bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 728: Genomic alterations in lung adenocarcinoma precursor lesions
Authors: Asiedu Michael K. , Reed Nanette R. , Aubry Marie Christine , Roden Anja C. , Wigle Dennis A. 
Published: August 2019

Abstract
Background: Adenocarcinoma of the lung is the most common type of non-small cell lung cancer and is the subtype found in approximately 50% of all lung cancer cases. Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are thought to be precursor lesions of invasive disease. It has been hypothesized that there is a step-wise progression to lung adenocarcinoma, but little is known about genomic alterations in these precursor lesions.
Methods: Genomic analysis including whole genome and exome sequencing, and SNP array analysis were performed on 9 AIS and 18 MIA pathologically confirmed samples to identify single nucleotide variants (SNVs), structural variations and copy number variations. Mutation significance and signature analysis were determined by MutSig and NMF analyses. Altered pathways were determined by Ingenuity variant effect pathway analysis.
Results: The tumor mutation burden (TMB) for AIS and MIA ranged from 0.8 to 23.1 mut/Mb with a median of 3.0mut/Mb and a mean of 5.1mut/Mb. Highly mutated genes identified in AIS and MIA were RPL10, NBPF1, KRAS, GPR52, CAMK2A, ATOX1, STK11, TP53, MET and EGFR. Genes with recurrent mutations included SPTA1, USH2A, CACNA1E, EGFR, KRAS, MUC16, MUC17, OTOG, RYR2, COL20A1, CSMD3, RFX6 and XIRP2, which implicated pathways involving the EGFR-KRAS-TP53-MAPK axis. Somatic mutations were characterized by a C&gt;T, T&gt;C transitions and C&gt;A transversion signature. There were comparable structural variations in the AIS cases compared to MIA.
Conclusion: In contrast to hypothesized models of tumor progression, AIS and MIA can harbor significant genomic alterations and tumor mutation burden, which suggests an intriguing concept of immunotherapeutic options for either treatment or chemoprevention. Deregulation of EGFR-KRAS-TP53-MAPK pathway indicates a role in early events of carcinogenesis.
Citation Format: Michael K. Asiedu, Nanette R. Reed, Marie Christine Aubry, Anja C. Roden, Dennis A. Wigle. Genomic alterations in lung adenocarcinoma precursor lesions [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 728.
Abstract 734: Large-scale radiogenomic profiling of patient derived xenografts (PDX)
Authors: Gopal Priyanka , Bera Titas , Peacock Craig , Abazeed Mohamed 
Published: August 2019

Abstract
The determinants of clinical failure after radiotherapy remains poorly understood. Although cancer derived cells grown in vitro have served as a valuable resource to identify tumor cell intrinsic determinants of radiation sensitivity, their propensity to undergo genetic selection due to non-native culture conditions reduces intratumoral heterogeneity and alters transcriptomic fidelity. We show that patient-derived xenografts (PDX) models recapitulate the genetic and transcriptomic features of the primary tumors from which they are derived. We extend this characterization to an extensive collection of PDXs derived from multiple cancer types. We propose our “10,000 mice” PDX effort, which seeks to profile up to 500 PDX across 20 cancer types with multiple single fraction doses of radiation (2, 4, 6, 8, 10 Gy). We establish the feasibility of our approach using a 3x1x1 experimental design (3 mice per PDX per dose of radiation). Initial treatment responses following single doses radiation revealed that tumors exhibit significant variation in their response to radiation. Responses in PDX correlated with clinical outcomes, mainly in patients treated with radiation or chemoradiation alone. We compare pre- and post-irradiation PDX and deoncstruct the phylogenetic architecture of tumors before and after treatment selection. We show that in a substantial proportion of the tumors profiled to date, treatment resistance is regulated by subclonal outgrowths. Taken together, our results demonstrate the feasibility of high-content profiling of PDX to identify determinants of radiation sensitivity.
Note: This abstract was not presented at the meeting.
Citation Format: Priyanka Gopal, Titas Bera, Craig Peacock, Mohamed Abazeed. Large-scale radiogenomic profiling of patient derived xenografts (PDX) [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 734.
Abstract 756: Whole exome sequencing identifies frequent mutations of PTPRB and KDR in secondary angiosarcoma
Authors: Gayden Tenzin , Dickson Brendan C. , Nikbakht Hamid , Fiset Pierre-Olivier , Jay Nicolas De , Nadaf Javad , Burk David L. , Berghuis Albert , Gladdy Rebecca , Wunder Jay , Turcotte Robert , Majewski Jacek , Jabado Nada 
Published: August 2019

