bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1067: Characterization of DNA hypermethylation in two cases of peritoneal mesothelioma
Authors: Oikawa Ritsuko , Watanabe Yoshiyuki , Hama Ryota , Yamamoto Hiroyuki , Itoh Fumio 
Published: August 2015

Abstract
Background: Malignant mesothelioma (MM) is a rare disease with a poor prognosis. Pleural mesothelioma, which is the most common type of MM, is considered to be caused by asbestos exposure and is increasing in incidence, with about 15,000 new cases diagnosed worldwide annually. On the other hand, peritoneal mesothelioma is a very rare type of MM; thus its pathogenesis is even less understood than pleural mesothelioma. Recent research on the pathogenesis of malignant pleural mesothelioma has indicated that both epigenetic and genetic alterations contribute to tumorigenesis. Here, we hypothesize that peritoneal mesothelioma also has an epigenetic alteration in the same genes (KAZALD1, TMEM30B and MAPK13). Our goal is to identify DNA methylation of these three candidate genes in two peritoneal mesothelioma cases. Methods: Laser capture microdissection (LCM) was used to separate diseased sections of formalin-fixed paraffin-embedded (FFPE) samples from one surgically resected tissue (epithelial type) and one autopsy tissue (sarcomatous type). Genomic DNA was subsequently extracted by the standard phenol chloroform method. The DNA was then treated with sodium bisulfite, and pyrosequencing analysis was used to quantitatively analyze the methylation of candidate genes reported to be hypermethylated in malignant pleural mesothelioma (KAZALD1, TMEM30B and MAPK13). Results: TMEM30B and MAPK13 were not methylated in either case. However, KAZALD1 was highly methylated in sarcomatoid type peritoneal mesothelioma. Discussion: We first report that the KAZALD1 gene was hypermethylated in sarcomatoid type malignant peritoneal mesothelioma.
Citation Format: Ritsuko Oikawa, Yoshiyuki Watanabe, Ryota Hama, Hiroyuki Yamamoto, Fumio Itoh. Characterization of DNA hypermethylation in two cases of peritoneal mesothelioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1067. doi:10.1158/1538-7445.AM2015-1067
Abstract 1069: DNA methylation in circulating free DNA as a new biomarker for pancreatic cancer
Authors: Shinjo Keiko , Ohka Fumiharu , Katsushima Keisuke , Hatanaka Akira , Ichimura Norihisa , Juan Zhao , Yamao Kenji , Kondo Yutaka 
Published: August 2015

Abstract
Despite the clinical advancement, pancreatic cancer remains one of the most deadly cancers. Pancreatic cancers are often difficult to diagnose and there is no reliable screening biomarker for early detection of this cancer. Epigenetic alterations have emerged as a common hallmark of many types of human cancers as well as pancreatic cancers. Studies have shown that epigenetic dysregulation is associated with multiple steps during carcinogenesis. Therefore, detection of aberrant DNA methylation from blood samples may be a promising diagnostic tool for pancreatic cancers.
First, we analyzed KRAS mutation status of 100 samples obtained by Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), which is a safe and accurate technique to perform the pancreatic tissue biopsy, and found that more than 80% of the cells in the samples harbors KRAS mutation indicating high amount of cancer cells in the specimens. Next, we performed genome-wide DNA methylation analysis of 38 EUS-FNA specimens using Illumina Infinium HumanMethylation450 BeadChip. We further analyzed the deposited DNA methylation profiles of other tumor types in the public databases, such as TCGA, and identified 8 marker genes with high frequency and specificity of DNA methylation in pancreatic cancers. We validated the DNA methylation status of these genes by bisulfite pyrosequencing and quantitative methylation specific PCR. These markers were frequently methylated in EUS-FNA samples (95% of samples are methylation positive in at least one marker gene). Now we are analyzing the DNA methylation status in pancreatic cancers and corresponding blood samples in order to identify the most effective set of markers for diagnose pancreatic cancers. Our results suggest that analysis of DNA methylation in the circulating free DNA might be a safe and potent tool for evaluating and staging pancreatic cancers.
Citation Format: Keiko Shinjo, Fumiharu Ohka, Keisuke Katsushima, Akira Hatanaka, Norihisa Ichimura, Zhao Juan, Kenji Yamao, Yutaka Kondo. DNA methylation in circulating free DNA as a new biomarker for pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1069. doi:10.1158/1538-7445.AM2015-1069
Abstract 1073: KRAS-mediated epigenetic reprogramming upregulates RELB-dependent CXCR2 expression to promote transformation
Authors: Durand Joel , Baldwin Albert 
Published: August 2015

