bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5191: Genome-wide mutational analysis reveals core signaling pathways in mucinous neoplasms of the appendix
Authors: Alakus Hakan , Babicky Michele , Ghosh Pradipta , Yost Shawn , Jepsen Kristen , Dai Yang , Arias Angelo , Samuels Michael , Mose Evangeline , Peterson Michael , Lowy Andrew , Frazer Kelly , Harismendy Olivier 
Published: May 2015

Abstract
Mucinous Neoplasm of the Appendix (MNA) is a rare malignancy often diagnosed after metastasis to the peritoneal surfaces resulting in Mucinous Carcinomatosis Peritonei (MCP). Genetic alterations in MNA are poorly characterized due to its low incidence, the hypo-cellularity of MCPs and a lack of relevant pre-clinical models. As such, application of targeted therapies to this disease is limited to those developed for colorectal cancer (CRC) and not based on molecular rationale. We sequenced the whole exomes of 10 MCPs to identify genome-wide somatic mutations and copy number aberrations and validated significant findings in 19 additional cases using deep sequencing and microdroplet PCR. These studies demonstrate that MNA has a different molecular makeup than CRC. Most tumors have co-existing oncogenic mutations in KRAS (26/29) and GNAS (21/29) and are characterized by cAMP-PKA pathway activation. High-grade tumors are GNAS wild-type (5/6), suggesting they do not progress from low-grade tumors. MNAs do share some genetic alterations with CRC including gain of 1q (5/10), Wnt and TGFβ pathway alteration. In contrast, mutations in TP53 (1/10) and APC (0/10), common in CRC, are rare in MNA. Coincident activation of the Ras-Raf-MEK-ERK and cAMP-PKA signaling pathways appears to be shared with pancreatic intraductal papillary mucinous neoplasm. Thus, MNA genome-wide mutational analysis reveals genetic alterations distinct from CRC, in support its unique pathophysiology and suggests MEK and PKA inhibition as new therapeutic opportunities.
Citation Format: Hakan Alakus, Michele Babicky, Pradipta Ghosh, Shawn Yost, Kristen Jepsen, Yang Dai, Angelo Arias, Michael Samuels, Evangeline Mose, Michael Peterson, Andrew Lowy, Kelly Frazer, Olivier Harismendy. Genome-wide mutational analysis reveals core signaling pathways in mucinous neoplasms of the appendix. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5191. doi:10.1158/1538-7445.AM2014-5191
Abstract 5193: Novel candidate oncogenes with mutation hot spots in microsatellite unstable colorectal cancer
Authors: Gylfe Alexandra E. , Tuupanen Sari , Hänninen Ulrika , Kondelin Johanna , Ristolainen Heikki , Katainen Riku , Pitkänen Esa , Taipale Minna , Taipale Jussi , Andersen Claus Lindbjerg , Renkonen-Sinisalo Laura , Järvinen Heikki , Böhm Jan , Mecklin Jukka-Pekka , Vahteristo Pia , Aaltonen Lauri A. 
Published: May 2015

