bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 448: Expression of Galectins in high grade serous ovarian cancer
Authors: Labrie Marilyne , Communal Laudine , Vladoiu Maria-Claudia , Dupont Pascal , Mes-Masson Anne-Marie , St-Pierre Yves 
Published: July 2016

Abstract
Ovarian cancer (OC) is the 5th leading cause of cancer-related deaths in the Western world. Despite improvements in various treatments, the five-year survival of patients with advanced stage disease remains less than 40%. Approximately 70% of malignant OCs are attributed to the high-grade serous carcinoma (HGSC) histological subtype, which is typically treated by a surgical tumor debulking followed by platinum/taxane chemotherapy. Unfortunately, although approximately 80% of patients respond well to the initial chemotherapy treatment, a large portion of patients develop drug resistance during subsequent cycles of chemotherapy. The non-uniformity of response to therapy complicates the clinical decision-making process and reflects the genetic complexity that gives rise to intra-tumor heterogeneity. Clearly, there is an urgent need to develop reliable clinical biomarkers to identify patients at different levels of risk for specific outcomes. Here, we have investigated the expression of galectins (gal) in HGSC and examined their potential as biomarkers. Galectins have been shown to play a dual role in cancer progression. When released in the extracellular space by cancer cells, they are particularly efficient in creating an immunosuppressive tumor microenvironment, both locally and systemically. Inside cancer cells, they provide cancer cells with increased resistance to apoptosis induced by chemotherapeutic agents. Using tissue microarrays constructed from formalin fixed paraffin embedded tissues from 209 patients with HGSC, we have identified a new protein signature that takes into account the expression of galectins in both cancer and stromal cells. Our study showed that increased protein expression of stromal gal-1 and epithelial gal-8/9 in primary tumors was associated with a poor response to treatment in patients with HGSC. This signature also increased the predictive value of CA-125 on five-year disease-free survival, chemotherapy treatment response and five-year overall survival. Univariate and multivariate analyses revealed that gal-8 and gal-9 were both independent predictors of chemoresistance and overall survival, respectively. From a fundamental point of view, our project also contributes to better define the heterogeneity of the disease. Overall, these data provide a rational for further studies of Galectins in OC.
Citation Format: Marilyne Labrie, Laudine Communal, Maria-Claudia Vladoiu, Pascal Dupont, Anne-Marie Mes-Masson, Yves St-Pierre. Expression of Galectins in high grade serous ovarian 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 448.
Abstract 4481: Phosphorylation regulates EZH2 neoplastic functions in triple-negative breast cancer
Authors: Anwar Talha , Arellano-Garcia Caroline , Burman Boris , Kleer Celina G. 
Published: July 2016

Abstract
Background: Triple negative (estrogen receptor, progesterone receptor, HER2-neu negative) breast cancers (TNBC) comprise 15% of all breast cancers but are responsible for a disproportionately high number of deaths. Overexpression of the histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2) is an independent prognostic biomarker significantly associated with poorly-differentiated TNBCs and poor patient outcome. We previously identified a novel link between EZH2 and the p38 mitogen-activated protein kinase, an important mediator of progression and metastasis of TNBC. We found that EZH2 binds to p38, and that EZH2 and activated p38 are concordantly expressed in the metastases of breast cancer patients. Based on these data and previous in vitro studies, we hypothesized that p38 MAPK may also regulate EZH2 through phosphorylation in breast cancer. We further hypothesized that this phosphorylation event may be important for EZH2 contribution to malignancy.
Methods: In order to test this hypothesis, we performed knockdown rescue experiments in triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-436. Stable knockdown of EZH2 was achieved using shRNA targeting the 3’UTR. Knockdown of EZH2 was rescued by reintroduction of myc-EZH2 (WT) or a T367A-EZH2 phosphorylation-deficient mutant. Cell lines were then used in functional assays of proliferation, migration, and invasion. In order to further interrogate the importance of this phosphorylation event, we developed a phospho-specific EZH2 T367 antibody.
