bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1158: Differential expression and functional impact of the alternatively spliced transcripts of Extracellular matrix protein 1 in esophageal squamous cell carcinoma
Authors: YU Valen Zhuoyou , Ko Josephine Mun-Yee , Law Simon , Wang Li Dong , Lung Maria Li 
Published: July 2016

Abstract
Background: Esophageal squamous cell carcinoma (ESCC) has an especially high incidence in China, with five-year survival rates in Hong Kong being of ∼14%. An oligonucleotide microarray was utilized to identify differentially-expressed genes in ESCC using 31 pairs of matched normal/tumor samples from Hong Kong and Henan, China. Extracellular matrix protein 1 (ECM1) was among the top down-regulated genes, indicating a potential tumor-suppressive role. Public cDNA microarray data also shows significant down-regulation of ECM1 expression in ESCC. Interestingly, this gene has been extensively studied in breast cancer and thyroid cancer for its oncogenic role. There are three alternatively-spliced variants of ECM1. Therefore, this gene was selected for further variant expression and functional analysis in ESCC.
Results: RNA sequencing analysis of matched normal/ESCC samples showed that ECM1b (NM_022664) is the dominant expressed variant in esophagus, followed by ECM1a (NM_004425). In tumor samples, the expression of ECM1a is down-regulated and that of ECM1b is down-regulated or lost, as compared to normal counterparts. Expression of ECM1c (NM_001202858) is not detected in either normal or tumor samples. Quantitative PCR using variant-specific primer sets confirms the findings of microarray and RNA sequencing analyses. When re-expressed in ESCC cell lines after lentiviral transduction, ECM1b expression shows a trend of tumor suppression in the orthotopic ESCC mouse tumorigenicity model; ECM1a shows no tumor-suppressive effect in either. ECM1b expression also shows a metastasis inhibitory effect in a tail vein experimental metastasis model. Immunohistochemical staining shows E-cadherin up-regulation in orthotopic tumors re-expressing ECM1b.
Conclusions: These results suggest differential roles of variants of ECM1 in ESCC. Unlike the cases in other types of cancer, both expression of ECM1a and ECM1b is down-regulated in ESCC compared to normal esophageal tissues. ECM1b represents the dominantly expressed variants in esophagus epithelium, and its expression is highly reduced in esophageal carcinoma. ECM1b plays a potential suppressive role in tumorigenesis and metastasis.
Acknowledgement: We acknowledge the Research Grants Council of Hong Kong Special Administrative Region for funding support (HKU 774413M to M.L.L).
Citation Format: Valen Zhuoyou YU, Josephine Mun-Yee Ko, Simon Law, Li Dong Wang, Maria Li Lung. Differential expression and functional impact of the alternatively spliced transcripts of Extracellular matrix protein 1 in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1158.
Abstract 116: Study of TERT promoter and FGFR3 mutations in upper-tumor urothelial carcinomas
Authors: Mouawad Roger , Bensalma Souheyla , Su Xiaoping , Allanic Frederick , Comperat Eva , Rouprêt Morgan , Spano JeanPhillipe , Malouf Gabriel , Khayat David 
Published: July 2016

Abstract
Background: Mutations in the promoter of the telomerase reverse transcriptase (TERT) and fibroblast growth factor receptor 3 (FGFR3) genes represent the most recurrent somatic alterations in urothelial carcinomas of the bladder. However, data regarding frequency and prognostic values of these alterations in upper-tumor urothelial carcinoma (UTUC) remain limited.
Methods: DNA was extracted from 31 UTUC including 12 cases arising in the ureter and 19 in renal pelvis. Somatic mutations of TERT promoter and FGFR3 gene were assessed by Sanger sequencing. The generated sequences were analyzed by seqscape and mutational status of each of those genes were correlated with clinico-pathological tumor features. Disease-free survival and overall survival were estimated using the Kaplan-Meier method.
Results: Median patient's age was 72 years (range: 41-83) with a male predominance (90.3%). Mutation status of TERT and FGFR3 were obtained in all tumors. Out of 31 UTUC, 81% were classified as high-grade including 56% which were muscle-invasive (≥pT2). TERT and FGFR3 mutations were detected in 19 (61%) and 14 (46%) tumors, respectively. Of note, 8 (26%) out of them harbored both mutations. In the TERT-mutated subgroup, we observed higher incidence of men as compared to TERT non-mutated subgroup (p = 0.04); in addition, we did not identify any other significant differences regarding other clinico-pathological features. This was also the case for FGFR3 mutations, although we observed a higher frequency in tumors arising in the ureter (66.6%) as compared to those located in renal pelvis (28.5%) (p = 0.11). Neither mutations of FGFR3 nor TERT were associated with progression-free survival and patient's overall survival.
