bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2767: Expression of defensin-associated genes may be correlated with lymph node metastasis of early stage tongue cancer
Authors: Lee Doh Young 
Published: August 2019

Abstract
OBJECTIVES: Appropriate patient selection for elective neck dissection in N0 tongue cancer has been controversial, while there has been no genetic consideration so far. We aimed to analyze genetic difference between early and late cervical lymph node metastasis in oral tongue cancer patients using the Seoul National University Hospital (SNUH) cancer cohort and cancer genome atlas (TCGA) data, and to suggest genetic background for choosing eligible patient for elective neck dissection. METHODS: A total of 35 cases with RNAseq in SNUH cancer cohort with tongue cancer were also enrolled in this study. To investigate gene expression in early cervical lymph node metastasis, genomic data of following 2 groups was compared; 1) N0 group: T1/2 and N0, 2) N+ group: T1/2 and N+. Differentially expressed genes (DEGs) were extracted using R and limma package in bioconductor program. Gene ontology and pathway enrichment analysis were performed using DAVID online tool. Immune cell infiltration was analyzed using CIBERSORT online program. Additionally, 70 cases with matched RNAseq data of primary tumor and clinical TCGA data were analyzed to validate the role of DEGs. RESULTS: N0 and N+ groups showed no difference in age, gender, size and thickness of tumor, and nearest resection margin. In addition, there was no significant difference in 22 types of immune cell infiltration. A total of 51 DEGs were identified, and 14 genes were significantly upregulated and 37 genes were significantly downregulated (p&lt;0.01, fold-change &gt;2). Significant genes were PLA2G4D, NELL2, PCOLCE2, PI3, and PLA2G3. On KEGG pathway analysis, calcium, muscle contraction, and arachidonic acid metabolism-related pathway was significantly correlated. The most significant difference was found in 6 genes as follows; DEFB4A, SPRR2B, DEFB103B, SPRR2G, DEFB4B, FAM25A.DEFB which was the most significantly difference in expression was associated with ‘antibiotic’, ‘antimicrobial’, ‘beta defensing type’, defense reponse to bacterium’, and ‘defensin’. In TCGA data, DEFB4A and DEFB103B were more highly expressed in N0 group than N+ group, although it did not attain significant significance. CONCLUSIONS: Defensin (DEFB4A, DEFB103B, DEFB4B) may be a novel biomarker for early regional metastasis in T1/2 tongue cancer. Considering that defensin can be detected in saliva, simple saliva test for prediction of metastasis can be developed in the future.
Note: This abstract was not presented at the meeting.
Citation Format: Doh Young Lee. Expression of defensin-associated genes may be correlated with lymph node metastasis of early stage tongue cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2767.
Abstract 2771: Identification of novel genes associated with metastasis from TCGA transcriptomic data
Authors: Koyama Takahiko , Parida Laxmi 
Published: August 2019

Abstract
Introduction: Many cancer patients suffer from metastasis in bone, brain, liver and lung. However, understanding of metastasis in molecular level is quite limited. To improve survival rate and quality of life, preventing metastasis is crucial. In this study, we analyzed transcriptomic data with tumor node metastasis (TNM) classification from The Cancer Genome Atlas (TCGA) to identify genes associated with metastasis.
Method: TCGA samples in 20 solid tumor types with both transcriptome and TNM annotation data are used. To obtain the best cut point separating cohorts of high and low gene expression, Hothorn and Lausen’s method is used. A contingency table is created with expression separated by the the cut point and presence of staging T, N, M for each gene. Association between the staging category and the gene was calculated with Fisher’s exact test.
Results: In total, 13,220 distinct genes including miRNAs are associated with either lymph node or distant metastasis for some cancer types with a loose criteria of p-value &lt; 1.0e-3. Among them, we identified 1,357 genes with p-value &lt; 1.0e-8. ADAMTS12, AURKB, BUB1, C17orf53, CCNA2, CEP55, EPR1, KIF4A, KIF11, KRT80, MELK, MKI67, NCAPG, NEIL3, PBK, PLK1, RRM2, TPX2, miR139, miR30a, miR375, and miR379 appear most commonly in lymph node metastasis for many cancer types. Likewise, NOP56, PKD1L2, miR150, miR365, miR9, miR149, miR210, miR425, miR675, and miR937 are most commonly associated genes in distant metastasis. Many of these genes have been already reported in association with metastasis.
Conclusions: This study created comprehensive list of metastasis associated genes for the 20 solid tumors in TCGA. They would be useful as diagnostic and prognostic biomarkers; however, we found therapeutically relevant genes such as PLK1, AURKB, MET, MELK, CDK1, BUB1, and PBK. Some adhesion molecules associated with a particular cancer type might explain its organ destination preference. Among distant metastatic miRNAs discovered, metastasis promoting miRNAs in high abundance might be engaged in homing as exosomal miRNAs by reprogramming destination niche in favor of migrating tumor cells. Further work to reveal metastasis mechanism and to discover some pharmaceutical agents to prevent metastasis will be conducted.
Citation Format: Takahiko Koyama, Laxmi Parida. Identification of novel genes associated with metastasis from TCGA transcriptomic data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2771.
Abstract 2778: ADD3-loss in glioblastoma is associated with increased angiogenesis and malignancy
Authors: Kiang Mei-Yee , Leung Gilberto Ka-Kit 
Published: August 2019

