bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A1-52: Identification of drug-sensitive Notch receptor alterations in human breast cancer
Authors: Wang Kai , Zhang Qin , Li Danan , Ching Keith , Zhang Cathy , Zheng Xianxian , Ozeck Mark , Shi Stephanie , Li Xiaorong , Wang Hui , Rejto Paul , Christensen James , Olson Peter 
Published: November 2015

Abstract
While the Notch pathway is reportedly activated in breast cancer, the molecular mechanisms leading to its aberrant activation remain elusive, hampering the optimal development of Notch inhibitors in the clinics. In an effort to identify predictive biomarkers of response to Notch targeted therapies in breast cancer, we used several computational approaches, including novel algorithms for detecting complex structural rearrangements, to analyze next generation sequencing and related omic datasets from The Cancer Genome Atlas (TCGA) breast cancer cohort. We identified simple mutations and complex rearrangements in NOTCH1, NOTCH2 and NOTCH3 that compromised the function of the PEST domain, a negative regulatory domain controlling the duration of active Notch signaling. Focal amplifications of NOTCH2 and NOTCH3 were also observed, as were heterodimerization or extracellular domain alterations, at lower incidence. Mutations and amplifications often activated the Notch pathway as evidenced by increased expression of canonical Notch target genes, and functional mutations were significantly enriched in the triple negative breast cancer (TNBC) subtype. We also sequenced a panel of breast cancer xenograft models and identified models that harbor functionally equivalent PEST domain alterations. These models were significantly more sensitive to a gamma secretase inhibitor (GSI) compared to models without Notch alterations. Gene expression and functional analyses were performed to study the mechanism of activation through mutation and inhibition by GSI. In summary, we demonstrated that Notch pathway is activated via multiple mutational mechanisms primarily involving the PEST domains of NOTCH1, NOTCH2 and NOTCH3. Collectively, approximately 13% of TNBC exhibits a genetic alteration coupled with pathway up-regulation and these alterations may serve as biomarkers to identify patients most likely to respond to Notch inhibitors.
Citation Format: Kai Wang, Qin Zhang, Danan Li, Keith Ching, Cathy Zhang, Xianxian Zheng, Mark Ozeck, Stephanie Shi, Xiaorong Li, Hui Wang, Paul Rejto, James Christensen, Peter Olson. Identification of drug-sensitive Notch receptor alterations in human breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-52.
Abstract A1-55: Combination of a three-microRNA signature and TP53 genotype predicts responses to platinum-based doublet chemotherapy in patients with lung adenocarcinoma
Authors: Shiraishi Kouya , Saito Motonobu , Kohno Takashi 
Published: November 2015

Abstract
Platinum-based doublet, i.e., a combination of a platinum agent and another agent, is a standard regimen to treat non-small cell lung cancer, since molecular target therapy using tyrosine kinase inhibitors is effective only in a subset of patients with tumors with druggable oncogene mutations. Therefore, to identify biomarkers that can discriminate responders who received platinum-based chemotherapy before treatment is important to improve the efficacy of chemotherapy for non-small cell lung cancer. We found that a SNP in TP53 tumor suppressor gene, TP53-Arg72Pro is associated with response to the platinum-based doublet therapy (Shiraishi et al, JCO, 2010). We recently assessed intra-tumor micro (mi)RNA expression as a biomarker for predicting responses to platinum-based chemotherapy in patients with recurrent lung adenocarcinoma. Microarray-based screening of 904 miRNAs followed by quantitative reverse transcription-PCR-based verification in 40 test cohort samples, including 16 (40.0%) responders, was performed to identify miRNAs that are differentially expressed in chemotherapy responders and non-responders. Differential expression was confirmed in a validation cohort (n = 63 samples), including 18 (28.6%) responders. A signature comprising three miRNAs (miR1290, miR196b, and miR135a*) enabled the prediction of a chemotherapeutic response (rather than progression-free and overall survival) with high accuracy in both the test and validation cohorts (82.5% and 77.8%). Examination of the latter was performed using miRNAs extracted from archived formalin-fixed paraffin-embedded tissues. Genotype data for the TP53-Arg72Pro polymorphism, which is associated with responses to platinum-based doublet chemotherapy, were subsequently incorporated into the prediction analysis. Finally, combining this miRNA signature with the TP53-Arg72Pro polymorphism genotype marginally improved the predictive power (Saito et al., Clin. Cancer Res. 2014).
Citation Format: Kouya Shiraishi, Motonobu Saito, Takashi Kohno. Combination of a three-microRNA signature and TP53 genotype predicts responses to platinum-based doublet chemotherapy in patients with lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-55.
Abstract A1-59: Multiple mechanisms of MYCN dysregulation in Wilms tumor
Authors: Williams Richard D. , Chagtai Tasnim , Alcaide-German Marisa , Apps John , Wegert Jenny , Popov Sergey , Vujanic Gordan , Tinteren Harm van , Heuvel-Eibrink Marry M. van den , Kool Marcel , Gisselsson David , Graf Norbert , Gessler Manfred , Pritchard-Jones Kathy 
Published: November 2015