Abstract
In addition to genetic aberrations, cancer cells harbor global epigenetic abnormalities. Mutant KRAS expression has been shown to induce aberrant DNA methylation and silencing of key tumor suppressors. However, nearly all attempts to directly target oncogenic KRAS have been unsuccessful, yielding an impetus for alternative strategies. Furthermore, in the majority of KRAS-driven tumors, the NF-κB pathway is constitutively active and contributes to cellular transformation. Previously, our lab has shown that knocking out the p65 subunit of NF-κB significantly reduces tumor development in a mouse model of KRAS-induced lung cancer. Here we aim to better understand KRAS-mediated epigenetic reprogramming and uncover novel effects on the NF-κB pathway. Our data suggests that KRAS-mediated epigenetic reprogramming alters the NF-κB pathway to promote transformation. Using the Infinium DNA Methylation Assay, we uncovered genome-wide changes in lung and pancreatic cells expressing KRAS(G12V) compared to wild-type cells. Expression of oncogenic KRAS was accompanied by promoter hypermethylation of tumor suppressors (e.g. FAS, BRCA1, IRAK3) and hypomethylation of oncogenes. Interestingly, we observed hypomethylation at the promoter of the RELB subunit of NF-κB in cells expressing KRAS(G12V). Hypomethylation at the RELB promoter correlated with increased expression of CXCR2, an NF-κB target gene. RNAi against RELB and CXCR2 significantly decreased colony growth in lung and pancreatic cancer cell lines expressing mutant KRAS. Together, these results support a role for KRAS in epigenetic reprogramming and suggest that RELB-dependent CXCR2 expression may be critical in KRAS-driven cancers. RELB and CXCR2 represent potential therapeutic targets that could lead to more effective treatments in the context of KRAS-driven malignancies.
Citation Format: Joel Durand, Albert Baldwin. KRAS-mediated epigenetic reprogramming upregulates RELB-dependent CXCR2 expression to promote transformation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1073. doi:10.1158/1538-7445.AM2015-1073
Abstract 1094: Deciphering driver mechanisms for tumorigenesis in BRAF/NRAS double wild-type melanoma through integration of heterogeneous genome-wide datasets
Authors: Mandal Amit , Girotti Maria Romina , Viros Amaya , Gremel Gabriela , Galvani Elena , Lee Rebecca , Lim Kok Haw Jonathan , Furney Simon J. , Lorigan Paul , Marais Richard 
Published: August 2015

