bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1994: Tobacco carcinogen-induced transformation of HBECs is associated with chromatin-mediated reprogramming of the epigenome
Authors: Tellez Carmen S. , Juri Daniel E. , Van Neste Leander , Hart Christopher , Liu Yushi , Do Kieu , Picchi Maria A. , Belinsky Steven A. 
Published: August 2014

Abstract
An in vitro model, hTERT/cdk4, immortalized human bronchial epithelial cells (HBECs), was used to identify key molecular changes driving cell transformation and the clonal outgrowth of preneoplastic lung epithelial cells. Low-dose weekly treatment (12 weeks) of HBECs with genotoxic, but not cytotoxic doses of the carcinogens methylnitrosourea (MNU), benzo(a)pyrene-diolepoxide 1 (BPDE), or both induced transformation. Transformation efficiency (0.2-3%) differed between HBECs and was associated with DNA repair capacity, increased levels of DNMT1 protein, promoter hypermethylation, EMT, and stem-like cell phenotype. Agilent 44K arrays were used to determine genome-wide changes in gene expression associated with transformation. Comparison of expression between HBEC1 and HBEC2 to cells transformed by BPDE, MNU, or the combination revealed 287-321 and 320-493 genes with increased or decreased (≥ 3-fold change) expression. Approximately 214 and 331 of the genes with decreased expression in HBEC1 and HBEC2 had CpG islands that extended through their transcriptional start site. HBEC2 MNU/BPDE transformed cells were treated with DAC or TSA to assess globally whether chromatin remodeling alone, or in combination with DNA methylation mediated gene silencing. Only 128 of 331 silenced genes in HBEC2 MNU/BPDE transformed cells responded to DAC alone. Promoter methylation arrays and genome-wide ChIP-chip for inactive chromatin marks were used to elucidate mechanisms of global gene silencing in HBEC2 MNU/BPDE transformed cells. Array analysis revealed 216 genes with reduced expression are enriched for H3K27me3 and 23 novel genes with reduced expression are hypermethylated in HBEC2 MNU/BPDE transformed cells. Our in vitro model suggests that the re-programming of the epigenome during carcinogen-induced transformation is initially mediated by chromatin remodeling with ensuing DNA methylation sustaining gene silencing. The authors’ work is supported by a research grant from National Institutes of Health (R01 ES008801).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1994. doi:10.1158/1538-7445.AM2011-1994
Abstract 1997: Changes in growth pattern and expression of epigenetic regulatory genes in human prostate epithelial cells exposed to arsenic and estrogen
Authors: Treas Justin , Singh Kamaleshwar P. 
Published: August 2014

Abstract
Chronic exposure to either arsenic or estrogen causes prostate cancer in animal model. However, the effects of co-exposure to estrogen and sodium arsenite on prostate epithelial cells are not known. Chromatin remodeling by epigenetic changes play important role in gene expression and carcinogenesis. Therefore, the objective of this study was to determine the effects of chronic exposure to 17-βestradiol and sodium arsenite on cell growth and the expression epigenetic regulatory genes in RWPE-1, a human prostate epithelial cell line. RWPE-1 cells were treated with estrogen and arsenic alone as well as in combination of these two chemicals for 4 months. The cell count and soft agar assay was performed to determine the growth and malignant transformation potential of arsenic and estrogen. The expression of genes that regulate DNA methylation and histone modifications was measured by quantitative real time PCR and was further confirmed at protein level by Western blot analysis. The result of this study revealed that exposure to arsenic causes increased growth and malignant transformation of RWPE-1 cells. Interestingly, co-exposure to arsenic and estrogen lead to a more dramatic and synergistic effects on alteration of gene expression than either of these two chemicals alone. The qRT-PCR data revealed that co-exposure causes a moderate to high decrease in expression of histone modifying genes HDAC1, 2, 3, and 7 as well as HAT1 and HMT1. The genes DNMT1, MBD1, and MeCP2 all showed slight downregulation, but MBD4 showed a dramatic downregulation. Western blot analysis further confirmed the arsenic and estrogen-induced changes in some of these genes as well as the changes in the level of acetylated and methylated histones. The findings of this study suggest that chronic co-exposure to arsenic and estrogen may cause synergistic effects on epigenetic reprogramming and consequently on carcinogenesis in human prostate epithelial cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1997. doi:10.1158/1538-7445.AM2011-1997
Abstract 3926: Chronic inflammatory levels of nitric oxide/reactive nitrogen species downregulate BRCA1 protein expression
Authors: Yakovlev Vasily A. 
Published: August 2014

