bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1279: Passenger mutation landscape in cancer genomes
Authors: Kumar Sushant , Warrel Jonathan , Mcgillivray Patrick , Meyerson William , Li Shantao , Salichos Leonidas , Harmanci Arif , Fundichely Alexander , Chan Calvin , Herrmann Carl , Nielsen Morten , Lochovsky Lucas , Zhang Yan , Li Xiaotong , Khurana Ekta , Getz Gad , Gerstein Mark 
Published: August 2018

Abstract
Cancer progression is an evolutionary process during which thousands of somatic variants are accumulated within an individual. In the classic view of cancer progression, a handful of driver variants are thought to give a positive selection advantage to the cancer cell. The remaining variants, termed passengers, represent the overwhelming majority of the variants in cancer genomes, and their functional consequences are poorly understood. Furthermore, the bulk of these passengers fall within noncoding regions of the genome, making these the main product of whole-genome sequencing of tumors. In this work, we explore the functional landscape of passenger variants in various cancer cohorts by leveraging extensive pan-cancer variant calls from ~2500 uniformly processed whole cancer genomes. More specifically, we integrate their annotations and predicted functional impact scores to quantify the overall burdening of various elements in cancer genomes. We show that disruption of genetic regulatory elements in the noncoding genome correlates with altered gene expression. Furthermore, we also show how overall functional burdening of various genomic elements correlate with patient survival time, and tumor clonality. Finally, we observe statistical signals consistent with the notion that aggregated subsets of passenger variants - particularly those we predict to be functionally impactful- might confer weak selective effects.
Citation Format: Sushant Kumar, Jonathan Warrel, Patrick Mcgillivray, William Meyerson, Shantao Li, Leonidas Salichos, Arif Harmanci, Alexander Fundichely, Calvin Chan, Carl Herrmann, Morten Nielsen, Lucas Lochovsky, Yan Zhang, Xiaotong Li, Ekta Khurana, Gad Getz, Mark Gerstein. Passenger mutation landscape in cancer genomes [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 1279.
Abstract 128: NKILA lncRNA promotes tumor immune evasion by mediating activation-induced cell death in tumor-specific CTLs
Authors: Song Erwei 
Published: August 2018

Abstract
Activation-induced cell death (AICD) of T lymphocytes may be exploited by cancers to eliminate cytotoxic T cells (CTLs). However, the mechanisms underlying AICD in tumor specific CTLs remain unknown. Here, we demonstrated excessive apoptosis of tumor antigen-specific CTLs in breast and lung cancers. Interestingly, NKILA, an NFκB-interacting lncRNA, mediates AICD of CTLs by inhibiting NFκB activities after their activation. Mechanistically, NKILA promoter is closed for transcription by histone deacetylation in resting T cells, while calcium influx by TCR signaling activates calmodulin to remove the deacetylase from NKILA promoter and enhances its transcription. In vivo, administering CTLs with NKILA silencing to immunocompromised mice with breast cancer patient-derived xenografts (PDXs) effectively inhibits PDX growth by increasing CTL infiltration. Clinically, NKILA was overexpressed in the tumor-specific CTLs of breast and lung cancers, which was associated with less CTL infiltration in the tumors and shorter patient survival. Our findings present the first evidence that AICD in tumor-specific CTLs is crucial to cancer immune evasion, and targeting NKILA in CTLs emerges as a novel antitumor immunotherapy.
Citation Format: Erwei Song. NKILA lncRNA promotes tumor immune evasion by mediating activation-induced cell death in tumor-specific CTLs [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 128.
Abstract 1285: Deep mutagenesis analysis on BRCA1 variants in high throughput DNA repair assays
Authors: Diabate Mariame , Adamovich Alexandrea , Banerjee Tapahsama , Freitas Michael , Parvin Jeffrey 
Published: August 2018

