bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 215: Developing an integrated prognostic score using germline risk variants and RNA expression from primary breast cancers for prognostication of survival across subtypes
Authors: Rajagopal Padma Sheila , Liang Yanyu , Barbeira Alvaro , Melia Owen , Zheng Jiamao , Zheng Yonglan , Yoshimatsu Toshio , Huo Dezheng , Gao Guimin , Olopade Olufunmilayo F. , Im Hae K. 
Published: July 2021

Abstract
Introduction: RNA expression offers prognostication in early-stage, hormone-receptor positive breast cancer. We hypothesized that germline risk variants may influence patients after breast cancer onset, and that integration of common germline risk variants with RNA expression may broaden prognostication across subtypes.
Methods: We designed two prognostic scores for women of European ancestry using genome-wide association study (GWAS) summary statistics on cancer risk from the Breast Cancer Association Consortium (133,384 cases and 113,789 controls) and individual-level genotype/clinical information from 694 women in The Cancer Genome Atlas (TCGA). PrediXcan, a transcriptome-wide association tool family, was used to generate gene-level weights of association to breast cancer risk that were then multiplied by gene expression levels. A predicted transcriptomic score (PTRS) used predicted expression levels based on germline genotypes, and an observed transcriptomic score (OTRS) used normalized RNA expression. Cox proportional hazards tested score performance on overall survival (OS) and progression-free survival (PFS).
Results: Estimation performance is shown in Table 1. A 1388-gene PTRS with range from -0.5 to 4 offered initial prognostic ability in OS across subtypes (HR: 0.69 per 1-point increase, 95% CI: 0.48-1.00, p-value 0.05). This trend persisted with clinical covariates in a multivariate regression (HR: 0.61, 95% CI: 0.36-1.00, p=0.06). No associations were seen between PTRS/PFS or OTRS/OS. OTRS/PFS trended toward statistical significance with clinical factors included (age, AJCC staging). PTRS for OS did not show subtype-specific performance.
Conclusion: Patients with breast cancer do not have broad access to prognostic data across subtypes. Integration of germline and somatic data types offers potential to improve current limitations in prognostic testing for patients.
Table 1.Performance of predicted transcriptomic score (PTRS) and observed transcriptomic score (OTRS)Cox regression hazard ratio95% CIp-valuePolygenic score - OS0.960.64-1.400.84PTRS-OS0.690.48-1.000.05OTRS-OS0.990.97-1.000.66Polygenic score - PFS1.100.77-1.600.55PTRS - PFS1.100.80-1.600.49OTRS - PFS0.980.96-1.000.10
Citation Format: Padma Sheila Rajagopal, Yanyu Liang, Alvaro Barbeira, Owen Melia, Jiamao Zheng, Yonglan Zheng, Toshio Yoshimatsu, Dezheng Huo, Guimin Gao, Olufunmilayo F. Olopade, Hae K. Im. Developing an integrated prognostic score using germline risk variants and RNA expression from primary breast cancers for prognostication of survival across subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 215.
Abstract 2154: Expression of androgen receptor splice variant, AR-V7, in high grade serous ovarian cancer
Authors: Wilson Benjamin , Xiu Joanne , Ulm Michael , Redfern Tiffany , Narayanan Ramesh , ElNaggar Adam 
Published: July 2021

Abstract
Objective: Androgen receptors (AR) are expressed in up to 55% of ERα-negative breast cancers overall and up to 35% of those classified as TNBC. Similarly, AR is expressed in approximately 40% of high grade serous ovarian cancer (HGSOC). The development of AR splice variants (AR-SV), particularly AR-V7, has been shown to be a poor prognostic feature, and mechanism of androgen resistance in breast and prostate cancers. We sought to determine if AR-V7 was present in HGSOC and if there was a correlation with platinum sensitivity and/or treatment outcomes.