Abstract
The link between inflammation and cancer was proposed more than 150 years ago when Virchow suggested that malignancies tend to arise at sites of chronic inflammation. Recent studies have established that elevated levels of nitric oxide/reactive nitrogen species (NO/RNS) generated in the inflammatory microenvironment are associated with several conditions critical for initiation and promotion of cancer.
The BRCA1 protein contributes to cell viability in multiple ways, including DNA repair, cell cycle checkpoint control, transcription, and regulation of chromosome segregation. Hundreds of mutations in the BRCA1 gene have been identified and associated with an increased risk of cancer. Sporadic breast carcinomas, on the other hand, rarely show mutations of this gene. Instead, BRCA1 protein expression is frequently reduced in sporadic cases. As sporadic tumors account for &gt;90% of the breast cancer, considerable research is directed towards the identification of mechanisms that down-regulate the function of the wild type BRCA1 and lead to genetic instability.
BRCA1 expression is negatively regulated at the transcriptional level by the repressive complex of retinoblastoma-like protein 2 (RBL2) and E2F4. Formation of the repression RBL2/E2F4 complex can be accelerated by, for example, RBL2 dephosphorylation. Recently, protein phosphatase 2A (PP2A), an enzyme responsible for RBL2 dephosphorylation, was shown to be nitrated and activated by NO/RNS (Ohama T., et al., JBC 285, 8711-18, 2010). In the present investigation I demonstrate that inflammatory levels of NO/RNS induce substantial dephosphorylation of RBL2. Normal human mammary epithelial cells (MCF-10A) were incubated with 0.1 mM of the NO-donor SNAP for 6 h. This concentration of NO-donor mimics the intracellular level of NO/RNS during chronic inflammation, hypoxia, and does not induce significant DNA damage and maintains the ATM/ATR-dependent pathways intact. After 6 h incubation with SNAP, significant decrease in total amount of BRCA1 protein was observed with no apparent changes in the levels of E2F1, E2F4, and the catalytic subunit of PP2A, all involved in the regulation of BRCA1. RBL2 dephosphorylation promotes a repressive RBL2/E2F4 complex formation, which inhibits expression of BRCA1. I hypothesize that NO/RNS generated by chronic inflammatory conditions posttranslationally modify proteins involved in the regulation of BRCA1 expression and downregulate BRCA1 expression, thereby constituting a critical role in genetic instability and ultimately carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3926. doi:10.1158/1538-7445.AM2011-3926
Abstract 3928: Different characteristic features of mitochondrial microsatellite instability in keratoacanthomas and squamous cell carcinomas
Authors: Lee Jae-Ho , Kim Dae-Kwang , Kang Ju-Hwan 
Published: August 2014

Abstract
Keratoacanthoma (KA) as a common cutaneous neoplasm often resembles typical squamous cell carcinoma (SCC) clinically and historically. Several studies have attempted to find alternative methods to distinguish between KA and SCC, however, these did not appear to play a significant role in these tumors. To contribute to a better understanding of these tumors, we studied mitochondrial microsatellite instability (mtMSI) in KA and SCC. DNA was isolated from paired normal and tumoral tissues in 42 patients with KA and 43 patients with SCC. MtMSI was analyzed by using eight microsatellite markers. MtMSI was found in 8 (19%) of 42 KA patients and 7 (16.3%) of 43 SCC patients, respectively. MtMSI has been observed in different location depending on tumors. In KA patients, mtMSI has been detected mostly in the (CA)n of the D-loop region (7/42, 16.7%), in contrast, all of SCC patient had mtMSI in the (C)n of the D-loop region (7/43, 16.3%). Similar frequency of mtMSI was found in KA and SCC, however, their different characteristics support the current concept that KA and SCC have different pathogenetic pathways for their developments.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3928. doi:10.1158/1538-7445.AM2011-3928
Abstract 3930: Integrative genomic analysis reveals SWI/SNF chromatin remodeling complex to be a TGFβ-mediating tumor suppressor pathway in pancreatic cancer
Authors: Shain Alan H. , Matsukuma Karen , Giacomini Craig , Karikari Collins A. , Hidalgo Manuel , Maitra Anirban , Pollack Jonathan R. 
Published: August 2014