Abstract
Genetic screening of Hereditary Breast and Ovarian Cancer (HBOC)-associated genes can aid in prevention of the onset of cancer by increased surveillance or preventative surgery if the genetic information is clear. Often, the genetic information is ambiguous since missense substitutions may be common in aggregate but individually these missense variants occur too infrequently for genetic segregation to be conclusive and are known as Variants of Unknown Significance (VUS). One commonly screened HBOC gene is BRCA1, with mutations found in 40-45% of hereditary breast cancer cases. The BRCA1 protein has the critical tumor suppressive function mediating homology-directed repair (HDR), which is used for the repair of double-stranded breaks (DSB) in DNA. Clinical mutant databases, such as ClinVar, contain the clinical classification of BRCA1, but, unfortunately, in many of these databases, most of the variants are classified as VUS or have conflicting data. We suggest that laboratory-based functional analysis can augment the genetic and clinical data, enabling the understanding of whether a specific variant is benign or pathogenic and predisposing to breast and ovarian cancer. We have developed a high-throughput method for analyzing the function of individual missense variants of BRCA1 in the DNA repair process. The goal is to have functional analysis for every possible amino acid substitution in BRCA1, and this will be publicly available for geneticists to consider when evaluating the likelihood of cancer predisposition an individual with a VUS in BRCA1. We have completed analysis of the amino-terminal RING domain, and we will present new results for the carboxy-terminal BRCT domain. We develop a computational pipeline that starts with sequence data from DNA repair assays to obtain a score for each variant. This pipeline will include statistical programs to evaluate the confidence level for these results, which will then be compared to the information provided in the ClinVar database. In summary, this work describes a computational framework for deconvoluting sequencing results of a high-throughput approach to measure the functional impact of each possible missense variant in the BRCT domain of BRCA1.
Citation Format: Mariame Diabate, Alexandrea Adamovich, Tapahsama Banerjee, Michael Freitas, Jeffrey Parvin. Deep mutagenesis analysis on BRCA1 variants in high throughput DNA repair assays [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 1285.
Abstract 1298: Mapping the comprehensive landscape of missense-mutation neoantigens across the human genome
Authors: Lee HoJoon , Greer Stephanie U. , Ji Hanlee P. 
Published: August 2018

Abstract
Specific somatic mutations in cancer genomes result in amino acid alterations and derivative novel immunogenic peptides called neoantigens. The MHC molecule mediates the immunologic presentation of these cancer mutation-derived peptides. Based on a limited number of polymorphisms, the configuration of the MHC molecule is one of the major factors in determining whether mutated peptides can elicit immune response or not. To provide insight in the full diversity of potential neoantigens across the entire human genome, we identified all possible amino acid substitutions and estimated their potential binding affinities to the 86 MHC genotypes. As a first step, we evaluated every possible nucleotide changes at every single position using exons and related alternative transcripts as defined by the Consensus Coding Sequence (CCDS) resource. We evaluated 159 million (M) possible nucleotide changes among ~31,000 autosomal transcripts from ~ 19,000 genes. Overall, this comprised a genome sequence “space” of 53 M nucleotides. Among this coding regions space, we evaluated 123 M candidate nonsynonmous mutations. Among these mutations, we identified short mutated peptides of nine amino acids in length across this mutation space. We estimated the binding affinity of all mutated peptides across 86 MHG polymorphisms. Based on the predicted binding affinity, 0.6% ~ 1.0 % were found to be potential strong binders to the one of MHC molecules while 1.7% ~ 2.5% of them are weak binder to the one of MHC molecules. HLA-A0201 had the high number of potential candidate neoantigens. The KRAS cancer had candidate epitopes that binds to &gt;50 different MHC molecules include KRAS D12V, which is very hot spot, that make epitopes that binds to 30 MHC molecules. In addition, we mapped the frequencies of missense mutations observed in TCGA and COSMIC to these candidate neoantigens. For releasing the results of our study, we are developing the “Immunogenomic Explorer” available at http://genomeportal.stanford.edu/immune. This portal enables users to explore the potential immunogenic epitopes from genes of their interest such as KRAS. Users can search by HLA genotypes as well. This web interface allows researchers to address important questions regarding their immunotherapy or cancer vaccine.
Citation Format: HoJoon Lee, Stephanie U. Greer, Hanlee P. Ji. Mapping the comprehensive landscape of missense-mutation neoantigens across the human genome [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 1298.
Abstract 1301: Using the evolutionary ages of genes to understand hallmark features of cancer
Authors: Goode David L. , Trigos Anna S. , Papenfuss Anthony T. , Pearson Richard B. 
Published: August 2018