Methods: Pair-matched chemo-naïve and platinum-treated HGSOC specimens were identified from our tissue repository. Formalin-fixed paraffin-embedded tumor (FFPE) blocks were collected and tested for expression of AR-V7. Gene fusion detection and variant detection were performed on mRNA isolated from a formalin-fixed paraffin-embedded tumor sample using the Illumina NovaSeq platform (Illumina, Inc., San Diego, CA) and Agilent SureSelect Human All Exon V7 bait panel (Agilent Technologies, Santa Clara, CA). FFPE specimens underwent pathology review to diagnose percent tumor content and tumor size; a minimum of 10% of tumor content in the area for microdissection was required.
Results: Twelve chemo-naïve specimens collected at time of diagnosis by initial biopsy (n=8) or primary debulking surgery (n=4) were pair-matched with the patients' subsequent platinum-treated specimens from either interval debulking surgery (n=6) or biopsy of recurrence (n=6). Following penultimate platinum, 50% were platinum resistant and 50% were platinum sensitive at time of second pathology. Only 19 of the 24 specimens submitted had sufficient RNA for testing, 8 chemo-naïve and 11 platinum-treated. AR-V7 variant transcript was not detected in any of the specimens submitted.
Conclusions: AR-V7 was not expressed in any specimen before or after platinum based chemotherapy suggesting it may not be a useful prognostic marker in the management of HGSOC. Further investigation into gynecologic malignancies with high AR expression and treated with androgen deprivation therapy may elucidate different results.
Citation Format: Benjamin Wilson, Joanne Xiu, Michael Ulm, Tiffany Redfern, Ramesh Narayanan, Adam ElNaggar. Expression of androgen receptor splice variant, AR-V7, in high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2154.
Abstract 2162: Spatially resolved image-based transcriptomics using high-throughput single-molecule fluorescence in situ hybridization (HITSFISH)
Authors: Coleski Andrej , Pitchiaya Sethu , D'Silva Jeremy , Cieslik Marcin , Chinnaiyan Arul 
Published: July 2021

Abstract
Single-cell transcriptomics enables the study of heterogeneity by uncovering the transcriptome of individual cells, which is averaged out in bulk analyses. This facilitates the grouping of cells based on similar transcriptomic profiles, potentially identifying cell subpopulations, such as rare tumor cells that mediate drug resistance or undergo metastasis. Image-based transcriptomic techniques can go a step further in uniquely profiling cells, by providing information about the spatial co-ordinates of transcripts and cells, whilst shedding light on cell morphology for phenotypic characterization. Single-molecule Fluorescence in situ hybridization (smFISH) is one image-based method in which fluorescently labeled tiling-oligonucleotide (TO) probes are bound along the length of complementary RNA strands, allowing for the detection of transcripts at nanometer-scale resolution. However, smFISH data analysis has been difficult to implement at scale due to the tradeoff between transcript resolution and imaging area, as well as the lack of automated feature detection tools. To address this issue, we have developed a pipeline called HIgh-Throughput Single-molecule FISH (HITSFISH), which uniquely combines smFISH with structured-illumination microscopy allowing for large-area high-resolution imagery with automated feature detection and analysis. We have validated our platform by showing high transcriptomic concordance between HITSFISH and other standard methods such as bulk RNA-seq and qPCR, demonstrating its ability to accurately measure RNA levels. With our pipeline we look to answer questions pertaining to the spatiotemporal landscape of gene expression within and across normal and cancerous cells. In addition, by using immunofluorescence in tandem with our platform, we can study transcript localization at various subcellular landmarks, such as membraneless organelles, to gain insight on subcellular mechanisms of gene regulation.
Citation Format: Andrej Coleski, Sethu Pitchiaya, Jeremy D'Silva, Marcin Cieslik, Arul Chinnaiyan. Spatially resolved image-based transcriptomics using high-throughput single-molecule fluorescence in situ hybridization (HITSFISH) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2162.