Abstract
Introduction: Adducin 3 (ADD3) is one of the major functional component in the cytoskeleton. Dysregulation of ADD3 has been implicated in various diseases including cancer and participate in different signaling transductions. However, little is known about the functional properties of ADD3 in cancer, its role in cancer biology remains unclear and controversial. We aim to delineate the role of ADD3 dysregulation in GBM pathogenesis and to unravel the underlying molecular mechanisms.
Methods: Microarray datasets were used to analyze the gene expression of ADD3 in normal tissue and grade II, III, IV gliomas. Gene expression levels were verified by western blot, qPCR and immuno-histological analyses by using human clinical specimens. Luciferase-expressing ADD3 stable knockdown U87 malignant glioma cells were injected to immunocompromised mice subcutaneously and orthotopically for xenograft models. ADD3 stable knockdown U87 cells were co-cultured with human endothelial cells (HUVEC) to assess the functional changes.
Findings: Our study demonstrated significant downregulation of ADD3 in human GBM when compared with lower-grade gliomas. Downregulation of ADD3 was only shown in GBM (i.e., WHO grade IV lesion) but not in grade II and grade III tumor. Importantly, we found that ADD3 downregulation is associated with poor clinical outcome in GBM patients. And that ADD3 knock-down enhanced tumor growth in vivo, possibly mediated by promoting angiogenesis.
Conclusions: These findings suggest that ADD3 is associated with glioma malignancy, implying that cancer progression may occur along with the loss of ADD3. It may contribute towards tumor growth by enhancing angiogenesis.
Citation Format: Mei-Yee Kiang, Gilberto Ka-Kit Leung. ADD3-loss in glioblastoma is associated with increased angiogenesis and malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2778.
Abstract 278: System xc- inhibition shares features of necroptosis and ferroptosis in hepatocellular carcinoma cells
Authors: Abdullah Md , Kim Do Hyung , Lee Seung Jin 
Published: August 2019

Abstract
Ferroptosis is characterized by iron-dependent non-apoptotic cell death involving the accumulation of lipid peroxides. Inhibition of system xc- which uptake L-cystine with the exchange of L-glutamate decreases glutathione synthesis, leading to ferroptosis. However, molecular interplay between ferroptosis and necroptosis has not been clearly identified. In this study, we investigated molecular process for cell death by SLC7A11 inhibition in hepatocellular carcinoma cell lines. The sensitivity for SLC7A11 inhibition by sulfasalazine was in the order of HepG2, Huh7 and Huh6, and then PLC/PRF/5. The decrease of cell viability by sulfasalazine and erastin was prevented by co-treatment of β-mercaptoethanol in all kinds of cell lines, indicating that the limited supply of L-cystine may contribute to cell death. Both ferrostatin and necrostatin, an inhibitor of ferroptosis and necroptosis, respectively, rescued sulfasalazine-induced growth inhibition by 60% in Huh7 and Huh6 and by 20% in HepG2. However, they failed to restore cell survival in PLC/PRF/5 cells. Sulfasalazine at the dose inducing equivalent level of cell death significantly increased lipid peroxidation in Huh7 and Huh6, but not in HepG2 and PLC/PRF/5 cells, as determined by C11-BODIPY dye. RIPK activation in necroptosis pathway by sulfasalazine was monitored in these cell lines. These results suggest that SLC7A11 inhibition triggers mixed-type of cell death via ferroptosis and necroptosis in a context-dependent manner in hepatocellular carcinoma cells (MD Abdullah and DH Kim are equally contributed to this work).
Citation Format: Md Abdullah, Do Hyung Kim, Seung Jin Lee. System xc- inhibition shares features of necroptosis and ferroptosis in hepatocellular carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 278.
Abstract 2784: Driver genes network promotes mesenchymal to epithelial transition and organ-specific metastasis
Authors: Chang Ming , Huang Xin , Lu Songjian , Zhang Wei , Liang Weiping , Keller Evan , Lu Xinghua , Zhang Jian 
Published: August 2019