Results: p38-mediated phosphorylation of EZH2 at T367 contributes to the migratory and invasive properties of TNBC. Mechanistically, phosphorylation by p38 does not affect binding to other PRC2 members but may affect EZH2 activity. We are currently investigating the relevance of pEZH2 as a biomarker of breast cancer survival with our new antibody.
Conclusions: We provide evidence that p38 phosphorylation of EZH2 at T367 contributes to malignancy of triple-negative breast cancers. Our data suggest a new mechanism by which EZH2 is regulated and may offer an additional mechanism by which EZH2 contributes to TNBC progression.
Citation Format: Talha Anwar, Caroline Arellano-Garcia, Boris Burman, Celina G. Kleer. Phosphorylation regulates EZH2 neoplastic functions in triple-negative breast 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 4481.
Abstract 4492: Investigation of the germline mutational landscape of GBA in general cancer patients and its role in the tumorigenesis
Authors: Shin Junghoon , Kim Daeyoon , Koh Youngil , Yoon Sungsoo 
Published: July 2016

Abstract
Introduction
Gaucher disease (GD) is an autosomal recessive disease resulting from defective enzymatic activity of acid β-glucosidase (β-glucocerebrosidase). Approximately 400 point mutations in GBA, located in 1q21, have been described and genotype-phenotype correlation was revealed. Previous studies have shown the association of type 1 GD and development of various types of cancers. However, the mutational landscape of GBA and its clinical implication in general cancer patients have not been systematically explored.
Methods
We used publicly available data obtained from ICGC and TCGA data portal (sftp://dccsftp.nci.nih.gov) for the analysis of single nucleotide variants (SNVs) in GBA in general cancer patients. GenBank reference sequence NM_001005741 was used for SNP identification.
Results
A total of 2124 cancer patients comprising 29 cancer types were included. Mutations with allele frequency lower than 0.3 or coverage depth lower than 15 were filtered out from analysis. Overall, 7% (151 out of 2124) were GBA mutation carriers, including 1 nonsense (involving exon 1) and 153 missense mutations, including 5 homozygous alternate. The most frequently detected SNVs included rs2230288 (c.1093G&gt;A:p.E365K, 3 homozygous alternate), rs75548401 (c.1223C&gt;T:p.T408M), rs143187997 (c.58A&gt;G:p.I20V, 1 homozygous alternate), rs150466109 (c.38A&gt;G:p.K13R, 1 homozygous alternate), rs76763715 (c.A1226G:p.N409S), and rs421016 (c.1448T&gt;C, p.L483P), accounting for 1.88%, 1.55%, 1.27%, 1.04%, 0.85%, and 0.28% of the entire cancer population, respectively. We compared our data with 1000 Genomes data of 2504 normal subjects (ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/release/20130502), which revealed that the prevalence of rs2230288, rs75548401, and rs76763715 carriers was significantly higher in the cancer group than 1000 Genomes population (p = 0.01, &lt;0.001, and &lt;0.001 by chi-square test, respectively). Regarding somatic mutational profile of tumor samples of 151 germline GBA mutation carriers, the most frequently mutated genes included TP53, PIK3CA, and KRAS, accounting for 28.5%, 7.9%, and 7.9%, respectively.
Conclusion
Although overall prevalence of germline GBA mutation carriers was not significantly different between cancer patients and general population collected from 1000 Genomes data, SNVs in some specific positions showed statistically significant difference in prevalence between 2 groups, implying association between specific mutational loci of GBA and cancer-developing mechanism, even in heterozygous carriers.
Citation Format: Junghoon Shin, Daeyoon Kim, Youngil Koh, Sungsoo Yoon. Investigation of the germline mutational landscape of GBA in general cancer patients and its role in the tumorigenesis. [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 4492.
