bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4461: Epigenetics in doxorubicin and docetaxel-resistant triple negative breast cancer
Authors: Sztain Terra , Chang Helena 
Published: July 2016

Abstract
Triple negative breast cancers (TNBC) do not express estrogen receptor, progesterone receptor, or Her2/neu hence there are no targeted therapies for this type of breast cancer. Chemotherapy is the systemic treatment option with doxorubicin and docetaxel being the two most commonly used drugs. It is well known drug resistance can lead to treatment failure in these patients. It is therefore essential to uncover information on the mechanism of these resistance pathways, and identify novel molecular markers for developing potential pathway driven treatment. Our previous studies have shown that genes, ataxia telangiectasia mutated (ATM), TGF-β, Bcl-2, NDRG1 and NDRG2 are closely related to cancer stem cell marker CD24 expression, and drug resistance toward doxorubicin and docetaxel in TNBC. In this study, two TNBC cell lines HCC1806 and HCC1937 were epigenetically examined by ChIP-qPCR. The gene promoters of the above five genes, within a 1kb range were analyzed. Results showed that both drugs significantly decreased total Histone 3 quantity, which is representative of total nucleosome density, at ATM and TGFB1 promoters, and additionally doxorubicin at NDRG1 promoter. Doxorubicin also decreased histone acetylation and methylation of H3K9 significantly at NDRG1 and consistently at the other gene promoters, while docetaxel showed consistent increase of methylation at H3K9. Results suggest that treatment with the two drugs affects an epigenetic pathway involving one or several epigenetic cofactors (methyltransferases, acetyltransferases, nucleosome remodeling complexes, etc.). Elucidating this pathway may provide valuable information for the treatment of TNBC.
Citation Format: Terra Sztain, Helena Chang. Epigenetics in doxorubicin and docetaxel-resistant 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 4461.
Abstract 4467: PRSS8 methylation and its significance in esophageal squamous cell carcinoma
Authors: Bao Yonghua , Wang Qian , Yang Wancai 
Published: July 2016

Abstract
Esophageal cancer is one of the most common cancers worldwide, and the incidence and mortality is increasing rapidly in recent years in China, but the underlying mechanisms are largely unclear. Herein we used immunohistochemical staining on an esophageal squamous cell carcinoma (ESCC) tissue microarray (TMA) containing 362 cases of ESCC and found that the expression of PRSS8, serine protease prostasin, was significantly decreased in ESCC. Interestingly, the reduction of PRSS8 was well correlated with poor differentiation, less stromal lymphocyte infiltration, and shorter survival time. PRSS8 mRNA levels were also significantly reduced in ESCC compared to the adjacent normal esophagus assayed by quantitative real-time PCR. Methylation specific PCR showed that PRSS8 promoter region was hypermethylated in ESCC tissues and cell lines, which was associated with downregulation of PRSS8 expression and decreased activities of PRSS8 promoter. Promoter deletion and truncation approaches showed that the CpG island in PRSS8 promoter region played an important role on the determination of promoter activities. De-methylation agent decitabine was able to restrore PRSS8 expression in esophageal cancer cell lines, leading to the inhibition of cancer cell proliferation, motility, migration and cell cycle arrest. However, the restoration of PRSS8 and its tumor inhibition could be reversed by small interfering RNA targeting PRSS8. Immunoblotting results showed that tumor inhibition of PRSS8 may be associated with proliferation- and epithelial-mesenchymal transition - related proteins (e.g. upregulation of E-cadherin and downregulation of Twist and Snail) in ESCC cells. The findings from current study strongly suggested that PRSS8 acted as a tumor suppressor and PRSS8 promoter region hypermethylation has clinical significance of in ESCC.
Citation Format: Yonghua Bao, Qian Wang, Wancai Yang. PRSS8 methylation and its significance 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 4467.
Abstract 4468: Targeted deep sequencing of plasma circulating cell-free DNA shows VIM and FBLN1 methylation as potential biomarkers for hepatocellular carcinoma
Authors: Holmila Reetta , Sklias Athena , Muller David C. , Degli Esposti Davide , Guilloreau Paule , Mckay James , Sangrajrang Suleeporn , Srivatanakul Petcharin , Hainaut Pierre , Merle Philippe , Nogueira da Costa Andre , Herceg Zdenko 
Published: July 2016

Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, but is still lacking sensitive and specific biomarkers for diagnosis and prognosis. HCC carcinogenesis is a multi-step process that usually arises in background chronic metabolic, inflammatory and/or infectious liver disease and it exhibits a wide range of epigenetic alterations that could potentially be used as biomarkers. In this study, we applied the targeted massively parallel semiconductor sequencing to assess in plasma circulating cell-free DNA (cfDNA) the methylation of a panel of genes (FBLN1, HINT2, LAMC1, LTBP1, LTBP2, PSMA2, PSMA7, PXDN, TGFB1, UBE2L3, VIM and YWHAZ) and to evaluate the potential of these genes as novel HCC biomarkers in two different series, one from France and one from Thailand. Methylation in cfDNA was detected for FBLN1, PSMA7, PXDN and VIM, with substantial differences in methylation patterns between cases and controls for FBLN1 and VIM. Further, the average methylation level across analyzed CpG-sites was associated with higher odds of HCC for VIM (1.48 [1.02, 2.16] for French cases, and 2.18 [1.28, 3.72] for Thai cases), and lower odds of HCC for FBLN1 (0.89 [0.76, 1.03] for French cases and 0.75 [0.63, 0.88] for Thai cases). We also analyzed a set of HCC and adjacent tissues as well as The Cancer Genome Atlas’ (TCGA) data to further investigate the origin of methylation pattern in cfDNA and noted that the analysis of VIM could be improved based on the methylation pattern detected in TCGA data. Overall, our study provides evidence that changes in methylation levels of cfDNA could be used as potential cancer biomarkers and that VIM and FBLN1 methylation in cfDNA are associated with HCC and may represent useful plasma-based biomarkers for improved detection and patient surveillance.
Citation Format: Reetta Holmila, Athena Sklias, David C. Muller, Davide Degli Esposti, Paule Guilloreau, James Mckay, Suleeporn Sangrajrang, Petcharin Srivatanakul, Pierre Hainaut, Philippe Merle, Andre Nogueira da Costa, Zdenko Herceg. Targeted deep sequencing of plasma circulating cell-free DNA shows VIM and FBLN1 methylation as potential biomarkers for hepatocellular 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 4468.
Abstract 4488: Targeted sequencing revealed distinctive and pathogenic mutations in African Americans with colorectal cancer
Authors: Ashktorab Hassan , Azimi Hamed , Nickerson Mike , Bass Sara , Boland Joseph , Yeager Meredith , Varma Sudhir , Daremipouran Mohamed , Sherif Zaki , Ghavimi Shima , Shokrani Babak , Lee Edward , Laiyemo Adeyinka , Brim Hassan 
Published: July 2016

