bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2951: Evaluation of methylation biomarkers for colon cancer using normal tissues
Authors: Sapienza Carmen , Truongcao May M. , Ghosh Jayashri 
Published: August 2015

Abstract
We have identified DNA methylation biomarkers that discriminate patients with colon cancer from patients without colon cancer using array-based profiling methods. Most DNA-based biomarkers for colon cancer rely on the detection of cancer cell-specific or cancer cell-prevalent mutations or DNA methylation changes in small numbers of tumor cells or small amounts of tumor cell-free DNA that are present in stool or lavage samples. Our hypothesis is that an individual's cancer-predisposing exposure history is recorded in normal tissues as “field cancerization”-related DNA methylation changes and that these changes will be present in normal colon, as well as other normal tissues, including peripheral blood. Consistent with the notion of changes based on “individual exposure history”, the bulk of the candidate biomarkers identified are genes involved in carbohydrate and lipid metabolism, as expected from epidemiological associations between colon cancer and “western” diets. We have now validated that our candidate methylation biomarkers are effective at discriminating cancer patients from controls using normal colon tissue from an independent population, and irrespective of whether the patients have left-side or right-side cancers. We have also found that a significant fraction of our candidate biomarkers also discriminate cancer patients from controls, using peripheral blood DNA analyzed by bisulfite pyrosequencing.
Citation Format: Carmen Sapienza, May M. Truongcao, Jayashri Ghosh. Evaluation of methylation biomarkers for colon cancer using normal tissues. [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 2951. doi:10.1158/1538-7445.AM2015-2951
Abstract 2960: DNA promoter hypermethylation of genes as potential diagnostic and prognostic biomarkers for ovarian cancer
Authors: Valle Blanca L. , Kuhn Elisabetta , Sidransky David , Guerrero-Preston Rafael 
Published: August 2015

Abstract
Till recently, epithelial ovarian cancers were thought to arise from the ovarian surface epithelial cells. However, recent studies suggest that the majority of high grade serous carcinomas (HGSCs) arise from lesions in the fallopian tubes. DNA promoter hypermethylation of certain genes is often an early event in tumorigenesis, and it can be detected in blood and other bodily fluids, making it a feasible biomarker strategy for early detection of tumors. Therefore, we sought to determine the methylation profile of HGSCs as compared to fallopian tube epithelium, using the Infinium HumanMethylation 450 Array. We compared the methylation in 12 HGSC tissue samples to 15 fallopian tube epithelium samples. In addition, we compared the methylation profile among long-term survivors (more than 5 years) and short-term survivors (2-3 years) of HGSCs. Our results identified the promoter regions of HIST1H2BB, MAGI2, and EPSTI1 to be differentially methylated when comparing HGSC with normal fallopian tube samples. Furthermore, these genes were differentially methylated in HGSC patients with long-term survival when compared to patients with short-term survival. Quantitative methylation specific PCR analysis confirmed our results of differential methylation among short-term and long-term survivors, and show that these genes are also methylated in ovarian cancer cell lines. Taken together, we have identified genes that could have potential as diagnostic and prognostic biomarkers. Our findings could lead to the development of a biomarker panel for the diagnosis and/or prognosis of ovarian cancer.
Citation Format: Blanca L. Valle, Elisabetta Kuhn, David Sidransky, Rafael Guerrero-Preston. DNA promoter hypermethylation of genes as potential diagnostic and prognostic biomarkers for ovarian 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 2960. doi:10.1158/1538-7445.AM2015-2960
Abstract 2964: Histology-specific patterns of DNA methylation in Lynch-associated and sporadic ovarian cancer
Authors: Niskakoski Anni , Kaur Sippy , Staff Synnove , Renkonen-Sinisalo Laura , Lassus Heini , Järvinen Heikki J. , Mecklin Jukka-Pekka , Bützow Ralf , Peltomäki Päivi 
Published: August 2015

