bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 393: Predicting DNA accessibility in the pan-cancer tumor genome using RNA-Seq, WGS, and deep learning
Authors: Wnuk Kamil , Sudol Jeremi , Rabizadeh Shahrooz , Soon-Shiong Patrick , Szeto Christopher , Vaske Charles 
Published: July 2017

Abstract
DNA accessibility, chromatin regulation, and genome methylation are key drivers of cancer transcription. However, there is much left to be understood about the functional implications of sequence-level data to the regulation of gene expression, especially when it comes to the noncoding genome. Recently [Kelley, D., Snoek, J., and Rinn, J., Genome Res. 2016] trained neural networks to effectively predict DNA accessibility in multiple cell types. These models make it possible to explore the impact of mutations on the predicted accessibility and thus directly link one aspect of the gene regulation puzzle all the way down to the sequence level. We present a model with improved performance on the original dataset of 164 ENCODE and Roadmap Epigenomics Consortium sample types, and then extend the method to provide predictions on any sample with RNA-Seq data without need of DNase-seq for the sample.
We first demonstrate that with several model and algorithmic changes we improve performance across 164 cell types from a mean AUC of 0.895 to a mean AUC of 0.910.
Unfortunately current accessibility models require DNase-seq for each new cell type. Models for detecting transcription factor binding sites, which rely on ChIP-seq for training data, also share this issue. In order to generalize sequence-based predictive models to apply to unseen cell types without requiring re-training we investigate using RNA-Seq as a proxy signature of cell type. The model aims to capture the interdependence of gene expression levels that characterize a cell with the regulatory logic in which sequence-level signatures are combined to determine accessibility without restriction to cell type. We explore the model’s performance when applied to held-out cell types in the ENCODE and Roadmap Epigenomics Consortium data as well as data from the TCGA Pan-Cancer initiative. We look for the impact of non-coding changes in whole-genome sequencing data in TCGA samples, and report on predicted differences in DNA accessibility across cancer subtypes.
Citation Format: Kamil Wnuk, Jeremi Sudol, Shahrooz Rabizadeh, Patrick Soon-Shiong, Christopher Szeto, Charles Vaske. Predicting DNA accessibility in the pan-cancer tumor genome using RNA-Seq, WGS, and deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 393. doi:10.1158/1538-7445.AM2017-393
Abstract 3934: Bladder cancer tumor heterogeneity: development of a system-level mutation assay
Authors: Patsch Katherin , Matasci Naim , Soundararajan Anjana , Nicoll John , Katz Jonathan , Sanchez Antonio , Feierstein Erika , Loy Christina Van , Xu Zhao , Agus David B. , Gross Mitchell E. , Ruderman Daniel 
Published: July 2017

Abstract
Survival rates for patients with muscle-invasive bladder cancer have not improved in the past 20 years, and new therapies are imperative. Intratumor heterogeneity can complicate molecular profiling attempts to optimize therapy for cancers harboring several actionable tumor subclones. To develop personalized treatment strategies, there is a need for assays to measure intratumor heterogeneity in bladder cancers.
We conducted a pilot study of two muscle invasive high-grade transitional cell carcinoma cases. We used a comprehensive cancer panel (Thermo Fisher) covering &gt;400 cancer genes to analyze distinct tumor loci and matched normal tissues. Based on the identified somatic mutations, we designed a bladder-specific panel to (1) validate our results with increased coverage, and (2) analyze liquid biopsy samples.
Using the comprehensive cancer panel, we sequenced 6 tumor loci to an average sequencing depth of approximately 100x. We detected intratumor heterogeneity in both patients: By applying a combination of frequency-based (minor allele frequency &gt;10%) and probabilistic (probability of difference between observed frequencies due to sampling) filters, we identified 44 credible somatic SNVs, including mutations that were not shared among all three loci. We used these SNVs to design a custom amplicon panel covering 42 SNVs across 38 genes that is suitable for highly fragmented DNA. The custom panel was used to validate the SNVs in the same tumor regions and in liquid biopsy samples from plasma and urine (approximate coverage 6,000x). In both cases, we identified private mutations reported in The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) data collection, reflecting tumor evolution. Liquid biopsy samples from urine revealed all trunk mutations but only 1 out of 5 private mutations.
We conclude that tumor evolution can affect distinct loci within bladder tumors, which may not be fully represented in liquid biopsy samples. These results suggest the need for analyzing multiple tumor regions to identify all actionable driver mutations. In the future, we plan to apply our assay to additional foci and patients in order to identify optimal bladder tumor sampling strategies.
Citation Format: Katherin Patsch, Naim Matasci, Anjana Soundararajan, John Nicoll, Jonathan Katz, Antonio Sanchez, Erika Feierstein, Christina Van Loy, Zhao Xu, David B. Agus, Mitchell E. Gross, Daniel Ruderman. Bladder cancer tumor heterogeneity: development of a system-level mutation assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3934. doi:10.1158/1538-7445.AM2017-3934
Abstract 3938: Dynamic interconversion of cancer cells: single-cell analysis of population-based equilibrium
Authors: Chan Yuen San , Yu Edwin-Wai Kin , Wang William Weimao , Fong Chi-Chun , Yip Timothy Tak-Chun , Au Joseph Siu-Kie , Yang Mengsu 
Published: July 2017

