FAK
Authors: Guin Sunny , Richmond Craig 
Published: August 2018

Abstract
Loss of glycogen debranching enzyme (AGL) has been shown to promote growth of bladder and non-small cell lung cancer. AGL loss predominantly assists anchorage independent growth of non-small cell lung cancer (NSCLC) cells. However the mechanism driving this anchorage independent growth with AGL loss is not well understood. To identify the driver pathways which contributions to increased anchorage independent growth with AGL loss, we carried out a phospho-kinase screen in A549 NSCLC cells with and without AGL expression. The kinase screen identified an increase in phospho-FAK (Tyr 576/577) levels with loss of AGL. The result of the screen was validated using separate independent Western blot experiments in A549 and other NSCLC cell lines which showed an increase in FAK activation at Tyr 576/577 with loss of AGL. We next treated NSCLC cells with and without AGL with FAK specific inhibitor (FAK inhibitor 14). Treatment with FAK inhibitor 14 had a greater cytotoxic effect (p&lt;0.05) on NSCLC cells that have AGL loss. These data suggest that activation of FAK is a major driver of anchorage independent growth in NSCLC cells that have lost AGL expression and inhibition of FAK activity can serve as a therapeutic avenue for NSCLC patients with low tumor AGL expression.
Citation Format: Sunny Guin, Craig Richmond. AGL loss promotes anchorage independent growth of non-small cell lung cancer by activating FAK [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 3449.
Abstract 345: Characterizing and therapeutically targeting G-quadruplex DNA in ATRX-mutant glioma
Authors: Wang Yuxiang , Danussi Carla , Kannan Kasthuri , Chan Timothy A. , Huse Jason T. 
Published: August 2018

Abstract
Inactivating ATRX mutations are defining molecular alterations in several cancer variants, including large subsets of malignant glioma. ATRX encodes a chromatin binding protein widely implicated in epigenetic and transcriptional regulation. However, ATRX is also thought to guard against genomic instability, in part by mitigating the formation of deleterious G-quadruplex (G4) DNA secondary structures. G4s have been shown to stall DNA replication leading to single-strand breaks and, potentially, DNA damage and genomic instability. To study this biology in a glioma-relevant context, we generated an isogenic astrocyte model featuring intact or deficient ATRX. While ATRX deficiency had no effect on baseline proliferation, cell cycle progression, and apoptosis, it led to markedly increased G4 formation, DNA damage, and replication stress signaling. These effects were reversed by ATRX re-expression. Moreover, ATRX-deficient astrocytes acquired copy number alterations over time, unlike ATRX-intact counterparts. Given these findings, we hypothesized that therapeutically targeting G4s might serve to exploit the inherent genomic vulnerabilities of ATRX-deficient cancer. Remarkably, treatment with a G4 stabilizing compound (CX3543) selectively inhibited growth and colony formation in ATRX-deficient astrocytes at nanomolar concentrations, and synergistically potentiated the effects of ionizing radiation and hydroxyurea. Finally, CX3543 significantly inhibited the growth of patient-derived, ATRX-deficient glioma xenografts in mice, with only minimal effects on ATRX-intact glioma xenografts. These results confirm and characterize a novel functionality for ATRX in the mitigation of genomic instability and point towards a viable strategy for therapeutically targeting ATRX deficiency in cancer.
Citation Format: Yuxiang Wang, Carla Danussi, Kasthuri Kannan, Timothy A. Chan, Jason T. Huse. Characterizing and therapeutically targeting G-quadruplex DNA in ATRX-mutant glioma [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 345.