Conclusion: Our study identified a high rate of somatic mutations in FGFR3 and TERT which were similar between muscle-invasive and non-muscle invasive tumors as well as between tumors arising in the ureter or renal pelvis. As targeted inhibitors are being investigated in this setting, these results might have implications for patient's management.
Citation Format: Roger Mouawad, Souheyla Bensalma, Xiaoping Su, Frederick Allanic, Eva Comperat, Morgan Rouprêt, JeanPhillipe Spano, Gabriel Malouf, David Khayat. Study of TERT promoter and FGFR3 mutations in upper-tumor urothelial carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 116.
Abstract 1169: Somatic MED12 mutations in hematological malignancies
Authors: Heikkinen Tuomas , Kämpjärvi Kati , Leppä Sirpa , Hokland Peter , Kuusanmäki Heikki , Mustjoki Satu , Sinisalo Marjatta , Heckman Caroline , Kontro Mika , Vahteristo Pia 
Published: July 2016

Abstract
Somatic mutations in exons 1 and 2 of the Mediator complex subunit 12 (MED12) have been identified in 70% of uterine leiomyomas, 7-20% of uterine leiomyosarcomas, 59% of breast fibroadenomas and 67% of breast phyllodes tumors. In addition to female hormone-dependent tumors we have recently found the same specific missense and small in-frame insertion and deletion mutations in approximately 5% of chronic lymphocytic leukemias (CLL). In CLL the presence of MED12 mutations was also associated with markers of poor prognosis (IgVH (-), Zap70 (+), and Zap70-methylation). The surprising finding of the same mutations in a completely different tumor type prompted us to further screen other hematological malignancies for MED12 mutations.
We have thus far collected samples of 107 T-cell acute lymphoblastic leukemias (T-ALL), 21 large granular lymphocyte leukemias (LGL), 33 acute myeloid leukemias (AML), 154 diffuse large B cell lymphomas (DLBCL), and 6 six follicular lymphomas (FL). Also a set of 30 additional CLLs was collected. The MED12 mutation status was determined by direct Sanger sequencing of exons 1 and 2 of the gene. A c.107T&gt;G, p.L36R mutation was found in a single DLBCL case and c.100-8T&gt;A, p.E33_D34insPQ in one AML sample. A novel variant of uncertain significance, c.-3A&gt;G, was detected on 5’UTR of one FL sample. One T-ALL patient harbored a nonsense mutation affecting the last codon of exon 1 c.97G&gt;T, p.E33X. No mutations were identified in the LGL or CLL samples. We are also analyzing approximately 100 new AML samples and 100 multiple myeloma samples.
MED12 mutations are present, in addition to CLL, also in other hematological malignancies. The frequency, however, seems to be low and, as the number of samples in the preliminary analysis is limited, screening of larger sample sets is needed. The c.107T&gt;G, p.L36R and c.100-8T&gt;A, p.E33_D34insPQ mutations have previously been detected recurrently in uterine leiomyomas and in CLL. Further studies are required for evaluation of the effects of c.-3A&gt;G and c.97G&gt;T, p.E33X mutations. The latter mutation affects the last codon of exon 1, which is also a mutational hotspot in CLL, with recurrent missense mutations. MED12 exon 1 and 2 missense mutations disrupt the interactions between the Mediator complex and Cyclin C and cause loss of CDK8 kinase activity. Studies to determine the impact of the c.97G&gt;T, p.E33X mutation on MED12 function are ongoing.
Citation Format: Tuomas Heikkinen, Kati Kämpjärvi, Sirpa Leppä, Peter Hokland, Heikki Kuusanmäki, Satu Mustjoki, Marjatta Sinisalo, Caroline Heckman, Mika Kontro, Pia Vahteristo. Somatic MED12 mutations in hematological malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1169.