Abstract 4506: Identification of druggable transcriptional outliers in urothelial carcinoma
Authors: Faltas Bishoy S. M. , Bareja Rohan , Shelkey Ethan , Mayer Rebecca , Sboner Andrea , Rubin Mark A. , Elemento Olivier 
Published: July 2016

Abstract
Background: Urothelial carcinoma (UC) is a major public health problem affecting new 75,000 patients and resulting in 15,000 deaths annually. Despite a variety of genetic and epigenetic alterations described in UC, few therapeutically exploitable drivers have been identified and validated. We hypothesized that transcriptional outliers from primary tumor biopsies could reveal such therapeutically exploitable weaknesses. Identification of these druggable outliers would be critical for individualized therapy of patients with UC. Methods: In order to identify transcriptional outliers we calculated Z-scores for a set of 72 druggable cancer-related genes from RNA sequencing data from our Institute of Precision Medicine (IPM) cohort of advanced platinum-resistant UC. We performed similar outlier analyses on The Cancer Genome Atlas (TCGA) cohort of UC and the Cancer Cell Line Encyclopedia (CCLE) database of urothelial cell lines. Common outliers between IPM and CCLE datasets or between TCGA and CCLE datasets were nominated for further in-vitro testing. Sensitivity scores of cell lines for 130 drugs were extracted from the publicly available cell line browser database and the variance these sensitivity scores across (640) cell lines was calculated. The drugs targeting the outlier genes (real sensitivity z-score) were compared to the mean z-scores of randomly chosen drugs associated with those genes (control sensitive z-score). To investigate the mechanisms underlying comparison of outliers methylation patterns of the promoter regions of outlier genes were examined. Results: 6 druggable outlier genes were common between IPM and CCLE cohorts, and 15 outlier genes between CCLE and TCGA cohorts. Common outliers included FGFR3, KIT, BCL2, ABL1, and SMO. The presence of outlier genes in cell lines correlated with higher sensitivity to drugs predicted to target these genes in comparison to randomly selected drugs (p&lt;0.05). In vitro cell viability assays confirmed sensitivity of RT112 and RT4 cell lines to Dovitinib, an FGFR3 inhibitor as predicted by our algorithm. Outlier genes were frequently involved in gene fusions, amplification or DNA hypomethylation (p&lt;0.02). Conclusions: Identification of druggable transcriptional outliers can elucidate novel oncogenic dependencies and aid in selecting precision therapies for UC patients.
Citation Format: Bishoy S. M. Faltas, Rohan Bareja, Ethan Shelkey, Rebecca Mayer, Andrea Sboner, Mark A. Rubin, Olivier Elemento. Identification of druggable transcriptional outliers in urothelial 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 4506.
Abstract 451: Large-scale evaluation of SLC18A2 in prostate cancer reveals diagnostic and prognostic biomarker potential at three molecular levels
Authors: Haldrup Christa , Lynnerup Anne-Sofie , Storebjerg Tine M. , Vang Søren , Wild Peter , Visakorpi Tapio , Arsov Christian , Schulz Wolfgang A. , Lindberg Johan , Grönberg Henrik , Egevad Lars , Borre Michael , Ørntoft Torben F. , Høyer Søren , Sørensen Karina D. 