Abstract
Background & Aim: We recently analyzed 12 pairs of African American CRC tumors and their matched normal tissue using whole exome sequencing and established a panel of novel mutations that are potentially useful for the detection of CRC in this population. In this study, we examined APC, MSH3, and MSH6 mutations using targeted exome sequencing (TES) to determine distinctive mutations frequencies and their chronology in the neoplastic transformation.
Materials & Methods: A total of 140 colon samples: (30 normal, 21 adenomas, 33 advanced adenomas & 56 tumors collected from African Americans were used as our discovery set on an Ion Torrent platform. A subset of 36 samples were used as validation set on an Illumina platform. Bioinformatic analysis was performed on both sets of data. Common mutations were considered validated.
Results: Two novel MSH6 mutations were validated. Four known mutations in MSH3 were validated and were located in nonsynonymous (exon 10) and 1synonomous mutation (exon 18). As for the APC, 20 mutations were validated include 4 novel mutations. The novel mutations were 3 stopgain and 1 nonsynonymous located at the EB1 binding site, in the mutational cluster region (MCR), and at the 15 Amino Acid repeat.
Conclusion: We here defined novel mutations that target DNA MMR and APC genes in African Americans with colorectal lesions. Greater frequency of mutations in cells defective for DNA repair and APC genes is an advantage in cell growth and genetic instability and relevant to the initiating events of colon tumorigenesis.
Citation Format: Hassan Ashktorab, Hamed Azimi, Mike Nickerson, Sara Bass, Joseph Boland, Meredith Yeager, Sudhir Varma, Mohamed Daremipouran, Zaki Sherif, Shima Ghavimi, Babak Shokrani, Edward Lee, Adeyinka Laiyemo, Hassan Brim. Targeted sequencing revealed distinctive and pathogenic mutations in African Americans with colorectal 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 4488.
Abstract 4490: Comparisons of genetic alterations of breast cancer between East and West: Special emphases on young patients with ER+/HER2- tumors
Authors: Lin Ching-Hung , Lu Tzu-Pin , Huang Ruby Yun-Ju , Lu Yen-Shen , Lo Ko-Yun , Kuo Kuan-Ting , Chuang Eric Y. , Wu Pei-Fang , Chen I-Chun , Thiery Jean Paul , Huang Chiun-Sheng , Cheng Ann-Lii 
Published: July 2016

Abstract
A rapid surge of female breast cancer has been observed in young East Asians. As a first step toward understanding this phenomenon, we compared the genetic alterations between breast cancer form Taiwan (East) and Western countries (West). Under the same array platforms, the differences in gene copy number alterations (n = 120 in East and 1,948 in West) and gene expressions (n = 327 in East and 423 in West) were analyzed as further stratified by age and estrogen receptor (ER)/ HER2 status. Gene-gene interaction networks were explored by analyzing the overlapping gene with ingenuity pathway analysis. The ingenuity pathway analysis revealed the common differences between East and West in NFkB, PI3K, Akt, MAPK, ERK, IFNα, and Jnk networks. Among the patients &lt;50 years with ER+/ HER2- tumors, we identified a uniquely higher frequency of the APOA1/C3/A4/A5 (the lipid metabolizing genes) gene cluster loss (29% vs. 12%, P = .005) and low expressions of these four genes (East/ West ratios ranged from .07 to .39) in East than that in West. We conclude that NFkB, PI3K, Akt, MAPK, ERK, IFNα, and Jnk networks are common differences between East and West, while APOA1/C3/A4/A5 loss and low expressions are unique genetic alterations for young Asian patients with ER+/ HER2- tumors.
Citation Format: Ching-Hung Lin, Tzu-Pin Lu, Ruby Yun-Ju Huang, Yen-Shen Lu, Ko-Yun Lo, Kuan-Ting Kuo, Eric Y. Chuang, Pei-Fang Wu, I-Chun Chen, Jean Paul Thiery, Chiun-Sheng Huang, Ann-Lii Cheng. Comparisons of genetic alterations of breast cancer between East and West: Special emphases on young patients with ER+/HER2- tumors. [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 4490.
Abstract 4495: Development and clinical application of an integrative genomic approach to personalized cancer therapy
Authors: Chen Rong 
Published: July 2016