Abstract
In cutaneous melanoma, the most lethal form of skin cancer, BRAF is mutated in ∼45% of cases and NRAS in a further ∼20% of cases. The lack of known drivers in the remaining proportion of samples represents a challenge for personalized medicine. We hypothesize that the BRAF/NRAS double wild-type (WT) samples are a heterogeneous group driven by multiple events that arise independently. We performed whole exome sequencing (WES) and complimentary RNA-seq of 23 tumor tissue samples from 21 patients. Six of these tumors were WT for BRAF and NRAS, so we studied these cases further. The SNV load in the WT samples is more variable than the BRAF or NRAS driven melanomas. The median number of SNVs/Mb (± SD) for BRAF mutant (n = 9), NRAS mutant (n = 7) and BRAF WT/ NRAS WT (n = 6) samples were: 12.2 ± 8.0, 42.2 ± 82.7 and 12.6 ± 90.2 respectively. Next we analyzed the TCGA cutaneous melanoma cohort where there are 154 BRAF and 92 NRAS mutated and 76 BRAF WT/NRAS WT samples. The median numbers of SNVs (± SD) were 374 ± 638.3, 577 ± 518.3 and 146.5 ± 1221.6 respectively. The p-value for the comparisons BRAF vs. WT and NRAS vs. WT were 0.087 and 0.002 respectively (two-tailed Mann-Whitney test). We identified the somatic mutations that are specifically enriched for double wild-type samples and observed that the top two hits, NF1 (30.2% in double WT vs. 5.7% otherwise) and KIT (15.8% in double WT vs. 0.8% otherwise) are known driver gene candidates for wild-type melanomas, but we also find other novel candidate driver genes. Thus, we present a framework for identification of driver mutations and therapeutic targets in double wild-type melanomas and integration of these types of data with other large datasets such as those derived from RNA-seq and RPPA will assist in the development of approaches to stratify double wild-type patients for targeted or immune-therapies.
Citation Format: Amit Mandal, Maria Romina Girotti, Amaya Viros, Gabriela Gremel, Elena Galvani, Rebecca Lee, Kok Haw Jonathan Lim, Simon J. Furney, Paul Lorigan, Richard Marais. Deciphering driver mechanisms for tumorigenesis in BRAF/NRAS double wild-type melanoma through integration of heterogeneous genome-wide datasets. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1094. doi:10.1158/1538-7445.AM2015-1094
Abstract 1095: In silico mapping of oncogene networks implicate the WNT pathway in the glioblastoma MES subtype
Authors: Joy Anna M. , Smirnov Ivan , Reiser Mark , Kim Seungchan , Feuerstein Burt 
Published: August 2015

Abstract
It is clear that glioblastoma (GBM) is a collection of molecular subtypes, however little is known of their oncogene signaling. To address this we are currently developing a new method to map PI3K/AKT/mTOR network activity. It uses TCGA reverse-phase protein array data and is based on correlations between active pathway members. This approach provides evidence the WNT pathway is active in the Mesenchymal subgroup and we are currently validating these results. Based on this data we hypothesize Mesenchymal patients will respond to WNT inhibitors.
Citation Format: Anna M. Joy, Ivan Smirnov, Mark Reiser, Seungchan Kim, Burt Feuerstein. In silico mapping of oncogene networks implicate the WNT pathway in the glioblastoma MES subtype. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1095. doi:10.1158/1538-7445.AM2015-1095
Abstract 11: Molecular mechanisms of inverse association between cancer and Alzheimer's disease
Authors: Yang Yoosoo , Lee EunJung , Kim In-San 
Published: August 2015

Abstract
Apoptosis has been implicated in both cancer and neurodegenerative disease such as Alzheimer's disease (AD). Defective or inefficient apoptosis is an acquired hallmark of cancer cells, while cytochrome c-dependent apoptosis is a crucial pathway in AD related neuronal cell death. Notably, recent studies have revealed an inverse correlation between development of cancer and AD—AD patients show a reduced risk of cancer, while cancer survivors are less likely to acquire AD. Here we propose that amyloid β (Aβ), a widely accepted pathological culprit of AD, hijacks the intrinsic apoptotic pathway eliciting different symptoms for cancer and AD. By developing an in vitro single-vesicle cytochrome c release assay, we show that even in the absence of death signal the oligomeric form of synthetic Aβ directly interacts with a pro-apoptotic bcl-2 family protein BAK and induces apoptotic pores sufficient for cytochrome c release. Furthermore, Aβ oligomers not only cause neuronal cell death in HT-22 cells but also the apoptotic effect was significantly reduced with suppressed BAK expression via siRNA, further substantiating its apoptotic interaction with BAK. Moreover, a significant reduction of cytochrome c release was also observed with isolated mitochondria from BAK siRNA-treated HT-22 cells which specifically identifies the target machinery. These results demonstrate Aβ oligomers’ efficacy as a potent apoptotic ligand. In collection, we suggest that while Aβ oligomers may cause neuronal cell death in AD it may also ameliorate tumor proliferation in relation to cancer. Thus, providing molecular level evidence for the inverse association reported between cancer and AD patients.
Citation Format: Yoosoo Yang, EunJung Lee, In-San Kim. Molecular mechanisms of inverse association between cancer and Alzheimer's disease. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 11. doi:10.1158/1538-7445.AM2015-11
Abstract 1117: Who's in the driver's seat? Identifying causative variants of colorectal cancer
Authors: Coggins Nicole , Carvajal-Carmona Luis , Segal David 
Published: August 2015