Abstract
Angiosarcoma is an uncommon malignant vascular tumor that can occur anywhere on the body, with a predilection for the skin or soft tissues of the scalp and face.
By whole exome sequencing, we identified recurrent somatic mutations in PTPRB, which encodes an endothelial-specific phosphatase that negatively regulates angiogenesis, in three secondary angiosarcoma tumors (3/10). In addition, four tumors harbored missense variants in the KDR gene, including three germline substitutions. Neither the PTPRB nor the KDR alterations were found in the 5 primary tumors studied. Copy number analysis derived from the exome and methylation data revealed frequent MYC amplification in the majority of secondary angiosarcoma tumors (9/10).
Altogether, our data provide a comprehensive overview of genetic and epigenetic landscapes of angiosarcoma, and demonstrate that aberrant angiogenesis associated with PTPRB and KDR mutations may contribute to the pathogenesis of angiosarcoma.
Citation Format: Tenzin Gayden, Brendan C. Dickson, Hamid Nikbakht, Pierre-Olivier Fiset, Nicolas De Jay, Javad Nadaf, David L. Burk, Albert Berghuis, Rebecca Gladdy, Jay Wunder, Robert Turcotte, Jacek Majewski, Nada Jabado. Whole exome sequencing identifies frequent mutations of PTPRB and KDR in secondary angiosarcoma [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 756.
Abstract 757: MiR-141-3p is upregulated in esophageal squamous cell carcinoma and targets pleckstrin homology domain leucine-rich repeat protein phosphatase-2, a negative regulator of the PI3K/AKT pathway
Authors: Akagi Ichiro , Ishibashi Osamu , Ogawa Yota , Takizawa Toshihiro 
Published: August 2019

Abstract
The phosphatidylinositol-3-kinase (PI3K)/AKT pathway is frequently activated in various human cancers and plays essential roles in their development and progression. Accumulating evidence suggests thatdysregulated expression of microRNAs (miRNAs) is closely associated with cancer progression and metastasis. Here, we focused on miRNAs that could regulate genes related to the PI3K/AKT pathway inesophageal squamous cell carcinoma (ESCC).To identify upregulated miRNAs and their possible target genes in ESCC, we performed microarraybased integrative analyses of miRNA and mRNA expression levels in three human ESCC cell lines and a normal esophageal epithelial cell line. The miRNA microarray analysis revealed that miR-31-5p, miR-141-3p, miR-200b-3p, miR-200c-3p, and miR-205-5p were expressed at higher levels in the ESCC cell linesthan the normal esophageal epithelial cell line. Bioinformatical analyses of mRNA microarray data identified several AKT/PI3K pathway-related genes as candidate targets of these miRNAs, which include tumor suppressors such as DNA-damage-inducible transcript 4 and pleckstrin homology domain leucine-rich repeat protein phosphatase-2 (PHLPP2). To validate the targets of relevant miRNAs experimentally, synthetic mimics of the miRNAs were transfected into the esophageal epithelial cell line. Here, we report that miR-141-3p suppress the expression of PHLPP2, a negative regulators of the AKT/PI3K pathway, as a target in ESCC.
Note: This abstract was not presented at the meeting.
Citation Format: Ichiro Akagi, Osamu Ishibashi, Yota Ogawa, Toshihiro Takizawa. MiR-141-3p is upregulated in esophageal squamous cell carcinoma and targets pleckstrin homology domain leucine-rich repeat protein phosphatase-2, a negative regulator of the PI3K/AKT pathway [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 757.
Abstract 759: microRNA 26a-5p inhibited stemness and enhanced the chemosensitivity of non-small cell lung cancer
Authors: Son Jiwoong , Kwon Sun Jung , Jeong In Beom , Kim Ji Hye 
Published: August 2019