Abstract
Around 15% of colorectal cancers (CRCs) show microsatellite instability (MSI). MSI CRCs are prone to repeat mutations due to defective mismatch repair. The high background mutation frequency has discouraged systematic mutations screens in this tumor type. However, these tumors might form a sensitive system for generation and selection of oncogenic mutation hot spots. The aim of this study is to identify novel oncogenes with mutation hot spots that drive MSI CRC tumorigenesis.
The exomes of 25 MSI tumors and respective healthy tissues were sequenced as the discovery set. The exome data was searched for mutation hot spots, with recurrent somatic missense mutations in at least two tumors. Potential mutation hot spots were observed in 43 genes and among these were the following known oncogenes: BRAF (V600E), CTNNB1 (T41A) and PIK3CA (H1047R). Novel potential mutation hot spots were identified in 40 genes and these were validated by Sanger sequencing. Mutation hot spots in 33 genes were confirmed and these were further screened in a validation set of 254 MSI CRCs. Fourteen genes displayed hotspot mutations also in the validation set with a total hot spot mutation frequency of 1.1-3.6 %. Many of the validated genes encode for known cancer-related proteins and for proteins with molecular and cellular functions relevant to cancer development and progression.
Further work is needed to clarify the functional role of the identified hot spot mutations in MSI CRC tumorigenesis. The novel mutation hotspots may be utilized to develop personalized tumor profiling and therapy.
Citation Format: Alexandra E. Gylfe, Sari Tuupanen, Ulrika Hänninen, Johanna Kondelin, Heikki Ristolainen, Riku Katainen, Esa Pitkänen, Minna Taipale, Jussi Taipale, Claus Lindbjerg Andersen, Laura Renkonen-Sinisalo, Heikki Järvinen, Jan Böhm, Jukka-Pekka Mecklin, Pia Vahteristo, Lauri A. Aaltonen. Novel candidate oncogenes with mutation hot spots in microsatellite unstable colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5193. doi:10.1158/1538-7445.AM2014-5193
Abstract 5194: MiR-200c expression and methylation status determines epithelial characteristics of NSCLC
Authors: Shien Kazuhiko , Toyooka Shinichi , Soh Junichi , Yamamoto Hiromasa , Hashida Shinsuke , Suzawa Ken , Otsuka Tomoaki , Asano Hiroaki , Tsukuda Kazunori , Miyoshi Shinichiro 
Published: May 2015

Abstract
Background: MicroRNA (miR)-200 family members are frequently silenced in advanced cancer and have been implicated in the process of epithelial-to-mesenchymal transition (EMT) and tumor invasion. In this study, we investigated the roles of miR-200c in non-small cell lung cancer (NSCLC). Materials and Methods: We analyzed miR-200c promoter methylation status by methylation specific PCR and expression by quantitative RT-PCR in 34 NSCLC cell lines and 10 NSCLC clinical samples. To eliminate the effects of contamination of normal lung epithelial cells and mesenchymal cells in clinical samples, we used primary cultured NSCLC cells obtained by surgical resection. We assessed the association of miR-200c status with histology, EMT-related protein expression, and genetic alteration. Results: Mir-200c was methylated in 10 (30%) NSCLC cell lines and partially methylated in 7 (21%) cell lines. Expression of miR-200c was silenced in all methylated cell lines and restored with 5-aza-2′-deoxycytidine treatment. In cell lines with miR-200c methylation and silenced, protein expression of epithelial markers was reduced and mesenchymal markers were increased. Introduction of miR-200c into highly invasive cells with miR-200c silencing inhibited cell invasion. Interestingly, miR-200c was unmethylated and not silenced in many EGFR mutated NSCLC cell lines and clinical samples. In HEK293T cells stably transfected with wild-type EGFR, mutant EGFR, wild-type KRAS, or mutant KRAS, miR-200c expression was up-regulated only in mutant EGFR transfectant. Conclusions: Mir-200c expression was regulated by promoter methylation in NSCLC, and related to epithelial characteristics and cell invasion. In EGFR mutated NSCLC cells, miR-200c was generally unmethylated and expressed, suggesting the existence of mechanism that retain EGFR mutated NSCLC cells to the epithelial state through the miR-200c expression.
Citation Format: Kazuhiko Shien, Shinichi Toyooka, Junichi Soh, Hiromasa Yamamoto, Shinsuke Hashida, Ken Suzawa, Tomoaki Otsuka, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi. MiR-200c expression and methylation status determines epithelial characteristics of NSCLC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5194. doi:10.1158/1538-7445.AM2014-5194
Abstract 5196: Different miRNAs expression in leiomyosarcoma and undifferentiated pleomorphic sarcoma
Authors: Pazzaglia Laura , Guled Mohamed , Borze Ioana , Benassi Maria Serena , Picci Piero , Knuutila Sakari 
Published: May 2015