Abstract
Epithelial ovarian cancer is a heterogeneous group of cancers, and molecular tools are urgently needed for a better understanding and targeted management of this often lethal disease. Since epigenetic methods can offer new tools for the management of ovarian cancer, our aim was to investigate epigenetic mechanisms in ovarian tumorigenesis representing different histological types. Expression profiling of ovarian and endometrial cancer cell lines treated with demethylating agents as well as literature were used to select gene candidates for epigenetic regulation. A methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay was constructed for thirteen genes to study methylation in 104 (85 sporadic and 19 Lynch syndrome-associated) ovarian carcinomas.
Increased methylation (hypermethylation) was characteristic of ovarian cancer tissues relative to the corresponding normal tissues and hypermethylation was consistently more prominent in non-serous than serous tumors. The highest frequencies of hypermethylation were detected in Lynch-associated clear cell ovarian carcinomas. An interesting finding among endometrioid ovarian carcinomas was a significant association of lower levels of methylation in HOXA9, RSK4 and SPARC with higher tumor grade; thus, the methylation patterns of high-grade endometrioid ovarian carcinomas resembled epigenetic characteristics of high-grade serous tumors. Overall, non-serous ovarian tumors of Lynch and sporadic origin (as opposed to serous tumors) showed frequent epigenetic inactivation in RSK4, SPARC, PROM1, HOXA10, HOXA9, WT1-AS, SFRP2, SFRP5, OPCML, and MIR34B.
Our findings provide important new information regarding some critical genes affected by epigenetic dysregulation in ovarian tumorigenesis. The results will be utilized in future experiments aiming to define the genetic and epigenetic origins of ovarian carcinomas of different types.
Citation Format: Anni Niskakoski, Sippy Kaur, Synnove Staff, Laura Renkonen-Sinisalo, Heini Lassus, Heikki J. Järvinen, Jukka-Pekka Mecklin, Ralf Bützow, Päivi Peltomäki. Histology-specific patterns of DNA methylation in Lynch-associated and sporadic ovarian 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 2964. doi:10.1158/1538-7445.AM2015-2964
Abstract 2965: Identification of SMARCA4/BRG1 mutation types in NSCLC cell lines and tumors
Authors: Zhang Wei , Yao Yibing , Zhou Yunyun , Ma Xiaotu , Yan Jingsheng , Wang Tao , Girard Luc , Minna John , Xiao Guanghua , Xie Yang , Gazdar Adi 
Published: August 2015

Abstract
Purpose: Identification of SMARCA4/BRG1 mutation types in NSCLC cell lines and tumors. Background: The SMARCA4 gene encodes the major catalytic subunit of the SWI/SNF chromatin remodeling complex and is necessary for the transcriptional regulation of multiple cellular pathways. SMARCA4 is frequently mutated in lung cancer cell lines and in lung cancers. Methods: Sixty four NSCLC cell lines were analyzed. The Cancer Genome Atlas (TCGA) data were examined. SMARCA4 mutations were identified by NextGen and/or Sanger sequencing using genomic DNA or cDNA. Gene expression profiles and global methylation was determined by Illumina BeadChips. BRG1 protein was detected by immunoblotting. Results: SMARCA4 abnormalities were divided into Type1 (loss of full length protein, usually due to deletions, non-sense mutations or splicing site mutations) and Type 2 (homozygous or heterozygous missense mutations with protein present). Sequencing often failed to detect large deletions. Loss of SMARCA4/BRG1 resulted in profound downstream effects on the transcriptome and methylome, while existence of BRG1 with mutations has much less effects. Analysis using most significantly regulated transcripts can distinguish SMARCA4 type 1 abnormality from WT group, and indicate that type 2 abnormality effects were heterogeneous. SMARCA4 regulated transcripts are involved in many important cellular functions such as cell movement, death and proliferation and participate in many cytokines and hormone/nuclear receptors-mediated pathways. The expressions of transcription factors FOXA2 and NKX2-1 were decreased, while two groups of cancer testis antigens (CTAs), PRAME and MAGEA family were elevated in NSCLC cell lines and tumors with SMARCA4 mutations/low expression. Furthermore, FOXA2 and NKX2-1 were downregulated in an inducible SMARCA4 knock- down immortalized human lung epithelial cell line. Conclusions: SMARCA4 mutations can be divided into two types having varying downstream effects.
Citation Format: Wei Zhang, Yibing Yao, Yunyun Zhou, Xiaotu Ma, Jingsheng Yan, Tao Wang, Luc Girard, John Minna, Guanghua Xiao, Yang Xie, Adi Gazdar. Identification of SMARCA4/BRG1 mutation types in NSCLC cell lines and tumors. [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 2965. doi:10.1158/1538-7445.AM2015-2965
Abstract 2966A: A comprehensive investigation of insertional variations of human endogenous retrovirus elements in tumor tissues
Authors: Kahyo Tomoaki , Yamada Hidetaka , Tao Hong , Inoue Yusuke , Kurabe Nobuya , Sugimura Haruhiko 
Published: August 2015

