bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2235: High frequency of fusion transcripts involving TCF7L2 in colorectal cancer: Novel fusion partner and splice variants
Authors: Hoff Andreas M. , Nome Torfinn , Bakken Anne Cathrine , Rognum Torleiv O. , Nesbakken Arild , Skotheim Rolf I. 
Published: May 2015

Abstract
VTI1A-TCF7L2 was reported as a recurrent fusion gene in colorectal cancer (CRC), found to be expressed in three out of 97 primary cancers, and one cell line, NCI-H508, where a genomic deletion joins the two genes (Bass et al. Nature Genetics, 2011). To investigate this fusion further, we analyzed high-throughput DNA and RNA sequencing data from seven CRC cell lines in addition to publicly available data from the NCI-H508 cell line. From both genome and transcriptome data, the gene RP11-57H14.3 (ENSG00000225292) was identified as a novel fusion partner for TCF7L2 in the HCT 116 cell line. The originally reported fusion VTI1A-TCF7L2 was identified as expected from the analysis of NCI-H508 data. By triplicate nested RT-PCR, we tested both the novel fusion transcript and VTI1A-TCF7L2 for expression in a series of 106 CRC tissues, 21 colon cancer cell lines, 14 normal colonic mucosa, and 20 normal tissues from miscellaneous anatomical sites. Altogether, 42% and 45% of the CRC samples expressed VTI1A-TCF7L2 and TCF7L2-RP11-57H14.3 fusion transcripts, respectively. The two fusion transcripts were both seen in 29% of the normal colonic mucosa samples, and in 25% and 75% of the tested normal tissues from other organs. Seven different splice variants were detected for the VTI1A-TCF7L2 fusion, of which three are novel. Four different splice variants were detected for the TCF7L2-RP11-57H14.3 fusion.
In conclusion, we have identified novel variants of VTI1A-TCF7L2 fusion transcripts, including a novel fusion partner gene, RP11-57H14.3. We demonstrated detectable levels of TCF7L2 involving fusion transcripts in a large fraction of CRC samples, as well as in normal colonic mucosa and other normal tissue types, revealing that these fusions, at transcript level, are neither specific to cancer nor to the colon and rectum.
Citation Format: Andreas M. Hoff, Torfinn Nome, Anne Cathrine Bakken, Torleiv O. Rognum, Arild Nesbakken, Rolf I. Skotheim. High frequency of fusion transcripts involving TCF7L2 in colorectal cancer: Novel fusion partner and splice variants. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2235. doi:10.1158/1538-7445.AM2014-2235
Abstract 2237: Acquisition of biospecimens to support the Genotype-Tissue Expression (GTEx) project
Authors: Carithers Latarsha , Rao Abhi , Moore Helen 
Published: May 2015

Abstract
The Genotype-Tissue Expression (GTEx) project is an NIH Common Fund study that is aimed at understanding how genetic variation influences gene expression in normal tissues. Here we describe a biospecimen collection platform that was developed to address the logistical challenges of acquiring a large collection of high-quality tissues from rapid autopsy and organ donors for GTEx. This complex infrastructure is utilized to procure specimens under a rigorous quality management program and a stringent ethical, legal, and regulatory framework. Ultimately, data from the GTEx study will be used to evaluate gene regulatory mechanisms and their contribution to human disease development.
Citation Format: Latarsha Carithers, Abhi Rao, Helen Moore. Acquisition of biospecimens to support the Genotype-Tissue Expression (GTEx) project. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2237. doi:10.1158/1538-7445.AM2014-2237
Abstract 224: The role of Bmi-1 in benzyl isothiocyanate-mediated suppression of breast cancer stem cell self-renewal
Authors: Kim Su-Hyeong , Singh Shivendra V. 
Published: May 2015