Abstract
Colorectal Cancer (CRC) is one of the leading causes of mortality in the US, being the third most common cancer among both men and women. While an exact cause of CRC has not yet been elucidated, the existence of a clear heritable genetic component has been established. With the recent surge of data from Genome-Wide Association Studies, a handful of CRC-associated loci have been identified via tagSNPs. While the probability of the tagSNPs themselves being the causative variants is low, the key may lie among the number of single-base variants linked to each tagSNP. It is crucial, in order to enhance our understanding CRC tumorigenesis, to extract these functional variants from the pool of associated SNPs and validate their causative significance within the cell.
This project combines bioinformatics and functional experiments to both identify and assess the role of functional variants in CRC pathogenesis. One of the major hurdles in understanding the role of CRC risk-associated SNPs is the fact that virtually all variants lie in Non-Protein Coding Region, often tens of thousands of bases away from flanking genes. By combining variant data from publically available databases, such as that of the ENCODE project, this research presents a method to prioritize all variants within a set of disease-associated loci based on potential regulatory functionality in silico. With this technique, we have identified a handful of SNPs with functional potential that may be functioning specifically in CRC initiation. In parallel, we are in the process of developing a method to effectively produce isogenic cell lines modeling the appropriate variant alleles, utilizing the CRISPR/Cas9 system to stimulate homologous recombination in the presence of a donor template. With this method, transcriptional and regulatory changes within the cell due to the single-base genomic edit can be measured in order to characterize these functional variants. Utilizing this technology, we have been able to create our first SNP model of SNP rs6983267, a known functional variant whose risk SNP promotes CRC development by means of increased binding and activation of WNT signaling pathway elements, c-Myc and β-Catenin. The ultimate goal of this project is to better understand the role of CRC risk-associated variants, the result of which could have substantial clinical relevance in the generation of new therapies and diagnostics for the treatment of CRC.
Citation Format: Nicole Coggins, Luis Carvajal-Carmona, David Segal. Who's in the driver's seat? Identifying causative variants of colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1117. doi:10.1158/1538-7445.AM2015-1117
Abstract 1122: Personalized oncogenomics in advanced stage breast cancer
Authors: Sun Sophie , Gelmon Karen A. , Chia Stephen , Lohrisch Caroline , Shenkier Tamara , Villa Diego , Shen Yaoqing , Jones Martin , Pleasance Erin , Kasaian Katayoon , Eirew Peter , Leelakumari Sreeja , Ma Yusanne , Ng Tony , Yip Stephen , Jones Steven JM , Marra Marco A. , Laskin Janessa J. 
Published: August 2015