Abstract 118: A comprehensive profile of the genomic architecture of curable prostate cancer
Authors: Fraser Michael E. , van der Kwast Theodorus , McPherson John , Collins Colin C. , Fradet Yves , Tetu Bernard , Bergeron Alain , Bristow Rob G. , Boutros Paul C. 
Published: July 2016

Abstract
There is an urgent need to develop novel biomarkers of treatment response for precision medicine in prostate cancer, particularly in the setting of localized, non-indolent disease, which represents the vast majority of cases at initial clinical presentation. The Canadian Prostate Cancer Genome Network (CPC-GENE) - a member of the International Cancer Genome Consortium - aims to identify multi-modal prognostic and predictive signatures of therapeutic outcome based on intrinsic tumour genomics, transcriptomics, and epigenomics, which are being incorporated into novel clinical trials of treatment escalation/de-escalation for image-guided radiotherapy and/or radical prostatectomy. Herein we report the results of the largest prostate cancer whole-genome sequencing study to date, consisting of 194 patients and whole-exome sequencing of 479 patients with localized, potentially curable disease; a sample size that allows for saturating discovery of genes mutated at ≥1% frequency. We show that tumours treated by curative local therapy have a paucity of clinically-actionable mutations relative to high-risk localized or metastatic disease, but instead harbor a significant number of recurrent non-coding aberrations and genomic rearrangements, including a novel inversion - and an associated reduction in gene expression - of the PTEN tumour suppressor gene on chromosome 10. The median tumour contains three distinct driver mutations, with &gt;86% of tumours possessing at least one known driver. Importantly, multiple driver aberrations are associated with patient outcome, including copy number aberrations and methylation events, but notably excluding well-described recurrent events such as TMPRSS2:ERG fusions and SPOP point mutations. Localized hypermutation events (e.g. kataegis) were detected in &gt;20% of tumours, and were strongly enriched for aggressive disease. Taken together, these data provide a comprehensive analysis of the genomic landscape of localized, non-indolent prostate cancer. Moreover, our results strongly suggest that specific molecular aberrations may serve as useful biomarkers for improved pre-treatment stratification of patients with localized, low/intermediate risk disease into escalation/de-escalation protocols, and support the development of clinical trials to assess this hypothesis, based on patient-specific molecular profiles.
Citation Format: Michael E. Fraser, Theodorus van der Kwast, John McPherson, Colin C. Collins, Yves Fradet, Bernard Tetu, Alain Bergeron, Rob G. Bristow, Paul C. Boutros. A comprehensive profile of the genomic architecture of curable prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 118.
Abstract 1186: Inhibition of topoisomerase 2β sensitizes acute myeloid leukemia cells to ATRA induced apoptosis independent of the MAPK/ERK pathway
Authors: Norris Eric J. , Dorszynski Amy , Lucander Aaron , Destephanis Darla , Ganapathi Ram , Ganapathi Mahrukh 
Published: July 2016

Abstract
Pharmacologic inhibition or molecular down-regulation of topoisomerase 2β (TOP2β) potentiates all trans retinoic acid (ATRA)-induced differentiation and apoptosis in acute myeloid leukemia (AML) cells. Since ATRA-induced myeloid differentiation involves activation of the MAPK/ERK signaling pathway and aberrant activation of MAPK/ERK is frequently observed in AML we tested the role of this pathway in modulating the cellular effects of ATRA when TOP2β is inhibited with the bisdioxopiperazines, ICRF 187 (dexrazoxane, Zinecard™) or ICRF193. Treatment of HL-60 AML (M2) cells with ATRA increased the percentage of differentiated cells, as assessed by the nitroblue tetrazolium reduction assay, and enhanced levels of phosphorylated ERK. Paradoxically, while combination treatment with ATRA/ICRF187 enhanced differentiation (P&lt;0.05), ERK phosphorylation was attenuated compared to treatment with ATRA alone. Moreover, pretreatment with the MEK inhibitor PD98059, which completely blocks ATRA-induced differentiation and ERK phosphorylation, only partially blocked (46% reduction) differentiation induced by ATRA/ICRF187 (P&lt;0.01) and had no effect on ATRA/ICRF187-induced apoptosis. In agreement with this observation, combination treatment with ATRA/ICRF187 induced apoptosis (P&lt;0.05) in KG-1 (M1) AML cells and primary AML cells from patients, that do not phosphorylate ERK or differentiate in response to ATRA treatment. In summary, our data suggest that inhibition of TOP2β sensitizes AML cells to ATRA induced differentiation and apoptosis primarily via an ERK-independent mechanism. Further, combination treatment ATRA and ICRF187 may be clinically relevant to overcome ATRA resistance in AML patients with a deregulated MAPK/ERK signaling pathway.