Abstract
The evolutionary age of a gene is closely tied to its role in cancer. As organisms evolved into multicellular forms, new pathways emerged to control core cellular processes formed in unicellular ancestors such as cell division, DNA replication and energy metabolism. Tumors rely on many of these core processes, at the same time as they suppress key pathways linked to the emergence of multicellularity. This suggests the guiding principles behind many hallmarks of cancer could be better understood in an evolutionary context, by investigating interactions between unicellular and multicellular genes and how they are disrupted in cancer. We have found the evolutionary histories of genes are associated with their expression and regulation (Trigos et al., PNAS 2017), the selection and response to genetic alterations, as well as the rewiring of transcriptional networks across 7 tumor types. Our results reveal different transcriptional and mutational patterns in cancer between genes with different evolutionary ages, with selection for genetic alterations in early metazoan genes leading to the transcriptional rewiring of the regulation between unicellular and multicellular genes, driving carcinogenesis. Examples of how this approach can help prioritize genes for drug treatment and inform novel treatment strategies will be given.
Citation Format: David L. Goode, Anna S. Trigos, Anthony T. Papenfuss, Richard B. Pearson. Using the evolutionary ages of genes to understand hallmark features of 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 1301.
Abstract 1312: Predicting ligand-dependent tumors from multi-dimensional signaling features
Authors: Hass Helge , Masson Kristina , Wohlgemuth Sibylle , Paragas Violette , Allen John E. , Sevecka Mark , Pace Emily , Timmer Jens , Stelling Joerg , MacBeath Gavin , Schoeberl Birgit , Raue Andreas 
Published: August 2018

Abstract
Receptor tyrosine kinases (RTKs) are high-affinity cell surface receptors for growth factors that are frequently deregulated in cancer. Signaling through these receptors has been associated with increased cancer cell proliferation and resistance to cytotoxic therapies. To block this detrimental signaling, many companies are developing inhibitory antibodies against various RTKs. A key challenge in clinical studies is the optimal stratification of patients who may benefit from these therapies. For an RTK targeted antibody, the detection of the respective growth factor in the tumor microenvironment may be an important bio-marker. Beyond the physical presence of the growth factor, the decision whether a cancer cell will respond to growth factor-induced signals is governed by complex intra-cellular signaling networks. We compared different approaches to predict cellular responses and will highlight a hybrid approach that combines mechanistic modeling based on ordinary differential equations with a machine learning algorithm. The models are trained on in vitro drug response screens and then applied to predict response in patient samples. The mechanistic models are trained on quantitative data from signal transduction studies as well as RNAseq data for cellular characterization. Using the hybrid approach, a correlation between growth factor expression in the tumor microenvironment and its predicted response was identified. This supports the hypothesis of addiction of tumors to growth factors abundant in the tumor microenvironment, and might enable more robust patient stratification in the future.
Citation Format: Helge Hass, Kristina Masson, Sibylle Wohlgemuth, Violette Paragas, John E. Allen, Mark Sevecka, Emily Pace, Jens Timmer, Joerg Stelling, Gavin MacBeath, Birgit Schoeberl, Andreas Raue. Predicting ligand-dependent tumors from multi-dimensional signaling features [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 1312.
Abstract 1320: An integrative and interactive colorectal cancer biomarker database
Authors: Zhang Xueli , Sun Xiao-Feng , Cao Yang , Ye Benchen , Peng Qiliang , Liu Xingyun , Shen Bairong , Zhang Hong 
Published: August 2018

Abstract
We created a colorectal cancer (CRC) biomarker database (CBD) with credible content as a powerful and time-saving tool to provide better and accurate information concerning CRC biomarkers. CRC biomarker database (http://sysbio.suda.edu.cn/CBD/) was established based on 870 identified CRC biomarkers and their relevant information from 1115 original articles in PubMed published from 1986 to 2017. In this version of the CBD, CRC biomarker data was collected, sorted, displayed, and analysed. The CBD with the credible contents as a powerful and time-saving tool can provide more comprehensive and accurate information for further CRC biomarker researches. The CBD was constructed under MySQL server. HEML, PHP and JavaScript languages have been used to implement the web interface. The Apache was selected as HTTP server. All of these web operations were implemented under the Windows system. The CBD was concluded the multiple individual biomarker information and categorised into the biological category, source and application of biomarkers; the experiment methods, results, authors and publication resources; the research region, the patient's age, gender, race, the number of tumours, tumour location, and stage. The key words for searching in PubMed are: (((biomarker[Title/Abstract] OR marker[Title/Abstract]) OR indicator[Title/Abstract]) OR predictor[Title/Abstract]) AND ((colorectal cancer[Title/Abstract] OR rectal cancer[Title/Abstract]) OR bowel cancer[Title/Abstract]). The CBD can provide a professional platform to researchers who are interested in CRC research to communicate, exchange their research ideas and further design high quality research in CRC. They can submit their new findings to our database via th submission page, and communicate with us in the CBD.
Citation Format: Xueli Zhang, Xiao-Feng Sun, Yang Cao, Benchen Ye, Qiliang Peng, Xingyun Liu, Bairong Shen, Hong Zhang. An integrative and interactive colorectal cancer biomarker database [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 1320.
Abstract 1329: Combination treatment with CB-839 and romidepsin induces apoptosis and suppresses cell viability in preclinical models of chondrosarcoma
Authors: Sheikh Tahir N. , Patwardhan Parag P. , Schwartz Gary K. 
Published: August 2018