Abstract
Background and Purpose: Wilms tumor (WT) is the commonest pediatric renal malignancy. A significant minority of cases have mutations in known genes or recurrent copy number aberrations, but few of these have prognostic value. We have previously observed MYCN copy number gain in WT, an aberration associated with poor outcome in several other childhood cancers. We therefore set out to assess the prognostic significance of MYCN gain in a large WT series, and to explore other mechanisms by which the function of this gene may be dysregulated.
Methods: MYCN copy number was measured in 293 tumours by Multiplex ligation-dependent probe amplification. Whole exome sequencing (Agilent SureSelect V4+UTR/Illumina HiSeq) was carried out on 51 WT tumour/germline pairs. Sanger sequencing was used to confirm variants of interest and to assess an independent panel of 168 WTs. 65 WTs were profiled on Affymetrix SNP arrays (250K Nsp or SNP 6.0), Illumina HumanMethylation450 arrays, and Illumina HumanHT-12 expression arrays, and additional selected tumors on Illumina HumanCytoSNP-12 arrays.
Results: MYCN gain is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. A somatic p.P44L (c.131C&gt;t) mutation was detected in 3/45 exomes that gave informative data at this position, and in 5/168 additional tumors screened for this variant, an overall frequency of 3.8%. MYCN overexpression in high risk tumors was associated with hypomethylation at specific loci. We observed parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumors of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolved over time. In a second bilateral case, we detected MYCN gain as a germline aberration.
Conclusions: MYCN gain is associated with poor outcome and anaplastic histology in WT. MYCN also appears to be disrupted by other mechanisms in WT, including DNA hypomethylation and a recurrent potential gain of function mutation, P44L. The discovery of a germline aberration suggests that MYCN dysregulation may contribute to tumor predisposition.
Citation Format: Richard D. Williams, Tasnim Chagtai, Marisa Alcaide-German, John Apps, Jenny Wegert, Sergey Popov, Gordan Vujanic, Harm van Tinteren, Marry M. van den Heuvel-Eibrink, Marcel Kool, David Gisselsson, Norbert Graf, Manfred Gessler, Kathy Pritchard-Jones. Multiple mechanisms of MYCN dysregulation in Wilms tumor. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-59.
Abstract A1-63: Characterizing the DNA damage repair defect in HPV-positive oropharyngeal squamous cell carcinoma
Authors: Weaver Alice N. , Cooper Tiffiny S. , Trummell Hoa Q. , Bonner James A. , Rosenthal Eben L. , Yang Eddy S. 
Published: November 2015