Abstract
Only a subpopulation of cells which have the ability to regulate self-renewal and differentiation of cancer cells, are able to tumorigenic capacity. This subpopulation of cells is called cancer stem cells (CSC). Cancer stem cells are also identified in lung cancer and exhibits resistance to chemotherapy, radiotherapy and targeted therapy. Therefore, the technology to control CSCs is a good strategy to overcome resistance to cancer therapy. Epithelial-mesenchymal transition (EMT) has been linked with the generation of cancer stem cells (CSCs). Recent evidence proposes that EMT-related transcriptomic alterations correlate with the acquisition of CSC phenotype. In previous study, we investigated the miRNA profiles of mesenchymal-like lung cancer cell lines to evaluate the relationship beween EMT and miRNA in non-small cell lung cancer (NSCLC). miR-26a-5p is down-regulated in mesenchymal like lung cancer cell lines. These findings suggested miR-26a-5p may be involved in cancer stemness of lung cancer cells. To test that miR-26a-5p has a role in stemness of lung cancer, we performed colony formation assay, sphere formation assay and fluorescence activated cell sorting. RNA polymerase III subunit G (POLR3G) was selected as a candidate target of miR-26a-5p related to cancer stemness. To verify that miR-26a-5p regulates POLR3G, we performed qRT-PCR, western blot and luciferase assays. Cell proliferation assay was performed to evaluate miR-26a-5p’s role of chemosensitizer. The overexpression of miR-26a-5p induced a marked reduction of the colony formation and sphere formation in non-small lung cancer cell lines. Overexpression of miR-26a-5p lead to reduction of CD133+ cells. Co-treatment with miR-26-5p and Paclitaxel treatment showed a significant reduction of growth. miR-26a-5p regulated the expression of POLR3G at the mRNA and protein levels. These data demonstrate for the first time that miR-26a-5p suppresses lung cancer stemness by repressing POLR3G expression. This provides new insight into a potential approach for the treatment of lung cancer by regulating cancer stemness.
Citation Format: Jiwoong Son, Sun Jung Kwon, In Beom Jeong, Ji Hye Kim. microRNA 26a-5p inhibited stemness and enhanced the chemosensitivity of 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 759.
Abstract 763: The regulation of miR-125b1-peroxiredoxin like 2A anti-oxidative activity in oral squamous cell carcinoma
Authors: Chen Yi-Fen , Wei Yun-Yen , Yang Cheng-Chieh , Chang Kuo-Wei , Lin Shu-Chun 
Published: August 2019

Abstract
Head and neck cancer, including oral squamous cell carcinoma (OSCC), is the sixth most common cancer worldwide. MicroRNAs are small non-coding RNAs that are involved in the modulation of biological/pathological properties. Peroxiredoxin like 2A (PRXL2A) has been reported to be an antioxidant protein that protects cells from oxidative stress. Our previous study identified an association between PRXL2A up-regulation in OSCC and a worse patient prognosis. The miR-125 family of genes drive pluripotent regulation across a wide variety of cancers. In this study, we identify the oncogene eligibility of PRXL2A and clarify miR-125b as its upstream regulator. Down-regulation of miR-125b can be observed in OSCC tumors. Lower miR-125b expression in tumors results in a worse patient prognosis at the relatively early stage. Reporter assays were able to validate that PRXL2A is a direct target of miR-125b. Exogenous miR-125b expression in OSCC cells results in increased oxidative stress and drug sensitivity, and suppressor activity that is paralleled by the knockout of PRXL2A gene. The suppressor activity of miR-125b is able to be rescued by PRXL2A, which suggests the existence of a miR-125b-PRXL2A regulatory axis that is part of OSCC pathogenesis. Nuclear factor erythroid-2-related factor was found to be a downstream effector of the miR-125b-PRXL2A cascade. As a whole, this study has pinpointed novel clues demonstrating that down-regulation of miR-125b suppressor underlies up-regulation of PRXL2A in OSCC, and this then protects the affected tumor cells from oxidative stress resulting in a worse prognosis.
Citation Format: Yi-Fen Chen, Yun-Yen Wei, Cheng-Chieh Yang, Kuo-Wei Chang, Shu-Chun Lin. The regulation of miR-125b1-peroxiredoxin like 2A anti-oxidative activity in oral squamous cell carcinoma [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 763.
Abstract 764: MicroRNA-1205 contributes to the risk of castration-resistant prostate cancer
Authors: Wen Wen , Wang Yicun , Zhang Yue , Cui Xuelian , Liu Xiaoguang M. , Liu Runhua 
Published: August 2019