Abstract
Rare and highly aggressive adult soft tissue sarcomas, leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS), contain complex genomics characterized by a multitude of rearrangements, amplifications and deletions. Since differential diagnosis between the two sarcoma histotypes continues to remain a challenge, we attempted to identify a specific signature useful for improving the differential diagnosis, and we performed miRNA profiling on series of LMS and UPS samples stored at Rizzoli biobank. First, we investigated the different miRNA expression profile in 20 primary sarcoma samples, 10 high-grade LMS and 10 UPS, MFH-like, using miRNA array technique. The top 5 differentially expressed (p&lt;0.01) miRNAs (miR-199b-5p, miR-320a, miR-199a-3p, miR-126, miR-22) were validated by RT-PCR on a series of further 27 UPS and 21 LMS. Confirming our microarray data, an higher expression of miR-199-5p and a lower expression of miR-320a was seen in UPS when compared to LMS. To evaluate the potential role of the above selected miRNAs, the gene targets recognized by three different target prediction databases (miRBase, TargetScan , miRanda) were combined with a list of LMS- and UPS-associated genes reported in literature. From an integrated analysis, IMP3, ROR2, MDM2, CDK4, and UPA genes were identified. By immunohistochemistry analysis, most of them showed strong protein expression in LMS group. Our data suggest a potential role of miR-320a and miR-199-5p in LMS and UPS development and expand our knowledge about these complex sarcoma histotypes. Association analysis between expression and chromosomal locations of miRNAs are ongoing to identify chromosomal regions involved in these tumors.
Citation Format: Laura Pazzaglia, Mohamed Guled, Ioana Borze, Maria Serena Benassi, Piero Picci, Sakari Knuutila. Different miRNAs expression in leiomyosarcoma and undifferentiated pleomorphic sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5196. doi:10.1158/1538-7445.AM2014-5196
Abstract 520: Functional genomic screens identify microRNA regulators of the oncogenic fusion transcription factor EWS-FLI1
Authors: Kim Suntae , Grohar Patrick J. , Klumpp Carleen , Lal Ashish , Martin Scott E. , Helman Lee J. , Caplen Natasha J. 
Published: May 2015

Abstract
Ewing sarcoma (ES) is a highly aggressive malignant pediatric cancer of the bone and soft tissue with a poor prognosis. The genetic hallmark of ES is the t(11:22)(q24:q12) translocation that generates a fusion transcript containing the 5’ end of EWSR1 and the 3’ end of FLI1 referred to as EWS-FLI1. This fusion generates an oncogenic transcription factor, EWS-FLI1 that is responsible for malignant transformation and is necessary for ES cell survival. To enhance our understanding of the molecular mechanisms underlying ES, with the long-term aim of enhanced treatment for this cancer, we are applying RNAi functional genomic approaches. MicroRNAs (miRNAs) are critical regulators of gene expression. There is evidence that many transcription factors and miRNAs act in concert to regulate gene expression. To identify miRNAs that directly or indirectly modulate EWS-FLI1 activity we conducted parallel screens of mimics or inhibitors of the human miRome using a cell-based reporter assay. The reporter assay consists of two isogenic reporter cell lines generated in the EWS-FLI1 expressing TC32 cell line. One line harbors a luciferase reporter driven by the promoter of an established EWS-FLI1 target NR0B1, while the second line expresses luciferase from a constitutive CMV promoter. A comparison of the effects of a miRNA on these two reporter constructs can identify proteins that specifically modulate EWS-FLI1 activity. We first identified those miRNAs for which a differential effect was seen when the NR0B1- and CMV-luciferase signals were compared and prioritized those where the mimic and inhibitor corresponding to a specific miRNA exhibited opposite effects. Twenty-eight miRNAs were identified, including miR-145, an established regulator of EWS-FLI1. The screen also identified miRNAs that have not been linked to EWS biology. One such candidate is miR-200b, a known regulator of epithelial-mesenchymal transition and tumor progression. We have confirmed that biotinylated-miR-200b captures the EWS-FLI1 mRNA when transfected into TC32 and ∼300 other mRNAs that includes EWS-FLI1 target genes. This functional genomic approach gives us an opportunity to investigate the co-regulatory activity of an oncogenic transcription factor and miRNAs in a systematic fashion that could be extended to investigate the co-regulation of other transcription factors and miRNAs.
Citation Format: Suntae Kim, Patrick J. Grohar, Carleen Klumpp, Ashish Lal, Scott E. Martin, Lee J. Helman, Natasha J. Caplen. Functional genomic screens identify microRNA regulators of the oncogenic fusion transcription factor EWS-FLI1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 520. doi:10.1158/1538-7445.AM2014-520
Abstract 5200: MicroRNA-634 induces caspase-dependent apoptosis by targeting anti-apopotic and mitochondria-related genes in human cancer cells
Authors: Fujiwara Naoto , Inoue Jun , Kawano Tatsuyuki , Kozaki Ken-ichi , Inazawa Johji 
Published: May 2015