Abstract 2197: Dysregulated alternative splicing landscape identifies intron retention as a hallmark and spliceosome as a therapeutic vulnerability in aggressive prostate cancer
Authors: Zhang Dingxiao , Hu qiang , Liu Xiaozhuo , Ji Yibing , Chao Hsueh-Ping , Tracz Amanda , Kirk Jason , Buonamici Silvia , Zhu Ping , Wang Jianmin , liu song , Tang Dean 
Published: July 2021

Abstract
Dysregulation of mRNA alternative splicing (AS) has been implicated in development and progression of hematological malignancies. How the global AS dysregulation contributes to the development and progression of solid tumors is under-studied and remains generally unclear. Here we describe the first comprehensive AS landscape in the spectrum of human prostate cancer (PCa) development, progression and therapy resistance. We find that the severity of splicing dysregulation correlates with disease progression and establish intron retention (IR) as a hallmark of PCa stemness and aggressiveness. Systematic interrogation of 274 splicing-regulatory genes (SRGs) uncovers prevalent SRG mutations associated with, mainly, copy number variations leading to mis-expression of ~68% of SRGs during PCa evolution. Consequently, we identify many SRGs as prognostic markers associated with splicing disruption and patient outcome. Interestingly, androgen receptor (AR) controls a splicing program distinct from its transcriptional regulation. The spliceosome modulator, E7107, reverses cancer aggressiveness and inhibits the growth of castration-resistant PCa (CRPC) xenograft models and of the autochthonous Hi-Myc tumors. Altogether, our studies establish aberrant AS landscape caused by dysregulated SRGs as a hallmark of PCa aggressiveness and a novel therapeutic vulnerability for CRPC.
Citation Format: Dingxiao Zhang, qiang Hu, Xiaozhuo Liu, Yibing Ji, Hsueh-Ping Chao, Amanda Tracz, Jason Kirk, Silvia Buonamici, Ping Zhu, Jianmin Wang, song liu, Dean Tang. Dysregulated alternative splicing landscape identifies intron retention as a hallmark and spliceosome as a therapeutic vulnerability in aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2197.
Abstract 2460: Oncogenic regulation of lipogenesis in docetaxel resistant prostate cancer cells
Authors: Martinez Shannalee R. , Aybar Adrián Pérez , Osterman Carlos J. Díaz 
Published: July 2021

Abstract
Prostate cancer is the second leading cause of cancer related deaths in men in the United States. Docetaxel is the standard chemotherapeutic agent available for patients with advanced prostate cancer, in both hormone sensitive and castration resistant settings. However, the development of resistance to docetaxel curtails the efficacy of the drug in prostate cancer patients. Aberrant lipid metabolism has been linked to poor outcomes and therapy resistance in prostate cancer, particularly through overexpression and activation of lipogenic enzymes including ATP citrate lyase, acetyl coA carboxylase, fatty acid synthase, and stearoyl coA desaturase. Together, these enzymes drive fatty acid biogenesis, which has been linked to docetaxel resistance. The purpose of this study is to delineate the molecular mechanisms underlying the lipogenic reprogramming of docetaxel resistant prostate cancer cells, as these represent targets for reversal of this drug resistance. Docetaxel resistant sublines of LNCaP, 22rv1, PC3 and DU145 cell lines were established through chronic continuous exposure to incrementally increasing concentrations of docetaxel, followed by authentication by single tandem repeat (STR) analysis and validation of resistance using MTT viability assays and immunoblot detection of multidrug resistance protein 1 (MDR1/p glycoprotein/ABCB1). Enhanced intracellular accumulation of lipids using BODIPY 493/593 staining and flow cytometric detection was used to confirm the lipogenic phenotype of docetaxel-resistant cells. Oncogenic cMYC expression was also detected by immunoblotting, and its role in regulating lipogenic enzyme expression was evaluated by siRNA interference in docetaxel resistant prostate cancer sublines. cMYC knockdown suppressed the expression of lipogenic enzymes including acetyl coA carboxylase, fatty acid synthase, and stearoyl CoA desaturase in docetaxel-resistant prostate cancer cells. Furthermore, pharmacological inhibition of cMYC production (JQ1) or activity (10058-F4) effectively resensitized resistant cells to docetaxel, as did targeting of key lipogenic enzymes. These data indicate that a cMYC associated lipogenic program is associated with docetaxel resistance in prostate cancer and may represent targets for interventions to enhance docetaxel response in patients with advanced prostate cancer.