Abstract
Metastasis, a major characteristic of malignancy, causes high mortality. Accumulating evidence suggests that cancer intends to metastasize to specific organ, however the molecular mechanisms remain unknown. Others and us have demonstrated that epithelial to mesenchymal transition (EMT) plays key roles in initiation of primary tumor adherent, migration, and invasion, whereas mesenchymal to epithelial transition (MET) revokes “sleeping” disseminated tumor cell (DTC) to colonization at distant metastatic organ sites and facilitates the tumor cell proliferation. We have successfully generated the lung-specific metastatic subclones of human prostate cancer PC3 and murine RM1 cells. Through omic bench work and data analysis and comparison with TCGA database, we, for the first time, identified a preliminary network of “driver genes” that potentially promotes the reversible EMT/MET process We utilized cutting-edge tools of data analysis to identify the selected driver genes (LAMA, SPP1, ITGB3, S100A8, SERPINE, DKK2) and further characterized the gene functions via in vitro bioassay of cell proliferation, migration, invasion, cell cycle, and apoptotic testing etc, and in vivo with our unique cell and animal metastatic models. We observed that the rate of organ-specific metastasis was dramatically reduced when these gene expression levels were changed. Finally, we confirmed our findings using TMA slides, Our results may provide novel mechanisms of metastasis and clinical targets of cancer therapy. Supported by NSFC projects 81773146; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research (2017B030301018); JCYJ20170412152943794, JCYJ20170412154619484, JCYJ20170307105128101, JCYJ2017030711041760
Note: This abstract was not presented at the meeting.
Citation Format: Ming Chang, Xin Huang, Songjian Lu, Wei Zhang, Weiping Liang, Evan Keller, Xinghua Lu, Jian Zhang. Driver genes network promotes mesenchymal to epithelial transition and organ-specific metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2784.
Abstract 2787: Artificial intelligence approach identifies IL2RB as a common prognostic and potential predictive biomarker associated with immune checkpoints in colorectal cancer
Authors: Alderdice Matthew , Craig Stephanie , Humphries Matt , Gilmore Alan , Bingham Victoria , Johnston Nicole , McQuaid Stephen , Salto-Tellez Manuel , Lawler Mark , McArt Darragh G. 
Published: August 2019