Abstract
Chondrosarcomas are the second most frequently occurring type of bone malignancy, and account for approximately 25% of all bone sarcomas. They are often highly aggressive neoplasms that rapidly progress and eventually recur and give distant metastases. They are largely considered to be resistant to conventional chemotherapy and radiotherapy. Several studies have reported that mTORC1 stimulates glutamine metabolism and increased mitogenic signaling through activation of the mTORC pathway, coupled with deregulation of the Cyclin D/retinoblastoma (Rb) pathway is a common feature of certain malignancies. In the present study, we hypothesized that concurrent inhibition of glutamine metabolism and histone acetylation could result in decreased viability of chondrosarcoma cells. To test this, we used a panel of chondrosarcoma cell lines including IDH wild type (CH2879), IDH1 mutant (JJ012) and IDH2 mutant (SW1353) cell line. Results from our in vitro proliferation assay showed that combination of sub-IC50 concentrations of the CB-839 (Glutaminase inhibitor) and Romidepsin (HDAC inhibitor) resulted in decreased cell viability of all the three chondrosarcoma cell lines when compared to either of the two drugs alone. Western blot analysis showed induction of cleaved Poly-ADP Ribose Polymerase (PARP) as well as cleaved caspase 3, known markers of apoptosis and down regulation of mTORC1 targets such as phospho-S6 and Phospho-p44/42 MAPK such as ERK1/2. Combination treatment also resulted in increased induction of histone acetylation (AcH3). Cell cycle analysis showed induction of sub-G1 population phase in combination treatment. Previous reports have shown that CpG methylation is a critical event in transcriptional repression of hyper methylated genes in cancer. To this end, we show that combination treatment with CB-839 and Romidepsin results in down regulation of (H3K9) methylation. Taken together, our data strongly suggests that combination treatment with CB-839 (Glutaminase inhibitor) and Romidepsin (HDAC inhibitor) is a novel treatment approach and merits evaluation in the treatment of chondrosarcoma.
Citation Format: Tahir N. Sheikh, Parag P. Patwardhan, Gary K. Schwartz. Combination treatment with CB-839 and romidepsin induces apoptosis and suppresses cell viability in preclinical models of chondrosarcoma [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 1329.
Abstract 1342: Mitochondrial dysfunction activates lysosomal-dependent mitophagy selectively in cancer cells
Authors: Biel Thomas , Rao Ashutosh 
Published: August 2018

Abstract
Mitochondria-targeted drugs are designed to accumulate in the mitochondrion to modulate metabolism. Triphenylphosphonium (TPP) conjugated agents are a class of mitochondria-targeted drugs that induce mitochondrial dysfunction in cancer cells. Mitochondrial dysfunction is known factor that facilitates the onset of mitophagy. However, the activation of mitophagy to remove drug-induced mitochondrial damage is unknown. Here, we subjected breast MDA-MB-231 cancer cells and MCF-12A noncancerous cells to a series of mitochondria-targeted redox-active agents (MTA) that contain TPP to investigate the onset and activation of autophagy, mitophagy and mitochondrial dysfunction. Collectively, we identified three different MTAs from the series that sequentially damage the mitochondria, enhance autophagic flux, and activate mitophagy selectively in MDA-MB-231 cells. Furthermore, we generated stably expressing mt-mKeima MDA-MB-231 and MCF-12A cell lines to establish a mitophagy flux assay for screening new agents. FACS analysis of mt-mKeima, a pH-sensitive fluorophore, revealed MTAs induced lysosomal dependent mitochondrial degradation and the presence of bafilomycin, a lysosomal inhibitor, suppressed MTA-induced mitophagy. To confirm MTAs induced mitochondrial autophagy, we identified mitochondria located within autophagosomes using confocal microscopy, an endogenous autophagy-related protein complex by coimmunoprecipitation and mitochondrial PINK1 accumulation using immunoblot. These in vitro studies were translated into an in vivo rat SST-2 xenograph breast cancer model to demonstrate that mitochondrial PINK1 accumulates in rat tumor tissue following MitoQ treatment. These data suggest that mitochondria-targeted agents selectively caused mitochondrial depolarization, PINK1 accumulation and mitophagy in MDA-MB-231 cancer cells as compared to MCF-12A noncancerous cells.
Citation Format: Thomas Biel, Ashutosh Rao. Mitochondrial dysfunction activates lysosomal-dependent mitophagy selectively in 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 1342.