Abstract
Although death rates for prostate cancer are down about 50% as a result of improvements in early detection and treatment, it is still the second leading cause of death (26,120 cases) for American men. However, the genetic mechanism underlying the development and progression of prostate cancer remains poorly understood. It is therefore important to identify the genetic risk factors for prostate cancer. Genome-wide association studies (GWAS) showed evidence for an association of prostate cancer risk with independent genetic variants on chromosome 8q24, conferring prostate cancer susceptibility at this locus. Nevertheless, at the locus with these genetic variants, no specific gene has been identified as responsible for the risk of prostate cancer. At 8q24.21, there is a long-range interaction of these genetic variants with c-MYC or long non-coding RNAs (lncRNAs) in a tissue-specific manner, including prostate, suggesting master genetic factors at 8q24.21 that contribute to this genetic risk. The chromosome 8q24.21 locus, which contains the proto-oncogene c-MYC, long non-coding RNA PVT1, and microRNAs (miRs), is the most commonly amplified region in human prostate cancer. Here, the copy numbers and expressions of miRs-1204~1208 were investigated using quantitative PCR for prostate cancer cell lines and primary tumors. The data revealed that copy numbers and expression of miR-1205 were increased in both castration-resistant prostate cancer cell lines and primary tumors. In castration-resistant prostate cancer specimens, the copy number at the miR-1205 locus correlated with expression of miR-1205. Furthermore, functional analysis with a miR-1205 mimic, a miR-1205 inhibitor, and CRISPR/Cas9 knockout revealed that, in human prostate cancer cells, miR-1205 promoted cell proliferation and cell cycle progression but not apoptosis. In these cells, miR-1205 downregulated expression of the Egl-9 family hypoxia inducible factor 3 (EGLN3) gene and targeted a site in its 3’-untranslated region to downregulate its transcriptional activity. Thus, by targeting EGLN3, miR-1205 has an oncogenic role and may contribute to the genetic risk of castration-resistant prostate cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Wen Wen, Yicun Wang, Yue Zhang, Xuelian Cui, Xiaoguang M. Liu, Runhua Liu. MicroRNA-1205 contributes to the risk of castration-resistant prostate 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 764.
Abstract 766: Mutual negative regulation of EZH2 and miR-4448 for tumor progression via epithelial mesenchymal transition in small cell lung cancer
Authors: Koyama Nobuyuki , Ishikawa Yuichi , Iwai Yuki , Aoshiba Kazutetsu , Nakamura Hiroyuki , Hagiwara Koichi 
Published: August 2019