Abstract
We implemented a personalized cancer therapy (PCT) program in a clinical setting, applying an integrative genomics approach to maximally elucidate the complexity of each tumor. For patients in the study, we performed whole exome sequencing and SNP microarrays on tumor and patient-matched normal samples, as well as RNA sequencing on available frozen samples, to identify somatic mutations, copy number alterations, gene fusions, and gene expression alterations in the tumor. Ion AmpliSeq Cancer Hotspot Panel v2 (CHPv2) was used to ensure high sensitivity in cancer mutation hotspots. Genomics results were integrated with cancer knowledge databases and for each cancer type a specific workflow was developed to optimize data interpretation. We returned genomics findings to 46 patients and their physicians, characterizing somatic alterations and predicting drug response, toxicity, and prognosis. Mean 17.3 cancer-relevant somatic mutations per patient were identified, 13.3-, 6.9-, and 4.7-fold more than could have been detected using CHPv2, Oncomine Cancer Panel (OCP), and FoundationOne, respectively. Our approach delineated the underlying genetic drivers at the pathway level and provided meaningful predictions of therapeutic efficacy and toxicity. Actionable alterations were found in 91% of patients (mean 4.9 per patient, including somatic mutations, copy number alterations, gene expression alterations, and germline variants), a 7.5-fold, 2.0-fold, and 1.9-fold increase over what could have been uncovered by CHPv2, OCP, and FoundationOne, respectively. The findings altered the course of treatment in 4 cases. These results show that a comprehensive, integrative genomic approach as outlined above significantly enhanced genomics-based personalized cancer therapy strategies.
Citation Format: Rong Chen. Development and clinical application of an integrative genomic approach to personalized cancer therapy. [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 4495.
Abstract 4526: Proscillaridin A effects on chromatin modifications and oncogene degradation in acute lymphoblastic leukemia
Authors: Armaos Gregory , Jacques-Ricard Simon , Da Costa Elodie , Beaudry Annie , Raynal. Noël J-M 
Published: July 2016

Abstract
Acute lymphoblastic leukemia (ALL) represents approximately 25% of all pediatric cancers diagnosed every year. In about 80% of cases, pediatric patients will attain an event-free 5-year survival. Unfortunately, patients who are resistant to treatment or who relapse have a poor prognosis. Hence, novel therapeutic approaches are necessary to increase survival rates. Epigenetic alterations, such as DNA methylation and histone modifications, are involved in disease development, progression, and in particular, resistance to treatment. These reversible alterations represent additional targets in ALL. Recently, we discovered candidate epigenetic drugs in FDA-approved drug libraries. We hypothesize that one drug in particular, the cardiac glycoside proscillaridin A, has both epigenetic and anti-cancerous properties in preclinical models of ALL and can therefore be repositioned for the treatment of the disease. To test our hypothesis, we treated two ALL cell lines Nalm-6 (pre-B ALL) and Molt-4 (T-ALL) in vitro with clinically relevant concentrations of proscillaridin A and analyzed cell growth, cell cycle, gene expression and chromatin modifications. We observed dose-dependent growth inhibition in all cell lines, with IC50 values of 3.0 and 2.3 nM in Nalm-6 and Molt-4, respectively. Our results using BrdU staining indicate a block in the G2/M phase of the cell cycle. By western blot, we detected a reduction in histone acetylation levels and in histone modifying enzymes CBP and Tip60, as well as the c-myc oncogene. These promising results illustrate the perspective of using the cardiac glycoside proscillaridin A as a novel epigenetic drug for the treatment of relapsed or refractory ALL.
Citation Format: Gregory Armaos, Simon Jacques-Ricard, Elodie Da Costa, Annie Beaudry, Noël J-M Raynal. Proscillaridin A effects on chromatin modifications and oncogene degradation in acute lymphoblastic leukemia. [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 4526.
Abstract 4530: EpiCapture: Benchmarking commercially available targeted bisulfite-sequencing platforms to gold-standard whole genome bisulfite sequencing
Authors: Tanic Miljana , Rodney Simon , Barrett James , Parker Hannah , Feber Andrew , Beck Stephan 
Published: July 2016