Published: July 2016

Abstract
Limitations of current diagnostic and prognostic tools for prostate cancer (PC) contribute to over-diagnosis and over-treatment. Here, we investigate the biomarker potential of the SLC18A2 (VMAT2) gene for PC at three molecular levels. Thus, SLC18A2 promoter methylation was analyzed in 767 malignant and 78 benign radical prostatectomy (RP) samples using methylation-specific qPCR and Illumina 450K methylation microarray data. SLC18A2 transcript levels were assessed in 412 malignant and 45 benign RP samples using RNAseq data. SLC18A2 protein was evaluated by immunohistochemistry in 502 malignant and 305 benign RP samples. Cancer-specificity of molecular changes was tested using Mann-Whitney U tests and/or receiver operating characteristic (ROC) analyses. Log rank, uni- and multivariate Cox regression tests were used for survival analyses. We found that SLC18A2 promoter hypermethylation was highly cancer-specific (area under the curve (AUC): 0.923-0.976) and associated with biochemical recurrence (BCR) after RP in univariate analyses. SLC18A2 transcript levels were reduced in PC and had independent prognostic value for BCR after RP (multivariate HR 0.13, P&lt;0.05). Likewise, SLC18A2 protein was down-regulated in PC (AUC 0.898) and had independent prognostic value for BCR (multivariate HR 0.51, P&lt;0.05). Reduced SLC18A2 protein expression was also associated with poor overall survival in univariate analysis (HR 0.29, P&lt;0.05).
Our results highlight SLC18A2 methylation as a new promising biomarker candidate for PC diagnosis. Furthermore, both SLC18A2 RNA and protein expression showed promising prognostic potential beyond routine clinicopathological variables. Thus, novel SLC18A2-based molecular tests could have useful future applications for PC detection and identification of high-risk patients.
Citation Format: Christa Haldrup, Anne-Sofie Lynnerup, Tine M. Storebjerg, Søren Vang, Peter Wild, Tapio Visakorpi, Christian Arsov, Wolfgang A. Schulz, Johan Lindberg, Henrik Grönberg, Lars Egevad, Michael Borre, Torben F. Ørntoft, Søren Høyer, Karina D. Sørensen. Large-scale evaluation of SLC18A2 in prostate cancer reveals diagnostic and prognostic biomarker potential at three molecular levels. [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 451.
Abstract 4510: KIT melanomas are developmentally racially biased
Authors: Sanchez Margaret I. , Grichnik James M. 
Published: July 2016

Abstract
KIT is a critical pathway for melanocytic homeostasis and it is often down-regulated in cutaneous melanoma. However, KIT activation plays a critical role in a subpopulation of melanomas especially those in acral locations and melanomas on chronically sun damaged skin. We analyzed exome and RNAseq data from The Cancer Genome Atlas (TCGA) Network (321 cutaneous melanomas in the data set) to identify patterns unique to KIT activation. The melanomas were divided based on known mutually exclusive mutations (BRAF, NRAS and KIT) vs those without (WT). We compared RNA data between each group. KIT group had significantly higher expression of KIT than BRAF, NRAS and WT (p&lt;0.01, FDR&lt;0.01) and isoform 2 expression was higher than 1. KIT melanomas were found to overexpress Wnt pathway, pigmentation and genes involved epithelial-mesenchymal transition. From the exome data, germline SNPs with incidence in ethnic groups (Caucasian, Asian and African) and more likely to be present in a specific melanoma groups were selected. Comparing the 3 ethnicity groups across the 4 tumor groups Asian SNPs were significantly enhanced in KIT tumors, African in WT and Caucasian in BRAF and NRAS melanomas. We evaluated the tumors for the primary type of genetic damage. The three signatures that appeared most divergent were CC&gt;TT for UV, (G/A)C(G)&gt;(G/A)T(G) for deamination, and G&gt;T for oxidative damage. UV and deamination appeared inversely proportional, while oxidative damage appeared to be independent of those other two features. KIT and WT had a greater% of non UV high deamination tumoral environments. A fraction of these tumors also had very high oxidative signatures. We then compared 2 KIT subgroups UV vs non UV (absence of CC&gt;TT mutations) for germline ethnicity differences. Asian SNPs were highly increased in non UV subgroup whereas Caucasian SNPs were in UV subgroup. Further, we divided KIT non UV subgroup into deamination and oxidative damage subgroups and compared ethnicity differences. Deamination was significantly higher in Asians whereas oxidative damage was higher in Caucasians. A similar analysis was done to the WT group, where African SNPs were significantly increased in the non UV subgroup and were primarily associated with oxidative damage. This data implies that KIT mutant melanomas develop in a unique genetic and mutational environments and makes this an ideal system to in which study racial disparities at the molecular level.