Abstract
Enhancer of zeste homolog 2 (EZH2) is a catalytic component of polycomb repressive complexes, promotes tumor progression and metastasis. Expression levels of EZH2 are associated with clinical outcomes in a variety of tumors. High expression levels of EZH2 have been reported in cell lines and tissues of small cell lung cancer (SCLC), which is characterized by its invasiveness and metastatic potentials. Epithelial-mesenchymal transition (EMT) is well recognized to contribute to aggressiveness of SCLC, and microRNA (miRNA) is known to be associated with both EMT and the biological characteristics of SCLC. The aim of this study was to identify a novel miRNA defining EZH2-assciated EMT and tumor aggressiveness in SCLC. Immunohistochemistry and quantitative PCR showed that EZH2 expressions levels were decreased in three types of SCLC cell lines and tumor tissues from 34 patients with SCLC. Small interfering RNA (siRNA) against EZH2 suppressed its expression and EMT in SBC3 and SBC5 cell lines, both of which had high EZH2 expression levels as SCLC cell lines. Comprehensive miRNA expression analysis was used to compare changes of miRNA expression between EZH2 siRNA-transfected cells and mock-transfected cells. As a result, miR-4448 expression was significantly decreased in
SBC3 and SBC5 cells transfected with EZH2 siRNA. Cell growth assay and cell invasion assay revealed that overexpression of miR-4448 inhibited cellular proliferation and invasion potential. Furthermore, we confirmed that overexpression of miR-4448 abrogated EMT and decreased EZH2 expression. In conclusion, EZH2 and miR-4448 mutually suppressed these expressions and functions, which was associated with tumor progression via EMT in SCLC. The findings of this study suggest that miR-4448 may play a crucial role in the biological characteristics of SCLC.
Citation Format: Nobuyuki Koyama, Yuichi Ishikawa, Yuki Iwai, Kazutetsu Aoshiba, Hiroyuki Nakamura, Koichi Hagiwara. Mutual negative regulation of EZH2 and miR-4448 for tumor progression via epithelial mesenchymal transition in 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 766.
Abstract 769: Mechanistic role of miR-29 in pancreatic ductal adenocarcinoma progression
Authors: Dey Shatovisha , Kwon Jason J. , Liu Sheng , Factoria Tricia , Hodge Gabriel A. , Wan Jun , Kota Janaiah 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with a 5-year survival rate of 8% (Kota et al., 2017, Cancer Lett.). Lack of curative treatment for PDAC warrants better understanding of its mechanisms. Our previous work demonstrated that miR-29 is commonly downregulated in PDAC, while its restoration exhibits tumor-suppressive effects (Kwon et al., 2016, Oncotarget; Kwon et al., 2015, Sci Rep.). To understand these mechanisms, first we performed siRNA mediated knockdown of several miR-29 promoter binding transcription factors, including MYC, which play a role in PDAC. Our results indicate MYC represses miR-29 expression, and MYC nuclear localization negatively correlates with miR-29 in pancreatic cancer cells (PCCs). Next, to identify global miR-29 targets associated with PDAC, we conducted RNAseq on two miR-29 overexpressing PCC lines. This identified 41 overlapping miR-29 targets downregulated in both datasets. Gene ontology and survival correlation analyses identified seven most prominent targets (LOXL2, MYBL2, TRIB2, HGK, NRAS, CD276 and CLDN1). Ectopic expression of miR-29 significantly altered protein levels of these genes, confirming a translational suppression mechanism mediated by miR-29. RNAi mediated silencing of these targets significantly reduced the migratory ability of the PCCs. Our top target LOXL2 is involved in regulation of EMT/migration and extracellular matrix (ECM) remodeling. Luciferase reporter assay verified LOXL2 as a direct miR-29 target in PDAC. Immunohistochemical analyses in clinical specimens from PDAC patients and KPC mice pancreatic tissues showed higher LOXL2 expression in regions of pancreatic intraepithelial neoplasia (PanIN) lesions as compared to non-cancerous areas. This increased LOXL2 level was accompanied by concomitant reduction in miR-29 expression. Thus, our current study provides insight into new miR-29 mediated regulatory pathways in PDAC and reveals the association of miR-29-LOXL2 axis in the disease progression. Together, our data suggest miR-29 to play a critical role in mechanisms of PDAC progression and could serve as a potential therapeutic target for the disease.
Citation Format: Shatovisha Dey, Jason J. Kwon, Sheng Liu, Tricia Factoria, Gabriel A. Hodge, Jun Wan, Janaiah Kota. Mechanistic role of miR-29 in pancreatic ductal adenocarcinoma progression [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 769.
Abstract 771: CMTM6-mediated maintenance of sarcoma malignancy
Authors: Nishiyama Yuko , Tsuchiya Naoto 
Published: August 2019

Abstract
Sarcomas are malignant bone and soft tissue tumors that have highly aggressive and metastatic features. To reveal molecular networks associated with sarcomas, comprehensive expression profiles were generated using clinical samples. We identified miR-451a, showing different levels according to the prognosis of Ewing’s sarcoma (EWS) patients. High expression of miR-451a was also associated with good prognoses of patients with other types of sarcomas, suggesting repression of malignant properties across histological subtypes. Although miR-451a did not affect cell proliferation, it strongly repressed migration of EWS cells. Using gene expression analysis, we identified that CMTM6, encoding a chemokine-like membrane protein, was a target of miR-451a. Depletion of CMTM6 suppressed cell migration and induced changes in the expression of genes encoding plasma membrane and secretory proteins. Interestingly, we found high levels of CMTM6 mRNA under low-glucose culture conditions. Unexpectedly, under the same conditions, high extracellular miR-451a levels were observed; this suggested that the glucose level might be a modulator of the miR-451a-CMTM6 axis. Our data suggest that the malignant properties of sarcoma are influenced by the nutrient status of the tumor microenvironment.
Citation Format: Yuko Nishiyama, Naoto Tsuchiya. CMTM6-mediated maintenance of sarcoma 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 771.