Abstract
Although tobacco-associated head and neck cancers (HNCs) are declining in incidence, overall HNC rates are escalating due to increasing prevalence of human papillomavirus (HPV)-associated tumors, especially oropharyngeal squamous cell carcinomas (OPSCCs). Clinically, patients with HPV-associated OPSCCs have improved overall survival and increased response to therapy, especially agents which act by damaging DNA. Based on these observations, we hypothesized that HPV-positive OPSCCs harbor a defect in DNA repair activity and are sensitive to DNA repair-targeted therapy. We evaluated DNA repair activity by immunofluorescent staining for DNA damage-induced formation of DNA repair protein foci. Baseline expression of DNA repair proteins was determined by NanoString nCounter analysis of transcript levels and immunoblotting for protein levels. Therapeutic sensitivity was assessed in vitro using the colony formation assay and in vivo using both cell line-derived xenografts and a patient-derived xenograft. Consistent with our hypothesis, in vitro disease models demonstrated delayed resolution of radiation-induced DNA double strand breaks (DSBs) as assessed by γH2AX foci staining and neutral comet assay. Investigation of the two main DSB repair mechanisms, non-homologous end joining (NHEJ) and homologous recombination (HR), indicated intact activation of both pathways but strikingly diminished recruitment of downstream repair factors DNA-Pk (NHEJ) and BRCA2 (HR) to sites of damage. In addition, protein expression of both DNA-PK and BRCA2 was decreased in HPV-positive compared to HPV-negative HNC cell lines. We next studied susceptibility of HPV-positive OPSCCs to PARP inhibition, a class of anticancer agents which block DNA repair signaling pathways and have proven effective clinically in DNA repair-deficient cancers. In vitro colony formation assays revealed a negative effect on cell survival in HPV-positive but not HPV-negative HNCs treated with the PARP inhibitor veliparib. Importantly, these results were confirmed in vivo in both cell line-derived xenografts and a patient-derived xenograft. In summary, our findings demonstrate for the first time the presence of a significant DNA DSB repair defect in HPV-positive OPSCCs encompassing both NHEJ and HR repair, and suggest therapies targeting DNA repair pathways may help improve therapeutic ratio in this disease.
Citation Format: Alice N. Weaver, Tiffiny S. Cooper, Hoa Q. Trummell, James A. Bonner, Eben L. Rosenthal, Eddy S. Yang. Characterizing the DNA damage repair defect in HPV-positive oropharyngeal squamous cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-63.
Abstract A2-01: SHP-1 is a negative regulator of epithelial-mesenchymal transition in hepatocellular carcinoma
Authors: Fan Li-Ching , Shiau Chung-Wai , Tai Wei-Tien , Hung Man-Hsin , Chu Pei-Yi , Lin Hang , Yu Hui-Chuan , Chen Kuen-Feng 
Published: November 2015

Abstract
Epithelial-to-mesenchymal transition (EMT) is well known to involve in tumor invasion and metastasis. SH2 domain-containing phosphatase 1 (SHP-1) functions as a potent tumor suppressor and also acts as a negative regulator of p-STAT3 (Tyr705) oncogenic signaling. However, little is known about the molecular mechanism(s) through which SHP-1 regulates EMT during hepatocellular carcinoma (HCC) progression. Here, we firstly reported that endogenous SHP-1 protein levels were significantly down-regulated in cells with mesenchymal characteristics and negatively correlated with p-STAT3 (Tyr705) and vimentin but positively correlated with E-cadherin. SHP-1 overexpression abolished TGF-beta-induced p-STAT3 (Tyr705) and EMT, as well inhibited migration and invasion but further rescued by STAT3 overexpression. Constitutively overexpressed SHP-1 tyrosine phosphatase activity by D61A mutated SHP-1 markedly reduced TGF-beta-induced p-STAT3 (Tyr705) and EMT features, but not altered by C453S catalytic dead mutant SHP-1. Consequently, SHP-1 acted as a powerful suppressor in preventing EMT by exerting its activity directly targeted p-STAT3 (Tyr705). Most notably, we discovered a novel SHP-1 agonist SC-43 better than sorafenib to exert more potent anti-EMT effects in vitro as well anti-metastatic growth in vivo. In conclusion, SHP-1 is a potent suppressor of HCC EMT and metastasis, thus, highlighting that SHP-1 may serve as a potential therapeutic target for HCC EMT and metastasis.
Note: This abstract was not presented at the conference.
Citation Format: Li-Ching Fan, Chung-Wai Shiau, Wei-Tien Tai, Man-Hsin Hung, Pei-Yi Chu, Hang Lin, Hui-Chuan Yu, Kuen-Feng Chen. SHP-1 is a negative regulator of epithelial-mesenchymal transition in hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-01.
Abstract A2-11: PLZF, a tumor suppressor genetically lost in metastatic castration resistant prostate cancer, is a mediator of resistance to androgen deprivation therapy
Authors: Hsieh Chen-Lin , Botta Ginevra , Gao Shuai , Li Tiantian , Allen Eliezer M. Van , Treacy Daniel J. , Cai Changmeng , He Housheng Hansen , Sweeney Christopher J. , Brown Myles , Balk Steven P. , Nelson Peter S. , Garraway Levi A. , Kantoff Philip W. 
Published: November 2015