Abstract
MicroRNAs (miRNAs) are endogenous small non-coding RNAs composed of 20∼25 base pairs that can negatively regulate gene expression by interfering with the translation of target transcripts. Since it has been known that some miRNAs function as tumor suppressors (TS) and their expression levels are often down-regulated in cancer, TS-miRNAs are expected to be therapeutic agents for cancer therapy. Thus, we conducted function-based screening using a miRNA library, and identified several TS-miRNAs, including miR-152, miR-218, miR-596.
Recently, we identified miR-634 as a new TS-miRNA, which induced cell death with mitochondrial dysfunction and caspase activation. The expression analysis and the target-prediction program revealed miR-634 might directly target genes related with anti-apoptosis and mitochondrial function.
Importantly, this miRNA was frequently down-regulated in primary tumor samples of esophageal squamous cell carcinoma (ESCC), compared with that in corresponding normal tissues. Furthermore, the combination therapy of miR-634 and cisplatin was effective to ESCC cell line in vitro and in vivo. Thus, these findings suggest that miR-634 may be useful as a potential therapeutic agent of ESCC.
Citation Format: Naoto Fujiwara, Jun Inoue, Tatsuyuki Kawano, Ken-ichi Kozaki, Johji Inazawa. MicroRNA-634 induces caspase-dependent apoptosis by targeting anti-apopotic and mitochondria-related genes in human cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5200. doi:10.1158/1538-7445.AM2014-5200
Abstract 5202: Yin Yang 1 is a target of miR-34 family and contributes to gastric carcinogenesis
Authors: Wang An-Ming , Huang Tzu-Ting , Hsu Kai-Wen , Chi Chin-Wen , Yeh Tien-Shun 
Published: May 2015

Abstract
Gastric cancer is one of the most common cancers and the second leading cause of cancer-related death worldwide. Transcription factor Yin Yang 1 (YY1) is a multi-functional protein and plays either oncogenic or tumor-suppressive roles in tumor development and progression. Herein, we investigated the role of YY1 in tumorigenesis of gastric cancer cells. Results showed that the forced expression of YY1 contributed to gastric carcinogenesis of SC-M1 cells. Whereas, the knockdown of endogenous YY1 suppressed tumorigenesis of SC-M1 cells. Additionally, the 3′-untranslated region (3′-UTR) of YY1 mRNA was the target of microRNA-34 (miR-34) family consisting of miR-34a, miR-34b, and miR-34c. The ectopic expression of miR-34 family down-regulated YY1 levels in gastric cancer cells. Endogenous YY1 expression was negatively correlated with miR-34b and miR-34c levels in gastric cancer cells. The overexpression of miR-34 family suppressed gastric carcinogenesis through down-regulation of YY1 in gastric cancer cells. Alternatively, the knockdown of endogenous miR-34 family promoted gastric carcinogenesis via up-regulation of YY1 in gastric cancer cells. The miR-34 family also regulated the xenografted tumor growth and lung metastasis of SC-M1 cells through YY1 in vivo. Taken together, these results suggest that miR-34 family-YY1 axis plays an important role in the control of gastric carcinogenesis.
Citation Format: An-Ming Wang, Tzu-Ting Huang, Kai-Wen Hsu, Chin-Wen Chi, Tien-Shun Yeh. Yin Yang 1 is a target of miR-34 family and contributes to gastric carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5202. doi:10.1158/1538-7445.AM2014-5202
Abstract 5209: MicroRNA-193a-5p suppresses tumor proliferation and enhances radio-sensitivity through ERBB2 in esophageal squamous cell carcinoma
Authors: Lu Pei-Jung 
Published: May 2015