Citation Format: Eric J. Norris, Amy Dorszynski, Aaron Lucander, Darla Destephanis, Ram Ganapathi, Mahrukh Ganapathi. Inhibition of topoisomerase 2β sensitizes acute myeloid leukemia cells to ATRA induced apoptosis independent of the MAPK/ERK pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1186.
Abstract 1209: Istiratumab (MM-141), a bispecific antibody targeting IGF-1R and ErbB3, inhibits pro-survival signaling in vitro and potentiates the activity of standard of care chemotherapy in vivo in ovarian cancer models
Authors: Curley Michael D. , Tan Gege , Yannatos Isabel , Camblin Adam , Iadevaia Sergio , Louis Chrystal , Lugovskoy Alexey 
Published: July 2016

Abstract
Insulin-like growth factor receptor 1 (IGF-1R) signaling has been implicated in the pathogenesis of ovarian cancer. However, clinical trials evaluating monospecific IGF-1R inhibitors have demonstrated limited clinical efficacy. Our data indicate that ErbB3, a member of the ErbB receptor tyrosine kinase family, can activate pro-survival AKT signaling in response to IGF-1R blockade and may represent a potential escape route in the development of resistance to therapy. Istiratumab (MM-141), an IGF-1R and ErbB3 directed bispecific antibody, inhibits ligand activation of these signaling pathways and degrades IGF-1R and ErbB3 receptor-containing complexes, leading to inhibition of downstream pro-survival signaling. Here we tested the activity of istiratumab, alone and in combination with chemotherapy, in in vitro and in vivo models of ovarian cancer.
Anti-proliferative activity of istiratumab monotherapy was evaluated in a panel of ovarian cancer cell lines in vitro. The effects of istiratumab and the ligands IGF-1 and heregulin on IGF-1R- and ErbB3-mediated survival signaling were tested by ELISA and immunoblotting. Co-treatment assays with istiratumab and chemotherapy investigated mechanisms of synergy and additivity. Anti-tumor activity of istiratumab, alone and in combination with chemotherapy, was tested in in vivo ovarian xenograft tumor models.
Our results indicated that istiratumab monotherapy inhibits ovarian cancer cell line proliferation in vitro. In addition, istiratumab blocked ligand-mediated resistance to chemotherapy. Co-treatment of istiratumab, ligands or chemotherapy indicated a strong correlation between drug activity and IGF-1R expression. Furthermore, co-treatment of chemotherapies and ligands potentiated AKT activation, which was inhibited by istiratumab. In vivo studies showed that istiratumab potentiates the activity of chemotherapy in ovarian xenograft tumor models.
Our findings demonstrate that co-inhibition of IGF-1R and ErbB3 signaling with istiratumab can potentiate standard of care chemotherapies in ovarian tumor models and warrant further investigation of istiratumab as a potential therapy for ovarian cancer patients.
Citation Format: Michael D. Curley, Gege Tan, Isabel Yannatos, Adam Camblin, Sergio Iadevaia, Chrystal Louis, Alexey Lugovskoy. Istiratumab (MM-141), a bispecific antibody targeting IGF-1R and ErbB3, inhibits pro-survival signaling in vitro and potentiates the activity of standard of care chemotherapy in vivo in ovarian cancer models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1209.