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer deaths in the developed world. A more complete characterization of molecular alterations may suggest new avenues for targeted therapy. Here we report the high-resolution genomic and transcriptional profiling of seventy PDAC early-passage tumor xenografts and cell lines – the largest PDAC dataset currently available of this sample size and resolution. Notable among novel loci, genomic deletion/mutation frequently targeted components of the SWI/SNF chromatin remodeling complex, including ARID1A, ARID1B, PBRM1, SMARCA2 and SMARCA4. Overall, focal deletion/mutation of a SWI/SNF component occurred in at least one-third of all PDAC specimens. In cell culture, RNAi-mediated knockdown of SWI/SNF subunits enhanced cell growth, growth-factor independence, and resistance to TGFβ growth-inhibition. Previously, SWI/SNF was reported to mediate TGFβ signaling. Remarkably, we found that five of the top ten SWI/SNF-mediated TGFβ-downregulated genes were focally amplified (MYC, BIRC3, PARD6B, KLF5, and CEBPD), while two of the top ten upregulated genes were focally deleted (PPAP2B, TNC), implying that its role in TGFβ growth-inhibitory signaling drives SWI/SNF loss in PDAC. In summary, we report the SWI/SNF chromatin remodeling complex, likely through mediating TGFβ signaling, to be a major tumour suppressor pathway in PDAC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3930. doi:10.1158/1538-7445.AM2011-3930
Abstract 3931: Whole genome and whole exome sequencing of head and neck cancer
Authors: Stransky Nicolas , Egloff Ann Marie , Tward Aaron , Auclair Daniel , Cibulskis Kristian , Lawrence Michael , Sivachenko Andrey , Berger Michael , Seethala Raja , Sougnez Carrie , Cortes Maria , Winckler Wendy , Gabriel Stacey , Getz Gad , Golub Todd , Grandis Jennifer , Garraway Levi 
Published: August 2014

Abstract
Head and neck cancer is responsible for an enormous cancer burden worldwide, with an estimated 500,000 new cases per year. However, knowledge of the spectrum of genetic alterations that drive this malignancy remains incomplete. Previous studies of this disease have identified recurrent somatic mutations in a few specific genes, but few systematic genome-scale studies have been performed. Accordingly, we have undertaken a pilot study of complete genome/exome characterization in this malignancy.
We obtained genomic DNA from 40 head and neck tumors together with matched normal DNA from whole blood. To date, we have obtained whole exome sequencing of 28 tumor/normal pairs and whole genome sequencing of two tumor/normal pairs. The average base mutation rate is 3.1 × 10-6 (range = 2.9 × 10-7 to 8.8 × 10-6), consistent with rates observed in lung cancer and other tobacco-related malignancies. We also identified 24 high-confidence somatic rearrangements in one sample and 120 in the other sample (including 7 and 44 inter-chromosomal rearrangements, respectively).
In addition to frequent mutations of TP53 (53%), HRAS, PIK3CA, and PTEN, we also observed other recurrently mutated genes that implicate several oncogenic pathways. Furthermore, layering of somatic mutation data onto known pathway information strengthens the evidence for several oncogenic processes not previously implicated in head and neck cancer. Altogether, these data should enhance our understanding of the mechanisms that drive head and neck carcinogenesis and progression and may also illuminate new therapeutic opportunities.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3931. doi:10.1158/1538-7445.AM2011-3931
Abstract 3934: Identification of novel cancer DNA sequence variants in human sarcomas
Authors: Abaan Ogan D. , Francis Princy , Pineda Marbin , Walker Robert , Bilke Sven , Davis Sean R. , Meltzer Paul S. 
Published: August 2014

Abstract
Understanding of the genetic basis of cancer initiation and progression is a fundamental goal of cancer research. Identification of cancer variants is of profound importance for both understanding disease mechanism and for developing novel therapies. Soft-tissue sarcomas are multiple uncommon histotypes with features of diverse connective tissue lineages. Although some of their underlying genetic changes have been elucidated, for example in those types which contain etiologic chromosome translocations, in general, the genetics of these tumors is incompletely described. Adult soft tissue sarcomas often exhibit highly complex genomic rearrangements. To search for novel variants in these tumors, we utilized a custom “targeted-resequencing” approach to sequence coding exons from over 1300 known cancer-related genes and candidate gene families in 65 soft-tissue sarcoma patient samples covering several subtypes and their matching normal tissues where available. We used the previously published method of “In-solution capture” to enrich for regions of interest and sequenced both the normals and the tumors using the Illumina GAII platform. The variant calls reveal the distribution of mutations affecting the exons of the targeted regions across histotypes, and reveal the role of critical functional pathways in sarcoma genesis. Preliminary data suggest that TP53 single nucleotide variants are mostly confined to one histotype. This work is an important step in cataloging novel cancer mutations in these cancers, with potential implications for understanding their biology and the development of new therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3934. doi:10.1158/1538-7445.AM2011-3934
Abstract 3935: International Cancer Genome Consortium (ICGC)
Authors: Hudson Thomas J. , Jennings Jennifer L. 
Published: August 2014