Citation Format: Shannalee R. Martinez, Adrián Pérez Aybar, Carlos J. Díaz Osterman. Oncogenic regulation of lipogenesis in docetaxel resistant prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2460.
Abstract 2484: Detection of loss of heterozygosity in GBM revealed the role of a tumor suppressive gene in regulating glioma progression and tumor recurrence
Authors: Kiang Mei-Yee , Sun Stella , Leung Gilberto Ka-Kit 
Published: July 2021

Abstract
Adducin 3 (ADD3) is a major cytoskeleton protein in glioma cells. Our previous studies demonstrated a significant downregulation of ADD3 in GBM when compared with lower-grade gliomas, and that ADD3 knockdown promoted malignant phenotypes. GBMs are usually characterized by high levels of genomic instability, including frequent loss of heterozygosity (LOH) of chromosome 10q, whilst ADD3 is also located in chromosome 10q25.1-25.2 where it is known to be a tumor-suppressor region. However, it is not known whether ADD3 downregulation in malignant gliomas is associated with allelic loss in 10q. To determine 10q LOH on different polymorphic DNA loci (covering ADD3 locus) on glioma tissues, specimens of Normal, Grade II, Grade III, Grade IV GBM and recurrent GBM tissue were included. DNA fragments were evaluated by using a PCR-based microsatellite capillary electrophoresis and analyzed by a fragment analyzer. LOH status were correlated with patient survival for potential prognostic and diagnostic implications. LOH on ADD3 locus was detected in high grade and recurrent GBMs. It is revealed that downregulation of ADD3 level in GBM is associated with genetic instability of LOH in 10q and associated with recurrence disease. This study would provide significant implications, particularly for understanding pathogenesis of GBM and add valuable credits on the diagnostic as well as prognostic implications.
Citation Format: Mei-Yee Kiang, Stella Sun, Gilberto Ka-Kit Leung. Detection of loss of heterozygosity in GBM revealed the role of a tumor suppressive gene in regulating glioma progression and tumor recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2484.
Abstract 2500: The Forkhead-like protein Dach1 governs sensitivity to WEE1 kinase and PARP inhibitors
Authors: Li Zhiping , Jiao Xuanmao , Robertson A. Gordon , Ashton Anthony W. , Kossenkov Andrew , Chen Hao , Phoon Lai Yee , Lan Li , Pestell Richard G. 
Published: July 2021

Abstract
Molecular analysis of all cancer types in the cancer genome atlas (TCGA) demonstrated that multiple pathways may be disrupted within a given tumor including PCa. Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. Substratification of PCa into genetic subtypes, forms the basis of rational therapy for PCa. Known genetic drivers to PCa include deletions of target genes (PTEN and NKX3.1 deletions), rearrangements/fusions of multiple genes (including TMPRSS2 and the oncogenic ETS transcription factor, ERG) and genetic predisposing factors (including germline DNA-repair gene mutations). An increasingly common finding in PCa are defects in DNA repair. The Drosophila Dac gene was initially cloned as dominant inhibitor of Elipse. The human homologue, DACH1, encodes a winged helix/Forkhead DNA-binding protein that binds in chromatin to FOXM1 sites. Herein, reduced expression of DACH1 is shown in PCa, correlating with DACH1 promoter methylation. Homozygous deletion of DACH1 occurred in up to 18% of human PCa, associated with increased AR activity, increased somatic copy-number alteration and poor prognosis. DACH1 increased DNA repair, as shown in comet assays, enhancing nonhomologous end joining (NHEJ) while reducing homology directed repair (HDR) in DNA repair reporter assays. Laser wounding showed DACH1 was recruited to sites of DNA damage, augmenting the recruitment of Ku70/Ku80. In Dach1 deletion cells reduced expression of Dach1 was associated with resistance to inhibitors of Poly-(ADP)-ribose polymerase (PARP) and enhanced sensitivity to inhibitors of WEE1 kinase and DNA-PK. The abundance of DACH1 in prostate cancer may define a subclass of prostate cancer warranting selective therapies.