Abstract
Human endogenous retrovirus (HERV) is a member of LTR-retrotransposon family. Retroviral invasions are thought to have occurred in the germ cell lines of human or human ancestors, and the fixed retroviral elements are recognized as HERV. A complete HERV sequence contains two long terminal repeats (LTRs) located at both ends. Because intact LTRs possess the highly conserved transcriptional promoter- and enhancer-sequences, to investigate insertional variations of HERV is a key process for understanding the etiology of human genetic diseases that remain unclear with the analyses targeting single nucleotide variations. However, genome-wide investigation of repetitive sequences including HERV is methodologically difficult, and comprehensive understanding of insertional variations of HERV, including a somatic retrotransposition of HERV, remains poor. In the previous study, we have identified two novel insertional polymorphisms of solo LTRs using the inverse PCR and cloning methods, and one of them was involved with the susceptibility to lung adenocarcinoma. Here, we detected multiple novel LTR loci in the human cancer tissues by developing the high-throughput sequencing method combined with inverse PCR. In this system, to preferentially detect insertional variations, primer sequences were designed based on the conserved region of the LTRs which have an identical sequence to the mate within the same HML-2 proviruse, because almost of known HERV insertional polymorphisms are found in HML-2, which is thought to be the most recently endogenized element of HERV, and the presence of an identical LTR sequence at both ends is necessary for the retrotransposition of exogenous retrovirus. The sequence reads generated from the high-throughput sequencer were trimmed, and the fragments consistent with the inverse PCR process were selected. Following the mapping to the reference genome, the sites not corresponding to known LTR loci were sorted out and subjected to the filtration to exclude the artificial fragments. As the result, some candidates of novel LTR loci were detected, and several of them were verified to be actually present both in tumor and non-tumor genomes using the Sanger method, suggesting they are insertional polymorphisms. By using this detection system, we are now challenging to investigate a novel LTR site specifically detected in tumor genome.
Citation Format: Tomoaki Kahyo, Hidetaka Yamada, Hong Tao, Yusuke Inoue, Nobuya Kurabe, Haruhiko Sugimura. A comprehensive investigation of insertional variations of human endogenous retrovirus elements in tumor tissues. [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 2966A. doi:10.1158/1538-7445.AM2015-2966A
Abstract 2984: Heterogeneous mechanisms of acquired resistance in high grade serous ovarian cancer
Authors: Bowtell David D L 
Published: August 2015