Abstract
Background
Breast cancer is a complex disease with clinical, pathological, and molecular heterogeneity. Recent studies have identified several subtypes of breast cancers driven by specific molecular pathways that can be inhibited by targeted drugs. We studied the feasibility of using molecular data from whole genome and transcriptome sequencing of breast cancers to guide treatment.
Methods
Patients were consented as part of the Personalized Onco-Genomics (POG) study at the British Columbia Cancer Agency. Fresh tumor, blood for normal DNA, and archival tumor were collected. Tissue and blood samples were sequenced using the Ion Torrent AmpliSeq panel, followed by comprehensive DNA and RNA sequencing. In-depth bioinformatic analyses were performed. Somatic mutations, copy number changes, structural variants and gene expression were characterized. Results from genomic analyses were reviewed in a multi-disciplinary team.
Results
From August 2012 to October 2014, tissue samples from 30 patients with advanced stage breast cancer were analyzed. The median age at diagnosis was 53 years (range 32-75). The median number of lines of cytotoxic therapy prior to sequencing was 2 (range 0-10). All cases were invasive ductal carcinoma; 63% were ER+ and HER2-; 27% triple negative; 7% ER+ and HER2+; and 3% ER- and HER2+. The most frequently mutated genes were TP53 (67%), PI3KCA (23%), ESR1 (20%), ATM (10%), ARID1A (10%), and BRCA1/2 (10%). Somatic mutations in other genes of interest including HER2, PARP1, NF1, BAP1, PTEN, NOTCH1, were also identified. Molecular data were informative for patient care and/or actionable to guide treatment in 57% (17/30) of cases.
Conclusion
The use of whole genome sequencing technology to identify valuable molecular information to guide personalized breast cancer treatment is feasible. Further studies are warranted to evaluate the usefulness of genome-wide sequencing of breast cancers in clinical practice.
Citation Format: Sophie Sun, Karen A. Gelmon, Stephen Chia, Caroline Lohrisch, Tamara Shenkier, Diego Villa, Yaoqing Shen, Martin Jones, Erin Pleasance, Katayoon Kasaian, Peter Eirew, Sreeja Leelakumari, Yusanne Ma, Tony Ng, Stephen Yip, Steven JM Jones, Marco A. Marra, Janessa J. Laskin. Personalized oncogenomics in advanced stage breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1122. doi:10.1158/1538-7445.AM2015-1122
Abstract 1126: Differential effects of metformin and phenformin vs. other complex 1 inhibitors in vitro and in vivo
Authors: Algire Carolyn , Ehrmann Alexander , Christian Sven , Neuhaus Roland , Menz Stephan , Schwede Wolfgang , Haerter Michael , Haegebarth Andrea 
Published: August 2015

Abstract
Biguanides, such as metformin and phenformin, are currently under investigation for their potential use as anti-neoplastic therapy. Recent publications suggest that both metformin and phenformin exert effects through inhibition of Complex 1 in the electron transport chain. We investigated the effects of metformin and phenformin compared to rotenone, in vitro, and known Complex 1 inhibitor BAY 872243, in vitro and in vivo.
As expected, rotenone and BAY 872243 showed strong inhibition of Complex I in cell-based and enzymatic assays with IC50 values in the nanomolar range. The high affinity binding to Complex I was also reflected by induction of cellular reactive oxygen species (ROS) with EC50 values in the nanomolar range. In contrast, the biguanides neither inhibited Complex I in cell-based and biochemical assays, nor led to an induction of ROS at concentrations up to 300 μM.
In vivo exposure analysis shows that at the maximal tolerated dose (100 mg/kg QD i.p for phenformin and 350 mg/kg i.p QD for metformin), neither metformin nor phenformin had plasma exposure levels over the IC50 for proliferation in vitro. Recent reports have suggested that biguanides, via the inhibition of Complex 1 and subsequent reduction in oxygen consumption, can be used to re-oxygenate tumor areas prior to radiation therapy. Pimonidazole staining demonstrated that metformin and phenformin effectively eliminated hypoxic regions in NCI-H460 xenografts in a time course dependent manner that reflected the exposure. In contrast to the biguanides, BAY 87-2243 effectively eliminated hypoxic regions up to 24 hours post compound administration. Finally, both phenformin and metformin had minimal effects on inhibition of tumor growth, even in LKB1-deleted xenografts which have been reported to be especially sensitive to biguanides. In conclusion, our in vitro experiments on the mode of action of biguanides raise questions as whether the in vivo effects on hypoxic tumor regions are related to direct inhibition of Complex I.
Citation Format: Carolyn Algire, Alexander Ehrmann, Sven Christian, Roland Neuhaus, Stephan Menz, Wolfgang Schwede, Michael Haerter, Andrea Haegebarth. Differential effects of metformin and phenformin vs. other complex 1 inhibitors in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1126. doi:10.1158/1538-7445.AM2015-1126