Abstract
Whole exome sequencing of metastatic castration-resistant prostate cancer (mCRPC) reveal that 5~7% of tumors harbor promyelocytic zinc finger protein (PLZF) homozygous deletions. PLZF is a canonical androgen-regulated tumor suppressor gene whose expression is inhibited by androgen deprivation therapy (ADT). Here, we demonstrate that knockdown of PLZF expression promotes a CRPC and enzalutamide resistant phenotype in prostate cancer cells. Reintroduction of PLZF expression is sufficient to reverse androgen-independent growth mediated by PLZF depletion. PLZF loss enhances CRPC tumor growth in a xenograft model. Bioinformatic analysis of the PLZF cistrome shows that PLZF negatively regulates multiple pathways including the MAPK pathway. Accordingly, our data support an oncogenic program activated by ADT and this acquired mechanism together with the finding of genetic loss in CRPC implicate PLZF inactivation as a mechanism promoting ADT resistance and the CRPC phenotype.
Citation Format: Chen-Lin Hsieh, Ginevra Botta, Shuai Gao, Tiantian Li, Eliezer M. Van Allen, Daniel J. Treacy, Changmeng Cai, Housheng Hansen He, Christopher J. Sweeney, Myles Brown, Steven P. Balk, Peter S. Nelson, Levi A. Garraway, Philip W. Kantoff. PLZF, a tumor suppressor genetically lost in metastatic castration resistant prostate cancer, is a mediator of resistance to androgen deprivation therapy. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-11.
Abstract A2-18: The challenges of using large-scale genomics data to identify novel drivers of lung cancer
Authors: Hudson Andrew M. , Yates Tim , Wirth Chris , Li Yaoyong , Trotter Wendy , Fawdar Shameem , Miller Crispin , Brognard John 
Published: November 2015

Abstract
Lung cancer is one of the major causes of cancer deaths worldwide and only 30% of patients survive the disease for at least one year after diagnosis. Patients are often too frail to receive systemic chemotherapy and there is an urgent need for less toxic, efficacious, targeted therapies. Despite recent efforts with large-scale genomics data we still lack knowledge about driver mutations for the majority of lung cancers.
Increasingly, cancer researchers are using online cancer genomic databases to identify novel targets to investigate. A comparison of two prominent databases from different institutes (CCLE and COSMIC) revealed marked discrepancies in the detection of missense mutations in identical cell lines (57.38% conformity). A major reason for this discrepancy is inadequate sequencing of GC-rich areas. This is a significant issue for lung cancer, with a mutation signature predominantly affecting guanine and cytosine nucleotides and therefore preferring GC-rich regions.
We have therefore focused on GC-rich regions that next-generation-sequencing struggle to cover and discovered over 400 of these regions (cold-spots) in Cancer Consensus and kinase genes alone. We demonstrate how a PAK4 mutation, found in a GC-rich cold-spot in a lung adenocarcinoma cell line, activates the pERK pathway. This suggests that specific targeting of GC-rich regions may be required to uncover further oncogenes and tumour suppressors in lung cancer.
The high mutational burden of lung cancer creates additional challenges in distinguishing driver mutations from a multitude of passenger mutations. One solution is to use siRNA knockdown screens on all genes that are mutated in a cell line and assess cell viability. However we demonstrate that inconsistencies in mutational profiling of cell lines and passaging effects have the potential to influence these types of studies. These limitations also offer new explanations for the discrepancies seen when comparing pharmacogenomics studies.
Citation Format: Andrew M. Hudson, Tim Yates, Chris Wirth, Yaoyong Li, Wendy Trotter, Shameem Fawdar, Crispin Miller, John Brognard. The challenges of using large-scale genomics data to identify novel drivers of lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-18.
Abstract A2-22: Mitochondrial dysfunction induces cancer stem-like phenotypes in Hep3B hepatocellular carcinoma cell line
Authors: Han Yu-Seon , Yi Eui-Yeun , Kim Yung-Jin 
Published: November 2015