Abstract
Identifying robust predictive biomarkers to enable stratification of colorectal cancer (CRC) patients, based on their response to immune checkpoint therapy, is an area of unmet clinical need. Genetic algorithms represent an exciting branch of artificial intelligence which can be used to extract meaningful associations from ‘big data’ now emerging more frequently in oncological research. We have employed Atlas Correlation Explorer (ACE), a user-friendly workbench that utilises a genetic algorithm to mine data deposited in The Cancer Genome Atlas (TCGA). Our aim was to establish common intersections between gene expression analyses in ACE using nine well established immune checkpoint markers (CD274, PDCD1, CTLA4, LAG3, TIM3, TIGIT, ICOS, IDO1 and BTLA). We observed IL2RB to be the common gene associated with immune checkpoints in both microarray and RNA sequencing data from the TCGA (7/9 gene lists). Assessment of IL2RB indicates that it is highly expressed on CD56+ natural killer cells and is associated with an increased infiltration of cytotoxic lymphocytes and a decreased infiltration of fibroblasts. It is also significantly enriched in the immune consensus molecular subtype group CMS1. We next demonstrated that patients with high IL2RB gene expression have better relapse free survival in the TCGA CRC cohort (n = 322, log-rank p = 0.011) and an all stage CRC validation cohort GSE39582 (n = 519, log-rank p = 0.006). It is also an independent prognostic factor by multivariate analysis (p = 0.01). We next observed strong correlations between IL2RB gene expression in CRC and previously published predictive gene signatures for anti-PD1 therapies in other solid tumours (Pearson correlation, R = 0.88). Finally, we optimised assessment of IL2RB immunohistochemistry in a large CRC cohort (n=661) using a digital pathology approach with the open-source QuPath software. To conclude, we have validated IL2RB as prognostic biomarker and have provided evidence to demonstrate that IL2RB expression could be used for CRC patient stratification in future immunotherapy based clinical trials.
Citation Format: Matthew Alderdice, Stephanie Craig, Matt Humphries, Alan Gilmore, Victoria Bingham, Nicole Johnston, Stephen McQuaid, Manuel Salto-Tellez, Mark Lawler, Darragh G. McArt. Artificial intelligence approach identifies IL2RB as a common prognostic and potential predictive biomarker associated with immune checkpoints in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2787.
Abstract 2790: Characterization of the immune microenvironment in brain metastasis from non-small cell lung cancer
Authors: Kudo Yujin , Haymaker Cara , Zhang Jiexin , Reuben Alexandre , Duose Dzifa Yawa , Fujimoto Junya , Roy-Chowdhuri Sinchita , Solis Luisa Maren , Dejima Hitoshi , Cuentas Edwin Roger , Mino Barbara , Abraham Ronald , Ikeda Norihiko , Luthra Rajyalakshmi , Lee Jack J. , Kadara Humam , Huse Jason T. , Wistuba Ignacio I. 
Published: August 2019

Abstract
Purpose Brain metastases can induce life-threatening events and their immune microenvironment is still unrevealed. To elucidate the probability of immune-oncology therapy for brain metastases, we utilized immune profiling of resected brain metastases and paired non-small cell lung cancer (NSCLC).
Methods To compare pure tumor-infiltrating lymphocytes (TILs) or tumor tissues between NSCLC and brain metastases, macro-dissection was performed before extracting DNA and RNA from 39 patients who received surgical resection of local NSCLC tumor lesions and brain metastases from matched patients. We applied gene expression analysis of mRNA by using a 770 gene panel related with cancer immune cells. Targeted sequencing of 50 cancer hotspot genes on extracted DNA was performed for genotyping. TCRß sequencing of extracted DNA was utilized for profiling of TCR repertoire.
Results We identified 161 differentially expressed genes, which reflected inhibition of dendritic cell maturation pathway, Th1 pathway, and leukocyte extravasation signaling pathway in brain metastases (p &lt; 0.01). VCAM1 was one of highly inter-connected network genes with low expression level in brain metastases. Immune cell profiling analysis illustrated low T-cell infiltration and higher ratio of macrophages against TILs in the brain metastases (p &lt; 0.001). The detected mutations in genotyping analysis were completely shared in 28 patients (71%). TCR sequencing analysis revealed that T-cell clones were expanded in 64% of patients with brain metastases. The majority of TCR repertoire in brain metastases were principally shared with the paired NSCLC, while the density of T cells was sparse in the brain metastases.
Conclusion The microenvironment in brain metastases from NSCLC was revealed to be immunosuppressive, with the majority of T-cell clones in brain metastases being shared with the primary lesion.
Citation Format: Yujin Kudo, Cara Haymaker, Jiexin Zhang, Alexandre Reuben, Dzifa Yawa Duose, Junya Fujimoto, Sinchita Roy-Chowdhuri, Luisa Maren Solis, Hitoshi Dejima, Edwin Roger Cuentas, Barbara Mino, Ronald Abraham, Norihiko Ikeda, Rajyalakshmi Luthra, Jack J. Lee, Humam Kadara, Jason T. Huse, Ignacio I. Wistuba. Characterization of the immune microenvironment in brain metastasis from non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2790.
Abstract 2791: RelB upregulates PD-L1 in advanced prostate cancer: An insight into tumor immunoescape
Authors: Zhang Yanyan , Zhu Shuyi , Qian Peipei , Wang Xiumei , Xu Zhi , Sun Wenbo , Xu Yong 
Published: August 2019