Abstract
Background Multiple subpopulations of cells with different phenotypes and genotypes coexist within malignant tumours. Different subpopulations seem to maintain themselves in an equilibrium position via stochastic interconversion. Such plasticity plays an important role in cancer progression, such as transition from epithelial states to mesenchymal state during metastasis, dedifferentiation of non-CSCs to CSCs and rapid transition to MDR cells during drug exposure. We attempt to explore this interconversion plasticity at both population and single cell levels to better understand the dynamics of phenotypic transition.
Methods: We isolated CD90+ and CD90- cells from A549 lung adenocarcinoma cell line by flow cytometry and then characterized their phenotypic behaviors and interconversion dynamics at both population and single cells level. Single cells were cultured in 96 well plate for 13 days. Viable cells were then transferred into 6 well plate for further expansion until enough cells were collected for measurement of CD90 expression in flow cytometry.
Results: A549 maintains a stable expression of CD90 (~50%) which is bimodal distributed. The sorted subpopulations eventually achieved a new equilibrium (CD90+ à 60% , CD90 - à 30%) and did not converge during the bulk cell interconversion. Individual single cell clones showed large variation of CD90 expression. The distribution of CD90 expression was significantly different between CD90+ and CD90- single cell clones, while both groups of clones achieved a similar average equilibrium as compared with the bulk cells. We noted two types of clones defined as transition clones and committed clones with differential interconversion capacities. The later one showed no sign of interconversion and was committed to the original CD90+/- expression level. Further experiments showed that the committed CD90+ cells were more mesenchymal with higher migration ability, while the committed CD90- cells were more epithelial and tumorigenic.
Conclusions: Interconversion plasticity varied from cell to cell and the committed cells prohibited the return of sorted cell subpopulations returned back to the original equilibrium. Phenotypic studies of CD90+ and CD90- revealed that the interconversion between them was EMT related.
Citation Format: Yuen San Chan, Edwin-Wai Kin Yu, William Weimao Wang, Chi-Chun Fong, Timothy Tak-Chun Yip, Joseph Siu-Kie Au, Mengsu Yang. Dynamic interconversion of cancer cells: single-cell analysis of population-based equilibrium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3938. doi:10.1158/1538-7445.AM2017-3938
Abstract 395: Activation mechanisms of cancer associated MEK1 mutants
Authors: Gao Yijun , Chang Matthew T. , McKay Daniel , Yaeger Rona D. , Torres Merna , Muniz Keven , Matthias Drosten , Abdel-Wahab Omar I. , Barbacid Mariano , Caponigro Giordano , Stuart Darrin , Solit David , Taylor Barry S. , Yao Zhan , Rosen Neal 
Published: July 2017