Abstract
Genomic DNA methylation is one of the most important epigenetic modifications in eukaryotes necessary for cellular differentiation and plays a crucial role in gene regulation of many oncogenes and tumor suppressor genes. Aberrant DNA methylation at the level of both individual gene promoters and on a genome-wide scale has been heavily implicated in cancer initiation and progression.
Whole genome bisulfite sequencing (WGBS) is the gold standard method for studying alterations in DNA methylation at a single base pare resolution. However, the high cost of WGBS is still prohibitive for high-throughput observational studies on large sample cohorts. Moreover, the WGBS data analysis requires substantial IT resources and a complex bioinformatics analysis. Targeted bisulfite sequencing enables a cost-effective and focused analysis of genomic regions of interest where most of DNA methylation alterations occur, such as promoters, CpG islands and shores, and enhancer regions. Currently, there are 2 main approaches for targeted bisulfite sequencing of medium-to-large genomic regions, reduced representation bisulfite sequencing (RRBS) and hybridization-based enrichment.
We have performed a comparison of 5 commercially available platforms for RRBS and in-solution hybridization-based enrichment panels. We analyzed a panel of two cancer cell lines (Hela and Coriell NA12878) and a normal blood reference gDNA sample, in duplicate on each platform using recommended sample inputs, and compared the results to WGBS data. Given that sample input requirements differ significantly between RRBS (∼100ng or less), and hybridization based methods (500ng - 1 μg), we have analyzed the normal blood reference gDNA sample at 500ng input in duplicate across all platforms. All samples were sequenced to a ∼30x depth on an Illumina HiSeq 2500 sequencer. We compared the genomic coverage, precision and off-target effects and overall concordance in methylome profiles for each method.
In summary, here we provide a comprehensive comparison of the performance of 5 different commercially available methods for medium to large scale targeted bisulfite sequencing, facilitating information to researchers for selection of appropriate method depending on required application.
Citation Format: Miljana Tanic, Simon Rodney, James Barrett, Hannah Parker, Andrew Feber, Stephan Beck. EpiCapture: Benchmarking commercially available targeted bisulfite-sequencing platforms to gold-standard whole genome bisulfite sequencing. [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 4530.
Abstract 4531: Dynamic long-range chromatin interaction controls expression of Il-21 in CD4+ T cells
Authors: Choi Yeeun 
Published: July 2016

Abstract
IL-21, a member of four-α-helical bundle type I cytokines, causes many pleiotropic effects, including terminal differentiation of B cells, immunoglobulin production, and the development of follicular helper T cells. IL-21 also promotes differentiation of Th17 cells and is implicated in the development of autoimmune disease. IL-21 can be strongly induced in CD4+ T cells by IL-6; however, very little is known about the mechanisms underlying the transcriptional regulation of the Il-21 gene at the chromatin level. Here, we identified insulator elements in the Il-21 locus with enhancer-blocking activity, which constitutively bind CTCF and cohesin. In naïve CD4+ T cells, these upstream and downstream CTCF-binding sites interact with each other to make a DNA loop; however, the Il-21 promoter does not interact with any cis-elements in the Il-21 locus. In contrast, stimulation of CD4+ T cells with IL-6 in the presence of αCD3 and αCD28 leads to recruitment of STAT3 and NFAT transcription factors to the promoter, as well as to novel distal enhancer region. This induces dynamic changes in chromatin configuration, bringing the promoter and the regulatory elements in close spatial proximity, facilitating IL-21 expression. The long-range interaction between the promoter and distal enhancer region was dependent on JAK/STAT3 signaling pathway but was disrupted in regulatory T cells, where IL-21 expression was repressed. In addition, we demonstrated that CTCF was required for optimal IL-21 expression and formation of chromatin looping in the Il-21 locus. Thus, our work uncovers a novel topological chromatin framework underlying proper transcriptional regulation of Il-21 gene.
Citation Format: Yeeun Choi. Dynamic long-range chromatin interaction controls expression of Il-21 in CD4+ T cells. [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 4531.