Abstract
In contrast to other solid cancers, overall survival for patients with high-grade serous ovarian cancer (HGSC) is little changed over the last 30 years and it has been difficult to advance beyond platinum-based combination chemotherapy. As HGSC are driven by genomic copy number change rather than recurrent point mutation, we undertook whole genome sequence (WGS) analysis of a large HGSC cohort in order to survey structural variation at high resolution. Utilizing 114 tumours from 92 patients, we performed transcriptome, methylation, and miRNA expression analyses to support the WGS data, and compared resistant, refractory, and sensitive primary disease. We evaluated tumour and normal DNA samples from patients with primary refractory, primary resistant or primary sensitive disease to better understand the drivers of these clinical phenotypes. We also characterized paired pre-treatment chemosensitive and post-resistance samples, and end-stage HGSC obtained from patients who underwent a research autopsy. We found that gene breakage involving tumour suppressors such as NF1 and RB1 is a common form of inactivation in HGSC and in other circumstances contributes to acquired chemotherapy resistance in some patients. We found evidence of a chemotherapy footprint in the genome of recurrent tumour samples. We observed a striking degree of diversity of other mechanisms of acquired resistance, including multiple independent germline BRCA1 or BRCA2 reversion events in individual patients, loss of BRCA1 promoter methylation, a shift in molecular subtype to a desmoplastic phenotype, and a recurrent promoter fusion associated with overexpression of a driver of drug resistance, validated in an independent dataset. Collectively our findings underscore the plasticity of the HGSC genome and indicate that pre-empting resistance by modifying current first line therapy or countering it when it emerges will require a diversity of approaches.
Citation Format: David D L Bowtell. Heterogeneous mechanisms of acquired resistance in high grade serous ovarian 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 2984. doi:10.1158/1538-7445.AM2015-2984
Abstract 2986: Meta-analysis of whole exome sequencing data reveals the mutational spectrum of testicular germ cell tumors
Authors: Litchfield Kevin , Houlston Richard S. , Huddart Robert , Summersgill Brenda , Shipley Janet , Turnbull Clare 
Published: August 2015

Abstract
Testicular germ cell tumors (TGCTs) are the most common cancer in young men. Although cure rates for TGCT are generally high, due to the sensitivity of malignant testicular germ cells to platinum-based chemotherapies, this comes at the cost of an increased risk of metabolic syndrome, infertility and secondary cancer. Furthermore, there are limited options for patients who are platinum resistant, a group for whom the long-term survival rate is less than 15%. Improved targeted therapies for TGCT are predicated on a greater understanding of mutational profile of these tumours, including identification of driver mutations and pathways disrupted. We recently published the first large-scale analysis of whole exome sequencing of TGCTs (comprising 42 tumors), which revealed a uniformly low mutation rate; some ∼ten times lower than average rates observed in other adult solid tumors, consistent with the embryological origin of TGCT. Aside from mutations in the previously known driver gene KIT, no additional novel genes with mutation frequency greater than 15% were associated with tumorigenesis. In parallel The Cancer Genome Atlas consortium is sequencing an additional series of TGCTs.
Given the apparent absence of high frequency driver genes aside from KIT, several lower frequency oncogenic pathways may exist, requiring identification through larger sample size studies and/or pooled analysis. Here we present meta-analysis across multiple datasets with variant calling re-processed through a consistent bioinformatic pipeline. We systemically searched for novel recurrent mutational events at three levels:- (i) driver genes (combined sample size was empowered to detect recurrent gene mutations of frequency &gt;5% with 89% power), ii) pathway based associations and iii) focal copy number alterations. In addition we assessed for clinicopathological-molecular associations, with particular focus on mutational events distinguishing treatment responsive and resistant tumors. Comprehensive cataloguing of the mutational spectra, through analyses of our data in combination with other initiatives such as TCGA, is leading to increasing insights into this biology of this cancer.
Citation Format: Kevin Litchfield, Richard S. Houlston, Robert Huddart, Brenda Summersgill, Janet Shipley, Clare Turnbull. Meta-analysis of whole exome sequencing data reveals the mutational spectrum of testicular germ cell tumors. [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 2986. doi:10.1158/1538-7445.AM2015-2986
Abstract 2987: Next generation sequencing analysis of genetically engineered mouse models of human cancers
Authors: Chung Wei-Jen , Long Jason , Cheng Jason , Tran Chris , Dey Anwesha , Daemen Anneleen , Junttila Melissa 
Published: August 2015