Abstract
Activating BRAF mutants drive human tumors by dysregulating ERK signaling despite ERK-dependent feedback suppression of RAS. These RAF mutants become RAS independent, by either of two mechanisms, and they are thus unaffected by feedback inhibition of upstream signaling. Recently, it has become clear that mutation activation of MEK1 or MEK2 occur at appreciable frequency in human tumors, but the mechanism of activation of these mutants and whether they remain dependent on upstream activation of RAS or RAF signaling remains unknown. Here we characterized the mechanism of activation of 18 recurrent MEK1 mutants identified in human cancer. Based on these data, they fall into three classes. The kinase activity of first class remains dependent on RAF mediated phosphorylation of S218 and S222; the second class of MEK mutants has basal RAF-independent activity, but can be further stimulated by RAF and the third class no longer requires phosphorylation of S218 and S222 and signals in a RAF independent manner. These features determined their sensitivity to ERK-dependent feedback regulation and the ability to drive ERK signaling output in cells. The more RAF-independent activity the mutants acquired, the better they could activate downstream ERK pathway, leading to increased transforming activities in MEF cells in the absence of RAF. This is consistent with their genetic association with RAS, RAF and NF1 mutations in human tumors. The Class 3 RAF-independent MEK1 mutants tend to be mutually exclusive with those mutants, while coexistence with RAS/RAF/NF1 mutations is frequently observed in tumors with Class 1 or 2 MEK1 mutants. Moreover, functional class correlated with sensitivities of ERK signaling driven by these mutants to MEK inhibitors that function by different mechanisms. Unlike RAF dependent or regulated MEK1 mutants, the ERK signaling driven by RAF independent MEK1 mutants is insensitive to an allosteric MEK inhibitor that functions by preventing RAF mediated MEK phosphorylation. However, signaling driven by all classes of MEK1 mutants is sensitive to an ATP competitive MEK1 inhibitor which targets MEK1 kinase activity.
Citation Format: Yijun Gao, Matthew T. Chang, Daniel McKay, Rona D. Yaeger, Merna Torres, Keven Muniz, Drosten Matthias, Omar I. Abdel-Wahab, Mariano Barbacid, Giordano Caponigro, Darrin Stuart, David Solit, Barry S. Taylor, Zhan Yao, Neal Rosen. Activation mechanisms of cancer associated MEK1 mutants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 395. doi:10.1158/1538-7445.AM2017-395
Abstract 3952: Rapid autopsy programs: A systematic review
Authors: Li Brian , Dhani Neesha , Yu WeiYang , Khan Shawn , Grose Elysia 
Published: July 2017

Abstract
A Rapid Autopsy Program (RAP) is an advanced method of biospecimen procurement whereby autopsies are conducted within 2-6 hours postmortem in order to obtain substantial amounts of high-quality, fresh tissue in support of current and future research. Rapid autopsies were first introduced in the late 1980’s and are still a relatively novel approach, but growing in popularity as a viable alternative to traditional tissue sampling methods for cancer research. In oncology, primary tumour, metastatic, and normal tissue from uninvolved organ sites are sampled and can be subsequently snap frozen in liquid nitrogen or preserved in formalin-fixed paraffin-embedded blocks. Fresh tissue can also be distributed immediately to cancer researchers allowing for analyses incompatible with archival frozen or fixed tissue. Tissue degradation has been found to be minimized in different tissue types by decreasing the postmortem interval – the time between death and tissue preservation. Institutions capable of executing the collection and maintenance of such a repository of biospecimens are a monumental asset to clinicians and researchers who are interested in investigating tumour biology, metastatic disease, and treatment response. In addition to the clear scientific benefits of RAPs, these programs offer a unique opportunity for palliative cancer patients to donate their bodies to aid cancer research. This systematic review was conducted to examine the scope of impact of RAPs thus far on biomedical, translational, and clinical research in the field of oncology, in hopes to inform best practice for collection and use of biospecimen in oncology. Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane CENTRAL, and Ovid MEDLINE will be searched with devised strategies and screened from inception until present. In addition, grey literature will be reviewed. Two independent reviewers will be responsible for study selection and data extraction. The results of the systematic review are pending.
Citation Format: Brian Li, Neesha Dhani, WeiYang Yu, Shawn Khan, Elysia Grose. Rapid autopsy programs: A systematic review [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3952. doi:10.1158/1538-7445.AM2017-3952
Abstract 3956: Intra-individual genomic heteroneity of ovarian cancer and clinical utility of ascitic cancer cells for mutation profiling
Authors: Choi Youn Jin , Kim Min Sung , Lee Sug Hyung 
Published: July 2017