Abstract
The International Cancer Genome Consortium (ICGC) is coordinating an extensive research effort to obtain a comprehensive description of genomic, transcriptomic and epigenomic changes in the major forms of cancer. This information will lead to better ways of diagnosing, treating and preventing cancer. The announcement of the ICGC Goals, Structure, Policies and Guidelines to the international scientific community in 2008 enabled funding agencies and research groups to plan their participation within the ICGC. Over 200 authors engaged in ICGC projects published a Nature paper in April 2010. The paper outlines the ethical framework, study design, use of common standards of data collection and analysis and describes how the projects will proceed. As of November 2010, the ICGC has received commitments from funding organizations in Asia, Australia, Europe and North America for the projects listed in the table (below). Over time, additional nations and organizations are anticipated to join the ICGC.

Each Cancer Genome Project is expected to involve specimens from approximately 500 patients. Over the next ten years, the ICGC expects to produce comprehensive catalogues of the full range of genetic mutations involved in 50 types of cancer, with key factors being the ability to detect all mutated cancer genes, data at the level of individual DNA bases, application of common standards for pathology and technology and comparison data from matched, non-tumour tissue.
The ICGC's informed consent and ethical oversight policies state that cancer patients enrolled in an ICGC-related study should be informed that their participation is voluntary, that their clinical care will not be affected by their participation and that data obtained from analyses using their samples will be made available to the international research community.
The genomic analyses of tumors conducted by ICGC members in the U.K. (breast, lung and skin cancer), Japan (liver cancer), and Australia and Canada (pancreatic cancer) are now available on the ICGC website at www.icgc.org.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3935. doi:10.1158/1538-7445.AM2011-3935
Abstract 3941: Amplifications of drug target genes in gastric cancer: Potential clinical implications
Authors: Labots Mariette , Haan Josien C. , Buffart Tineke E. , van Grieken Nicole CT , Tijssen Marianne , Ylstra Bauke , Carvalho Beatriz , van de Velde Cornelis JH , Grabsch Heike I. , Verheul Henk MW , Fijneman Remond JA , Meijer Gerrit A. 
Published: August 2014

Abstract
Background: The treatment of advanced gastric cancer remains a challenge for the clinical oncologist. Once distant metastases are present, median survival is around one year with the most active chemotherapeutic regimen. Besides the recent approval of trastuzumab in combination with chemotherapy, thus far no other molecular targeted agents have been approved for the treatment of this disease. There is an urgent need to improve selection of effective treatment for individual patients. A potentially promising approach for selecting active antitumor agents in individual patients could be the evaluation of tumor DNA for amplifications of genes coding for drug targets.
Material and Methods: 183 primary gastric adenocarcinomas were analyzed by genome wide array Comparative Genomic Hybridization (arrayCGH) using microarrays consisting of 5000 BAC clones. High level amplifications were defined as a minimum of 2 consecutive clones showing a log2 tumor to normal ratio of &gt; 1. Amplification frequencies for each BAC clone were calculated among the 183 tumors, and genes located within the amplicons were identified by using the RefSeq genes in the UCSC genome browser, version hg16/NCBI34. Drug target genes were selected with Ingenuity Pathway Analysis (IPA) and the Pharmacogenomics Knowledge Base (PharmGKB). Genes amplified in at least 4 patients (2%) were classified according to the mechanism of action of the drug interacting with this specific gene.
Results: In 183 gastric cancers a mean number of 2.0 amplifications per tumor (range 0-21) was found. 167 genes out of more than 6000 at these loci were annotated as drug target genes by IPA, with 30 genes having an amplification frequency of at least 4 (2%). Most frequently amplified regions were located on chromosome 6, 8, 11, 16, 17 and 20. Genes for molecular targeting agents included VEGFA (6.5%), ERBB2 (6%), HSP90AB1 (5.5%) and EGFR (3.8%). Interestingly, also genes for non-anticancer agents, including HRH3 (10.4 %) and RARA (4.9%), and potential therapeutic targets such as TNFRSF4B (7.1%) were found. Conclusion: ArrayCGH analysis of a large series of gastric tumors revealed many non-randomly amplified gene loci, including substrates for targeted agents with potential antitumor activity in advanced gastric cancer. Moreover, targets of agents without established anticancer activity were identified as well. Our results provide a molecular rationale for the investigation of new treatment strategies in advanced gastric cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3941. doi:10.1158/1538-7445.AM2011-3941