Abstract 121: Analysis and comparison of somatic copy number alterations in gastric cardia adenocarcinoma and gastric non-cardia adenocarcinoma
Authors: Liu Manjiao , Liu Zhen , Bai Jian , Cai Hong , Ke Yang , Zeng Changqing 
Published: July 2016

Abstract
Gastric adenocarcinoma is one of the most common cancer type worldwide. Anatomically it may raise from the cardia or non-cardia part of the stomach and previous studies have shown differential susceptibilities loci and prognosis between gastric cardia adenocarcinoma (GCA) and gastric non-cardia adenocarcinoma (GNCA). To better understand the genomic alterations that drive gastric adenocarcinoma and to investigate the differences of genetic aberration between GCA and GNCA, we analyzed somatic copy-number aberrations in 205 gastric adenocarcinomas resected samples, including 114 GCAs and 91 GNCAs using Illumina Human OmniZhongHua BeadChips. We identified 49 significantly recurrent focal alterations in gastric adenocarcinoma. In addition to those previously reported in stomach cancer, several novel focal changes were also observed, including gain of 11p11.2, 6q23.3, 12p11.1, 5p15.33 and loss of 8p11.22, 9p22.2, 18q22.1, 15q21.2, 17q23.3. A few known or potential oncogenes such as TERT, MYB, and IRS2, were included in the focal amplified regions that were not reported in gastric cancer before. Also, a few potential tumor suppressors were seen in these focal loss regions, including DOK6, BRIP1 and NDST4. Especially, HDC, a gene involved in gastric acid secretory, was harbored in the newly identified focal loss region, 15q21.2. Three focal changes, loss of 20p12.1 (containing MACROD2), 6q26 (containing PARK2), and gain of 11p11.2 (containing CRY2), were identified to correlate to the post-surgery overall survival, which may deserve to be further investigated as the potential prognosis markers. Comparison of somatic copy number alternation patterns revealed that in chromosome arm level, 16p and 5q had distinct copy number status between GCA and GNCA samples. The frequencies of three novel focal changes were significantly different between GCA and GNCA. Furthermore, KRAS amplification, a well characterized gastric adenocarcinoma prognosis marker was associated with worse clinical outcome in GNCA, but not in GCA.
Taken together, these results provided novel candidate oncogenes or tumor suppressors for gastric adenocarcinoma and different features in structural alterations between GCA and GNCA, which potentially inform novel opportunities for targeted therapeutic interventions.
Citation Format: Manjiao Liu, Zhen Liu, Jian Bai, Hong Cai, Yang Ke, Changqing Zeng. Analysis and comparison of somatic copy number alterations in gastric cardia adenocarcinoma and gastric non-cardia adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 121.
Abstract 1224: Insights into the mechanism of action of NVP-HDM201, a differentiated and versatile Next-Generation small-molecule inhibitor of Mdm2, under evaluation in phase I clinical trials
Authors: Ferretti Stéphane , Rebmann Ramona , Berger Marjorie , Santacroce Francesca , Albrecht Geneviève , Pollehn Kerstin , Sterker Dario , Wartmann Markus , Hueber Andreas , Wiesmann Marion , Jensen Michael R. , Hofmann Francesco , Sellers William R. , Holzer Philipp , Jeay Sébastien 
Published: July 2016

Abstract
Activation of p53 by blocking p53-Mdm2 interaction using small-molecule inhibitors is being pursued as a promising cancer therapeutic strategy in p53 wild-type tumors. Here, we report the identification of NVP-HDM201, a novel, highly potent and selective inhibitor of the p53-Mdm2 interaction, with optimized drug-like properties allowing a versatile use with regard to route of administration, dose and scheduling. We determined the pharmacokinetics, pharmacodynamics and efficacy relationship of NVP-HDM201 with various dosing schedules in xenograft bearing mouse and rat models. NVP-HDM201 administered either daily at a low dose or once at a high dose revealed a differentiated engagement of the p53 molecular response. In contrast to the daily low dose treatment regimen, the single high dose NVP-HDM201 regimen resulted in a rapid and dramatic induction of p53-dependent PUMA expression and apoptosis. This was consistent with the finding that a single high dose NVP-HDM201 treatment, administered orally or intravenously, resulted in a robust and sustained tumor regression. Overall, both daily and once every 3 weeks dosing regimen showed comparable long term efficacy in preclinical studies. The ongoing clinical trial is currently designed to compare both dosing regimens with regard to efficacy and tolerability.
Citation Format: Stéphane Ferretti, Ramona Rebmann, Marjorie Berger, Francesca Santacroce, Geneviève Albrecht, Kerstin Pollehn, Dario Sterker, Markus Wartmann, Andreas Hueber, Marion Wiesmann, Michael R. Jensen, Francesco Hofmann, William R. Sellers, Philipp Holzer, Sébastien Jeay. Insights into the mechanism of action of NVP-HDM201, a differentiated and versatile Next-Generation small-molecule inhibitor of Mdm2, under evaluation in phase I clinical trials. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1224.