Abstract
Genetically engineered mouse models (GEMM) of cancer are invaluable tools for oncology research. They recapitulate critical aspects of tumor etiology and allow for unique interrogation of the tumor stroma interactions during tumorigenesis. In addition, these models are poised for assessing therapeutic drug efficacy and resistance mechanisms. Although these models are widely used, the mutational landscape and transcriptional profile of GEMMs have yet to be thoroughly characterized.
In this study we sought to investigate the precise mutational landscape of four well-validated GEMMs representing three types of cancers, non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC) and melanoma. Using next generation sequencing techniques, we profiled one adenovirally-induced Kras mutant NSCLC model (KrasLSL.G12D; p53frt/frt), two Kras mutant models of spontaneous PDAC (KrasLSL.G12D; p16/p19fl/fl; Pdx1.Cre and KrasLSL.G12D; p16/p19fl/wt; p53LSL.R270H/wt; Pdx1.Cre) and one Braf mutant melanoma model (BrafV600E/wt; PTENfl/fl; TyrCreER). All four GEMMs incorporate mutations that are well documented to occur in the human patient population. Additionally these models have been documented to approximate histological and phenotypic aspects of their human correlate.
We carried out whole exome sequencing for each model (NSCLC n = 120; PDAC n = 73 and n = 40, respectively; melanoma n = 17) to comprehensively characterize the baseline genomes. We also looked for additional recurrent driver mutations beyond those engineered within each model. Interestingly, both intra and intertumoral heterogeneity was evident. Furthermore, we performed RNA sequencing and identified significantly affected genes and gene sets. Finally, we compared our GEMMs to human tumors from TCGA (LUAD, LUSC, PAAD and SKCM) at the genomic and transcriptomic level. Taken together, the results we will present provide a clearer understanding of the genomic and transcriptional landscape of these GEMMs and their relationship with human patients. More importantly, these analyses will allow us to better interpret results from previous and future experiments using these GEMMs of cancer.
Citation Format: Wei-Jen Chung, Jason Long, Jason Cheng, Chris Tran, Anwesha Dey, Anneleen Daemen, Melissa Junttila. Next generation sequencing analysis of genetically engineered mouse models of human cancers. [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 2987. doi:10.1158/1538-7445.AM2015-2987
Abstract 2988: International cancer genome consortium (ICGC)
Authors: Jennings Jennifer L. , Hudson Thomas J. 
Published: August 2015

Abstract
The International Cancer Genome Consortium (ICGC) was established to bring together researchers from around the globe to comprehensively analyze the genomic, transcriptomic, and epigenomic changes in 50 different tumour types or subtypes that are of clinical and societal importance across the globe (International network of cancer genome projects. Nature 464, 993-998 (15 April 2010)).
As of December 2014, the ICGC has received commitments from researchers and funding organizations in Asia, Australia, Europe, North America and South America for 77 project teams in 17 jurisdictions to study more than 25,000 tumour genomes.
More than 27,000 tumours that meet ICGC requirements for consent have been obtained and research pathologists have approved over 27,000 samples as meeting ICGC standards.
Processed data is available via the Data Coordination Centre (http://dcc.icgc.org) based at the Ontario Institute for Cancer Research and is updated quarterly. The data release (Version 17) in October 2014 included datasets from 42 ICGC members. The ICGC Data Portal has been improved to provide enhanced support to the research community browsing this vast dataset.
The ICGC and The Cancer Genome Atlas (TCGA) PanCancer Analysis of Whole Genomes (PCAWG) project is committing more than 2,500 tumour-normal whole genome pairs from 23 different tumour types to uniform alignment and variant calling. More than 600 researchers will contribute to the interpretation of the data and writing of papers that will focus on specific analyses covering: Identification of driver mutations outside coding regions, including those that affect cis-regulatory regions and non-coding RNAs; and identification of gene regulatory pathways altered by non-coding mutations. Because the projected size of the pan-cancer dataset for 5,000 WGS is very large, PCAWG is using a distributed compute cloud environment (at different computing centres in the USA, Europe and Asia) that meet technical requirements of the project and the bioethical framework of ICGC and its member projects. More information can be found on www.icgc.org.
Citation Format: Jennifer L. Jennings, Thomas J. Hudson. International cancer genome consortium (ICGC). [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 2988. doi:10.1158/1538-7445.AM2015-2988