Citation Format: Zhiping Li, Xuanmao Jiao, A. Gordon Robertson, Anthony W. Ashton, Andrew Kossenkov, Hao Chen, Lai Yee Phoon, Li Lan, Richard G. Pestell. The Forkhead-like protein Dach1 governs sensitivity to WEE1 kinase and PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2500.
Abstract 2565: Detection of ETV1 expression in human prostate tissue specimens using a novel and highly specific rabbit monoclonal antibody
Authors: Tan Shyh-Han , Young Denise , Elsamanoudi Sally , Kagan Jacob , Srivastava Sudhir , Dobi Albert , Petrovics Gyorgy , Sesterhenn Isabell A. , Chesnut Gregory T. 
Published: July 2021

Abstract
Introduction: ETV1 is frequently involved in genomic fusions and translocation events that lead to its overexpression in multiple cancers. These events occur in approximately 5% of prostate cancers, which are mutually exclusive from tumors harboring TMPRSS2-ERG fusion or PTEN deletion. Studies suggest a correlation between strong ETV1 protein expression and poor outcome in prostate cancer. ETV1 has been reported to synergistically cooperate with KIT as a lineage survival factor in gastrointestinal stromal tumors. The expression of ETV1 in a subset of sarcomas that harbor CICrearrangements or CIC-DUX4 gene fusions presents a reliable molecular signature for the diagnosis of this cancer. Our understanding of the role that ETV1 plays in the activation of prostate cancer has been limited by the lack of ETV1 specific antibodies.
Methods: A novel ETV1 monoclonal antibody (MAb) was raised by immunization of ETV1 peptides in rabbit followed by screening of hybridomas by ELISA and immunoblot assays. Further screening using exogenously expressed ETV1, ETV4, ETV5, ERG, SPDEF, and FLI1 proteins identified the clone with the most reactive MAb. Purified MAb was used to evaluate ETV1 expression on a tissue micro-array (TMA) constructed from radical prostatectomies of 50 African American (AA) and 50 Caucasian American (CA) patients by immunohistochemistry (IHC). Key residues required for Mab binding were mapped by ELISA using overlapping peptides and alanine scanning.
Results: IHC evaluation using the ETV1 specific rabbit Mab on a prostate cancer TMA derived from 100 patients identified five ETV1 positive cases, of whom four were CA. The index tumors for these five ETV1 cases were ERG negative. One patient harbored both ERG positive and ERG negative tumor foci, and as expected, the ETV1 positive tumor focus was ERG negative, and vice versa.
Conclusions: We developed a novel rabbit monoclonal ETV1 antibody that is suitable for IHC assay in human prostate tissue. An evaluation of prostate cancer specimens confirmed the reported frequency of ETV1 alteration. Further evaluation using tissue specimens from larger cohorts to establish the sensitivity and specificity of this antibody and validate the utility of ETV1 detection in improving the diagnosis and stratification of prostate and other cancers are in progress.
Citation Format: Shyh-Han Tan, Denise Young, Sally Elsamanoudi, Jacob Kagan, Sudhir Srivastava, Albert Dobi, Gyorgy Petrovics, Isabell A. Sesterhenn, Gregory T. Chesnut. Detection of ETV1 expression in human prostate tissue specimens using a novel and highly specific rabbit monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2565.