Abstract
Cancer stem cells (CSCs) are a small population of cancer cells that possess characteristics associated with normal stem cells such as self-renewal and differentiation into multiple cell types. Additionally, CSCs have been reported to relationship on tumor relapse after cancer therapy. Mitochondrial dysfunction (MD) has also been known to be associated with cancer malignancy. In this report, the relation of MD and CSCs were initially investigated using mitochondrial-depleted rho0 cells derived from Hep3B hepatocellular carcinoma cell line. The Hep3B/rho0 cells showed cancer stem-like phenotypes including tumor initiation, tumor malignancy, stem cell-related signaling, chemotherapies and radiotherapy resistance. These results suggest that mitochondrial dysfunction induces cancer stem-like phenotypes. Taken together, mitochondrial dysfunction plays an important role in the acquisition of cancer stem-like phenotypes and could be a novel therapeutic target to cancer therapy.
Citation Format: Yu-Seon Han, Eui-Yeun Yi, Yung-Jin Kim. Mitochondrial dysfunction induces cancer stem-like phenotypes in Hep3B hepatocellular carcinoma cell line. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-22.
Abstract A2-25: Identification of RASA1 as a novel melanoma tumor suppressor gene
Authors: Sung Hyeran , Kanchi Krishna L. , Messina Jane , Lee Ji-Hyun , Kim Youngchul , Ding Li , Wilson Richard K. , Weber Jeffrey S. , Kim Minjung 
Published: November 2015

Abstract
Hyperactivation of the Ras-Raf-Mitogen-activated protein kinase (MAPK) pathway has been commonly observed in melanoma via frequent activating mutations in NRAS and BRAF. Novel mutations in other components of this pathway such as MEK1, MEK2, MAP3K5, and MAP3K9 have been reported recently by high-throughput sequencing efforts. In addition, NF1 (neurofibromatosis type 1), one of the Ras GTPase activating proteins (RasGAPs) that negatively regulate Ras, has been shown to be mutated or suppressed in melanoma. However, importance of other RasGAPs has not been addressed in melanoma.
To obtain a comprehensive view of melanoma genomes, we conducted whole genome sequencing (WGS) of 15 metastatic melanomas and matched normal PBMC genomes from 13 melanoma patients. All melanoma genomes from these 13 patients contained at least one mutation in genes of Ras-Raf-MAPK pathway (MAPK1, MAP3K1, MAP4K2, MAP3K14, NRAS, and BRAF). In addition, we identified two novel, clustered somatic missense mutations (p.Tyr472His and p.Leu481Phe) in RASA1 (RAS p21 protein activator 1, p120RasGAP). In this study, we addressed functional roles of RASA1 in melanoma tumorigenesis. The RNAi-mediated down-regulation of RASA1 promoted, while ectopic expression of wild type RASA1 decreased, anchorage-independent colony formation, tumor growth, and RAS activation. Interestingly, RASA1 Y472H mutant enhanced soft agar colony formation and tumor growth, while RASA1 L481F mutant lost its tumor suppressive activity. Mechanistically, RASA1 required RasGAP activity to suppress colony formation and showed higher activity toward R-Ras (related RAS viral (r-ras) oncogene homolog) isoform among the Ras superfamily of small GTPases. In addition, RASA1 suppressed Ral-A among Ras downstream effectors. Interestingly, RASA1 expression was frequently down-regulated in metastatic melanoma samples (11.4% (4/35) of lymph node metastasis and 3.4% (1/29) of distal metastases) compared to primary melanomas (33.3% (21/63)) and dysplastic nevi (44.1% (15/34)). We also observed significantly shorter overall survival of melanoma patients with BRAF mutations when RASA1 mRNA expression is low. Thus, these data support that RASA1 is a novel melanoma tumor suppressor that is inactivated by suppressed expression or by mutation.
Citation Format: Hyeran Sung, Krishna L. Kanchi, Jane Messina, Ji-Hyun Lee, Youngchul Kim, Li Ding, Richard K. Wilson, Jeffrey S. Weber, Minjung Kim. Identification of RASA1 as a novel melanoma tumor suppressor gene. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-25.