Citation Format: Margaret I. Sanchez, James M. Grichnik. KIT melanomas are developmentally racially biased. [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 4510.
Abstract 4514: Transcription down-regulation of c-Myc through nucleic acid clamp-mediated stabilization of the promoter G-quadruplex
Authors: Hao Taisen , Brooks Tracy 
Published: July 2016

Abstract
MYC overexpression occurs in up to 80% of all cancers. Down-regulating MYC's expression is an effective therapeutic strategy for the treatment of many of these cancers, and particularly for non-Hodgkin's lymphoma (NHL). NHL is the fifth most common cancer type, accounting for 5% of all cancers and 4% of all cancer deaths. Developing MYC-targeting therapeutics will be very impactful to NHL patients. In the current study, we have developed a nucleic acid clamp to transcriptionally down-regulate MYC expression by stabilizing the G-quadruplex (G4) formed in the nuclease hypersensitivity element III1 promoter region. The clamps complement nucleotides on the 5’- and 3’- regions flanking the G4-forming sequence, linked together with an 18 angstrom abasic moiety. To date, the binding affinity and specificity, G4 structure stabilizing ability, MYC down-regulation capability, and the selective cytotoxicity on cancerous vs non-cancerous cell lines of these clamps have been confirmed by EMSA and electronic circular dichroism, DMS footprinting, luciferase reporter assay, and MTS viability assay respectively. Recently, various replacements have been explored to replace the abasic moiety with non-complementary nucleic acids and to optimize the phosphate backbone with peptide nucleic acids. In addition, complexation with block co-polymers is under investigation to develop a functionalizable nanotherapeutic for NHL. The highly selective G4 stabilizing ability of the clamps used in the current approach offers an advantage over traditional G4 stabilizing small molecules. This novel approach is a promising therapeutic for the treatment of MYC related malignancies, and provides a framework for future G4-therapeutic development for other high-value genes, such as kRAS, VEGF, c-KIT and many more.
Citation Format: Taisen Hao, Tracy Brooks. Transcription down-regulation of c-Myc through nucleic acid clamp-mediated stabilization of the promoter G-quadruplex. [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 4514.
Abstract 4516: Evaluating the chromatin state as a predictive biomarker for BET inhibitor sensitivity in hematological malignancies
Authors: Castillo Joseph , Raisner Ryan , Gascoigne Karen , Dos Santos Gary , Clarke Emer , Huang Alex , Lackner Mark , Mounir Zineb 
Published: July 2016

Abstract
The BET (bromodomain extra-terminal) family of proteins are a group of epigenetic regulators that control gene transcription by reading acetylated lysines on histone tails and recruiting transcription complexes. The various BET inhibitors developed show strong anti-tumor effects against a broad range of hematologic malignancies. The BET inhibitor JQ1 shows strong anti-proliferative activity in sub-sets of multiple myeloma (MM), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and lymphoma cell line models. At present, however, predictive biomarkers of BET inhibitor sensitivity have not been identified. We hypothesize that the chromatin state characterized by various histone post-translational modifications (acetylation, methylation, etc.), can drive sensitivity to BET inhibition. By examining basal expression of epigenetic marks in panels of sensitive and resistant heme cell line models and further validating these histone modification trends in primary AML and multiple myeloma cultures, we may be able to identify predictive biomarkers of BET inhibitor sensitivity in hematological malignancies.
Citation Format: Joseph Castillo, Ryan Raisner, Karen Gascoigne, Gary Dos Santos, Emer Clarke, Alex Huang, Mark Lackner, Zineb Mounir. Evaluating the chromatin state as a predictive biomarker for BET inhibitor sensitivity 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 4516.