Abstract
We have shown previously that benzyl isothiocyanate (BITC), a nontoxic small-molecule constituent of edible cruciferous vegetables (eg, garden cress) inhibits breast cancer stem cells (bCSC) in vitro and in vivo but the underlying mechanisms are not fully understood. Bmi-1 is a member of the polycomb group family of proteins that function in the epigenetic silencing of genes governing self-renewal, differentiation, and proliferation. The present study was undertaken to investigate the role of Bmi-1 in BITC-mediated inhibition of bCSC. BITC treatment downregulated protein level of Bmi-1 in cultured human breast cancer cells (MCF-7, SUM159 and MDA-MB-231), and in MDA-MB-231 xenografts in vivo. Ectopic expression of Bmi-1 alone was sufficient to drive stemness in MCF-7 cells. In addition, Bmi-1 overexpression in MCF-7 cells conferred marked protection against BITC-mediated inhibition of bCSC as evidenced by mammosphere frequency and aldehyde dehydrogenase 1 (ALDH1) activity. Consistent with these observations, silencing of Bmi-1 in SUM159 cells remarkably reduced the portion of bCSC. Apoptosis induced by BITC was also partially attenuated by overexpression of Bmi-1 in MCF-7 cells but its silencing had no effect on BITC-induced apoptosis in SUM159 cells. Previous studies have shown that miRNA128 inhibits cell proliferation and self-renewal by direct regulation of Bmi-1. BITC treatment modestly but statistically significantly increased the expression of miRNA128 in both MCF-7 and SUM159 cells. Inhibition of miRNA128 increased the mammosphere formation in MCF-7 and SUM159 cells and partially attenuated BITC-mediated inhibition of mammosphere formation. These observations led us to conclude that Bmi-1 is a novel target of BITC-mediated inhibition of bCSC. This study was supported by the grant RO1 CA129347 awarded by the National Cancer Institute.
Citation Format: Su-Hyeong Kim, Shivendra V. Singh. The role of Bmi-1 in benzyl isothiocyanate-mediated suppression of breast cancer stem cell self-renewal. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 224. doi:10.1158/1538-7445.AM2014-224
Abstract 2240: TERT promoter mutations are highly prevalent in bladder cancer and represent a potential new urinary biomarker
Authors: Hurst Carolyn D. , Platt Fiona M. , Knowles Margaret A. 
Published: May 2015

Abstract
Somatic mutation of the promoter region of the telomerase reverse transcriptase (TERT) gene was recently reported as a potential mechanism by which telomerase becomes activated in cancer cells. Here, we aimed to assess the frequency and spectrum of TERT promoter mutations in bladder cancer and detect mutations in voided urine. A SNaPshot assay designed to simultaneously interrogate two positions (-124bp and -146bp) previously reported as mutated in melanoma was used to screen 47 bladder cancer cell lines and 262 tumors. Forty cell lines and 201 tumors carried mutations at either -124bp or -146bp. Mutations at these positions were mutually exclusive. A germline mutation at -57bp (T&gt;G) was previously reported in a melanoma-prone family. A second SNaPshot assay was designed to interrogate position -57bp and we screened all samples that were wildtype at positions -124bp and -146bp. Mutations at -57bp were detected in two cell lines and eight tumors. Matched blood samples were available for six of the tumors and one cell line, and somatic mutation status was confirmed. Sanger sequencing of the TERT core promoter in samples that were wildtype at positions -57bp, -124bp and -146bp revealed a further nine somatic mutations. Four mutations at positions -45bp, -72/-77bp, -141bp, and -54bp were novel, and all but one (-54bp) created new binding sites for ETS/TCF transcription factors. Overall, TERT promoter mutations were detected in 89% of cell lines and 83% of tumors. There was no association of TERT promoter mutation status with stage (p=0.1089, chi-square test) or grade (p=0.2438, chi-square test). As mutations are highly frequent in both non-muscle-invasive and invasive bladder cancer, these represent potential biomarkers for urine-based disease monitoring. For sixty-four tumors used in this study, matched urine samples were also collected prior to surgery. Fifty-three of the tumors had mutations at -124bp or -146bp and using the -124bp/-146bp SNaPshot assay we were able to detect 51 of these in the corresponding urine samples including all mutations (n=23) in 29 patients with low-grade noninvasive tumors. The use of TERT promoter mutation analysis in combination with other DNA-based biomarkers could markedly improve the sensitivity for urine-based detection of recurrent disease.
Citation Format: Carolyn D. Hurst, Fiona M. Platt, Margaret A. Knowles. TERT promoter mutations are highly prevalent in bladder cancer and represent a potential new urinary biomarker. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2240. doi:10.1158/1538-7445.AM2014-2240
Abstract 2242: Comprehensive genome methylation and whole genome expression analysis in penile carcinoma: Uncovering new molecular markers
Authors: Kuasne Hellen , Colus Ilce Mara de Syllos , Hernandez-Vargas Hector , Busso-Lopes Ariane Fernanda , Barros-Filho Mateus C. , Marchi Fabio A. , Scapulatempo-Neto Christovan , Faria Eliney F. , Lopes Ademar , Guimaraes Gustavo C. , Herceg Zdenko , Rogatto Silvia R. 
Published: May 2015