Abstract
Interaction between programmed death (PD)-1 receptor and its ligand (PD-L1) is essential for suppression of activated T-lymphocytes. Thus, the high level of PD-L1 in tumors is critical for triggering the inhibitory effect on T cell responses leading to immunoescape. However, the mechanism underlying PD-L1 overexpression in cancers remains fully elucidated. Hence, we demonstrate that PD-L1 is uniquely expressed at a high level in advanced prostate cancer with high constitutive RelB, a member to drive the NF-κB alternative pathway. Clinical investigation indicated that the high levels of RelB/PD-L1 are correlated to the patient’s Gleason scores, which was confirmed by quantification of their levels in several prostate cancer cell lines vs. normal prostate epithelial cell. Knocked out RelB in androgen-independent PC-3 cells resulted in reducing PD-L1 expression. Consistently, ectopic expression of RelB in androgen-dependent 22Rv1 cells led to increasing PD-L1 level, implicating that RelB participates in PD-L1 regulation in prostate cancer. Cytokine IFN-γ is able to induce PD-L1 expression through promoting RelB nuclear translocation, revealing that RelB may directly regulate PD-L1 transcription. Accordingly, an NF-κB enhancer element was identified in the promoter region, which is responsible for RelB-mediated PD-L1 transcriptional activation. These results suggest that overexpression of PD-L1 in advanced prostate cancer is, at least in part, through RelB activation. The finding from this study provides a potential approach for enhancing immunotherapeutic efficiency by targeting RelB-activated NF-κB alternative pathway.
Note: This abstract was not presented at the meeting.
Citation Format: Yanyan Zhang, Shuyi Zhu, Peipei Qian, Xiumei Wang, Zhi Xu, Wenbo Sun, Yong Xu. RelB upregulates PD-L1 in advanced prostate cancer: An insight into tumor immunoescape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2791.
Abstract 2793: Mismatch repair proficient colorectal cancer and adaptive immunosuppression of endogenous anti-tumor immune response: Implications for immunotherapy
Authors: Llosa Nicolas , Awan Anas H. , Tam Ada J. , Fan Hongni , Smith Kellie N. , Sears Cynthia L. , Wang Hao , Pardoll Drew M. , Anders Robert A. , Housseau Franck 
Published: August 2019

Abstract
The tumor immune microenvironment (TiME) of mismatch-repair deficient (MMRd) colorectal cancer (CRC) is characterized by a cytotoxic T cell immune signature and counter-expression of IFNγ -inducible T cell checkpoints, features underlining intratumoral adaptive immunosuppression and sensitivity to immune checkpoint blockade. Since single-agent checkpoint inhibitors have not demonstrated, so far, similar meaningful clinical activity for MMR proficient (MMRp) CRC, we compared the tumor immune microenvironment (TiME) in CRC patients that responded to anti-PD1 therapy with the TiME of patients that did not (NCT01876511) to identify immune signatures and biomarkers that could help deciding on combinatorial immunotherapies to treat patients with MMRp CRC. With this approach, we detected immunoreactive MMRp (irMMRp) tumors characterized by a dense infiltration with cytotoxic T cells (CTL) as well as high expression of IFNγ and CD274 (PD-L1), despite their low tumor mutation burden. We observed that these irMMRp colon tumors are characterized by a negative association between Indolamine 2,3 dioxygenase 1 (IDO1) expression and Th17 infiltration. Despite the high expression of CD8 and PD-L1 expression, only irMMRp CRC with high expression of IDO1 on tumor cells and low infiltration with Th17 cells have a TiME resembling the TiME of CRC responding to anti-PD1. Since IDO1-derived tryptophan metabolites, kynurenines, are known to repress Th17 differentiation, these results suggested that the use of IDO1 small molecule inhibitors may derepress Th17 infiltration in CRC and blunt the effect of anti-PD1. Combining therapy with IDO1/PD1 inhibitors with drugs inhibiting IL-17 signaling pathway may help to treat irMMRp CRC patients.
Citation Format: Nicolas Llosa, Anas H. Awan, Ada J. Tam, Hongni Fan, Kellie N. Smith, Cynthia L. Sears, Hao Wang, Drew M. Pardoll, Robert A. Anders, Franck Housseau. Mismatch repair proficient colorectal cancer and adaptive immunosuppression of endogenous anti-tumor immune response: Implications for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2793.