Abstract
Intra-individual tumoural heterogeneity (ITH) is a hallmark of solid tumours and impedes accurate genomic diagnosis and selection of proper therapy. The purpose of this study was to identify ITH of ovarian high-grade serous carcinomas (OSCs) and to determine the utility of ascitic cancer cells as a resource for mutation profiling in spite of ITH. We performed whole-exome sequencing, copy number profiling, and DNA methylation profiling of four OSC genomes using multiregional biopsy from 13 intra-ovarian lesions, 12 extra-ovarian tumour lesions (omentum/peritoneum), and ascitic cells. We observed substantial levels of heterogeneity in mutations and copy number alterations (CNAs) of the OSCs. We categorized the mutations into 'common', 'shared' and 'private' according to the regional distribution. Six common, 8 shared, and 24 private mutations were observed in known cancer-related genes. Common mutations had a higher mutant allele frequency and included TP53 mutations in all four OSCs. Region-specific chromosomal amplifications and deletions involving BRCA1, PIK3CA, and RB1 were also identified. Of note, the mutations detected in ascitic cancer cells represented 92.3-100% of overall somatic mutations in the given case. Phylogenetic analyses of ascitic genomes predicted a poly-seeding origin of somatic mutations in ascitic cells. Our results demonstrate that despite ITH, somatic mutations, CNAs, and DNA methylations in both “common” category and cancer-related genes were highly conserved in ascitic cells of OSCs, highlighting the clinical relevance of genome analysis of ascitic cells. Ascitic tumour cells may serve as a potential resource to discover somatic mutations of primary OSC with diagnostic and therapeutic relevance.
Note: This abstract was not presented at the meeting.
Citation Format: Youn Jin Choi, Min Sung Kim, Sug Hyung Lee. Intra-individual genomic heteroneity of ovarian cancer and clinical utility of ascitic cancer cells for mutation profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3956. doi:10.1158/1538-7445.AM2017-3956
Abstract 3967: High microsomal PGE2synthase-1 levels associate with low CD8 T cells and poorer melanoma patient survival
Authors: Kim Sun-Hee , Roszik Jason , Peng Weiyi , Ekmekcioglu Suhendan , Grimm Elizabeth A. 
Published: July 2017

Abstract
COX-2 and its product PGE2 are reported to enhance carcinogenesis and tumor progression and to support immunosuppression, as reported by others in melanoma and other cancers. As most COX-2 inhibitors result in cardiotoxicity, the downstream microsomal PGE2 synthase-1 (mPGES1) is now also an alternative consideration for therapeutic targeting. Our previously published results (Kim, et al., 2016) showed that mPGES1 protein increased with melanoma patient clinical stage and that its intense expression was associated with reduced patient survival. We also reported that mPGES1 inhibition attenuated cell survival and increased apoptosis in human melanoma cells and significantly suppressed tumor growth in melanoma xenografts. This current study was designed to evaluate whether expression of mPGES1 contributes to immune evasion. Tumors in a Stage III melanoma TMA analysis demonstrated that high mPGES1 expression (intensity 3) was significantly associated with low CD8 levels (lower than median CD8 percent value) (r=-0.2722, p=0.0128). Importantly, stage III melanoma patients with this high mPGES1 and low CD8 signature had significantly increased risk of death as determined by Kaplan-Meier method and Univariate Cox proportional hazards regression models, and compared with patients with low mPGES1/low CD8 and low mPGES1/high CD8. Furthermore, the differential levels of several chemokines including CXCL1 and CXCL2 to regulate T cell migration were correlated the mPGES1 expression in the TCGA melanoma data set. Collectively, our study continues to resolve the potential role of mPGES1 in regulation of immune evasion and is designed as a preclinical approach to develop a rational therapeutic strategy targeting PGE2-driven inflammatory mediators as useful adjuvants for immune-based therapy.
Citation Format: Sun-Hee Kim, Jason Roszik, Weiyi Peng, Suhendan Ekmekcioglu, Elizabeth A. Grimm. High microsomal PGE2synthase-1 levels associate with low CD8 T cells and poorer melanoma patient survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3967. doi:10.1158/1538-7445.AM2017-3967
Abstract 3976: Resolving cellular complexity in renal cell carcinoma with droplet-based single cell transcriptomics
Authors: Vijayakumar Siva , Bolisetty Mohan , Sivajothi Santosh , Robson Paul 
Published: July 2017