Abstract
Esophageal cancer is the ninth leading cause of cancer death in Taiwan. Esophageal squamous cell carcinoma (ESCC) is usually managed with combined modalities, but the prognosis for ESCC patients is still dismal. MicroRNAs (miRNAs) have been implicated in a variety of human cancers progression, and their expression signatures can provide insight into the diagnosis and prognosis of human cancers. However, the dysregulated miRNAs promoted tumor progression in ESCC remain unclear. To address this goal, 1097 miRNAs were analyzed in nine pairs of ESCC and corresponding normal parts with microarray. Tumor suppressive miRNA, miR-193a-5p, was characterized and inversely correlated with poor prognosis of ESCC patients. Manipulating miR-193a-5p in ESCC cell lines and mouse tumor model, the cell proliferation was decreased and the radio-sensitivity was increased. We further used reporter assay to identify ERBB2 as the target of miR-193a-5p. Restored the ERBB2 expression abolished the effects of miR-193a-5p on cell proliferation and radio-sensitivity. These results indicated that miR-193a-5p played a tumor suppressive role through suppressing ERBB2, expression in esophageal squamous cell carcinoma.
Key words: miR-193a-5p, esophageal squamous cell carcinoma, radiotherapy
Note: This abstract was not presented at the meeting.
Citation Format: Pei-Jung Lu. MicroRNA-193a-5p suppresses tumor proliferation and enhances radio-sensitivity through ERBB2 in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5209. doi:10.1158/1538-7445.AM2014-5209
Abstract 521: Glioma-associated IDH mutation induces miR-34a repression and stem cell-like physiology through enhanced PDGF signaling
Authors: Silber Joachim , Harinath Girish , Parthasarathy Prasanna Tamarapu , Fabius Armida W.M. , Turcan Sevin , Chan Timothy A. , Huse Jason T. 
Published: May 2015

Abstract
Point mutations in isocitrate dehydrogenase enzymes (IDH1 and IDH2) have been identified in 70-90% of lower-grade gliomas (LGGs; WHO grade II and III) as foundational genomic alterations. Glioma-associated IDH mutations occur in active site arginine residues and confer a neomorphic activity resulting in overproduction of the oncometabolite R(-)-2-hydroxyglutarate (2HG). The affects of 2HG on cellular physiology are widespread and include global shifts in epigenomic profiles. LGGs have also been repeatedly linked with dysregulated platelet-derived growth factor (PDGF) signaling. We have recently demonstrated that miR-34a is downregulated in gliomas in response to dysregulated PDGF signaling and that miR-34a directly targets the PDGF receptor (PDGFRA) in high-grade gliomas. Analyzing a panel of diffuse gliomas, we find that miR-34a is specifically downregulated in LGG in response to IDH mutation. Similarly, in multiple isogenic cell line systems, IDH mutation induces repression of miR-34a. Also in these contexts, IDH mutation induces neurosphere formation and the expression of stem cell-associated genes. miR-34a has been reported to target pluripotency factors such as LIN28, OCT4 and NANOG. Accordingly, we find that murine neuroglial progenitor cells expressing IDH mutant isoform express higher levels of these factors than isogenic controls. The stem cell-like phenotype of IDH mutant-expressing cells is morphologically reversed by restoring miR-34a expression in the cells. Despite findings that IDH mutation correlates with hypermethylation at the MIR34a locus in LGG tumors, we have not been able to demonstrate the functional relevance of this. Instead, we find that IDH mutation is associated with enhanced PDGF signaling, and we demonstrate that inhibition or stimulation of PDGF signaling in IDH mutant cells increases or decreases miR-34a expression, respectively. Our studies support a model in which glioma-associated IDH mutation induces miR-34a repression and stem cell-like physiology through enhanced PDGF signaling.
Citation Format: Joachim Silber, Girish Harinath, Prasanna Tamarapu Parthasarathy, Armida W.M. Fabius, Sevin Turcan, Timothy A. Chan, Jason T. Huse. Glioma-associated IDH mutation induces miR-34a repression and stem cell-like physiology through enhanced PDGF signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 521. doi:10.1158/1538-7445.AM2014-521