Abstract
Purpose: The development, growth, invasion and metastasis of cancer is supported and sustained by complex tissue microenvironments. Interactions between the stromal cells, cancer cells and immune cells through autocrine and paracrine signaling, influences many stages of cancer progression. Furthermore, understanding the identity of the tumor infiltrated immune cell populations is known to predict survival outcomes. Kidney cancer is the 12th most prevalent cancer in the world and is predicted to affect 62,700 new cases in 2016 in the United States alone (American Cancer Society). Existing studies on renal cell carcinoma utilizing bulk profiling methods have been unable to deconvolute the role of the various cell types in promoting the progression this cancer type.
Method: Single cell transcriptomics of primary tumors is a powerful approach to study not only the cancer cells but also the cells of the microenvironment. We profiled the various cell types that comprise primary renal cell carcinoma using the Chromium Single Cell 3’ system (10X Genomics).
Results: With this single cell approach, we have generated thousands of single cell transcriptomes leading to the identification of numerous cell types and cell states in renal cell carcinoma and matched normal kidney. The microenvironment of renal cell carcinoma tumors contains a heterogeneous mix of stromal, immune and kidney cell types. Compared with the matched normal, the tumors are heavily infiltrated with lymphocytes, mast cells and cells of the myeloid lineage. We identified pathways enriched in specific cell types that illuminate potential mechanisms underlying the cell-cell interactions between cancer cells, stromal cells, and the infiltrating immune cells thus highlighting potentially new targeting strategies for the treatment of this disease. In addition, the single cell data described here will be used to deconvolute existing and new bulk analyses of renal cell carcinoma patients and to establish targeted antibody panels for use in flow and imaging mass cytometry. We anticipate both will lead to better patient stratification to inform patient-specific treatment regimes.
Conclusion: Droplet-based single cell transcriptomics can successfully identify the numerous cell types that comprise a tumor, providing a foundation of knowledge to inform biomarker selection and provide insight into novel treatment strategies. This approach reflects a more comprehensive view of renal tumors that is often masked by bulk profiling analyses.
Citation Format: Siva Vijayakumar, Mohan Bolisetty, Santosh Sivajothi, Paul Robson. Resolving cellular complexity in renal cell carcinoma with droplet-based single cell transcriptomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3976. doi:10.1158/1538-7445.AM2017-3976
Abstract 3986: Regulation mechanism and clinical significance of KPNA2 promotes MDSCs infiltrating in epithelial ovarian cancer
Authors: Huang Shuting , Zheng Min , Wu Yuanzhong 
Published: July 2017

Abstract
Myeloid-Derived Suppressor Cells (MDSCs) are a population of immune cells that negatively regulate immune responses, which could promote tumor invasion and metastasis. Recently research has revealed that tumor could actively reshape the immune-microenvironment for its progression. We recently demonstrated that KPNA2 is a candidate oncogene in ovarian cancer that was closely related to MDSCs density, and found there was a positive position feedback between KPNA2 expressed and MDSCs density, which might contribute to the poor prognosis of patients. Based on these results, we combined clinical sample analysis, animal model and experimental studies to do further molecular and genomic research. The conduction of this project will help explain the molecular mechanisms of how KPNA2 regulates ovarian cancer through suppressing the immune system, and provide new strategies by molecular targeted therapy combining biological therapy for ovarian cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Shuting Huang, Min Zheng, Yuanzhong Wu. Regulation mechanism and clinical significance of KPNA2 promotes MDSCs infiltrating in epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3986. doi:10.1158/1538-7445.AM2017-3986