Abstract
Background: Penile carcinoma (PeCa) is frequently associated with high morbidity rates. Unlikely of the vast majority of tumors, there is no molecular markers described that are able to assist in diagnosis and prognosis or with potential to be therapeutic targets in PeCa.
Patients and methods: DNA methylation status (244K Human DNA Methylation Microarray platform, Agilent Technologies) and large-scale expression analysis (4x44K Whole Human Genome Microarray, Agilent Technologies) were performed in 35 and 37 PeCa, respectively. Quantitative bisulfite pyrosequencing (qBP) and RT-qPCR were used to validate the findings in 93 samples. HPV status was assessed using the Linear Array HPV Genotyping kit (Roche Molecular Diagnostics, CA, USA).
Results: Methylome analysis revealed 171 hypermethylated and 449 hypomethylated CpGs sites and the transcriptome profiling showed 2986 down- and 2817 over-expressed genes. HPV positivity was found in 32.7% of the cases, mainly the HPV16. The integrative analysis in 32 PeCa revealed a panel of 96 genes with inverse correlation between methylation and gene expression levels. The CpG hypermetlylation and gene downexpression, was confirmed for TWIST1, RSOP2, SOX3, SOX17, CD133, OTX2, HOXA3 and MEIS. In addition, BIRC5, DNMT1 and DNMT3B presented low levels of methylation and overexpression. The comparison of the results with clinical findings revealed that LIN28A, NKX2.2, NKX2.3, LHX5, BDNF, FOXA1 and CDX2 were associated with poor prognosis features.
Conclusion: Putative prognostic markers were detected revealing that DNA methylation modulates the expression of several genes in PeCa. These data may prove instrumental for biomarker discovery in clinics and molecular epidemiology of PeCa.
Citation Format: Hellen Kuasne, Ilce Mara de Syllos Colus, Hector Hernandez-Vargas, Ariane Fernanda Busso-Lopes, Mateus C. Barros-Filho, Fabio A. Marchi, Christovan Scapulatempo-Neto, Eliney F. Faria, Ademar Lopes, Gustavo C. Guimaraes, Zdenko Herceg, Silvia R. Rogatto. Comprehensive genome methylation and whole genome expression analysis in penile carcinoma: Uncovering new molecular markers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2242. doi:10.1158/1538-7445.AM2014-2242
Abstract 2244A: Prion protein cross-talks with Notch1 to promote pancreatic ductal adenocarcinoma progression
Authors: Wang Yiwei , Huang Dan , Zhou Lan , Xin Wei 
Published: May 2015

Abstract
Human prion protein (PrP) is a glycosylphosphatidylino¬sitol (GPI)-anchored membrane protein and has been found to be up-regulated in some of the pancreatic ductal adenocarcinoma (PDAC). Current literature also suggests that over-expression of PrP induces inherent resistance to cancer therapeutics, while repression of PrP induces sensitization to cancer therapeutics. Our previous studies revealed the increased level of PrP expression associated with worse prognosis in PDAC patients. In PDACs, instead of forming normal GPI anchored protein, PrP exists as a pro-prion protein that binds Filamin A (FLNa) and exerts a cascade of activities subsequently augment the invasiveness of PDAC. In this study, we would like to investigate whether PrP also involves other signal transduction pathway in PDACs, especially Notch pathway.
Using immunoprecipitation and immunocytometry, we investigated the binding partners for PrP in several PDAC cell lines and found that PrP associates with Notch1 but not with Notch2 or Notch3 in cytoplasm and cell membrane. The association of PrP and Notch1 was further validated by confocal microscopy. Silencing PrP by siRNA not only decreased PrP expression, but also decreased Notch1 in the cytoplasm and the nuclear localized cleaved Notch1. Knocking down PrP in PDAC cells with high levels of PrP led to decreased cell proliferation and tumor invasion and increased apoptosis. PDAC cells showed Increased tumor necrosis after inhibition of PrP in xenografts, which accompanied by down-regulation of intracellular domain of Notch1 (Notch1NTM). In comparison, over-expression of PrP in PDAC cells with lower levels of PrP increased Notch1NTM expression, cell proliferation, tumor invasion, and xenograft tumor growth which could be blocked by the gamma secretase inhibitor. These findings suggest that PrP cross talking Notch1 in PDAC cells regulates pancreatic cancer cell survival and invasion. Elucidating the mechanisms for PrP mediated Notch activation in PDAC will further our long-term goal of understanding the role of oncogenic PrP in conferring pancreatic cancer aggressiveness, and potentially will lead to novel therapeutic options for treatment of pancreatic cancer.
Citation Format: Yiwei Wang, Dan Huang, Lan Zhou, Wei Xin. Prion protein cross-talks with Notch1 to promote pancreatic ductal adenocarcinoma progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2244A. doi:10.1158/1538-7445.AM2014-2244A
Abstract 2245: Mechanism of replicative senescence induced by SNF5 loss
Authors: Wei Darmood , Chung HoYoon , Simpson Dennis A. , Kaufmann William K. , Weissman Bernard E. 
Published: May 2015

Abstract
Cellular senescence was initially described as the phenomenon by which normal diploid cells cease to divide after reaching the Hayflick limit. However, with the identification of replicative senescence, other inducers of this process have appeared in the literature including oncogene induced senescence (OIS). Of interest, different oncogenes can initiate OIS through alternative pathways e.g. HRAS (G12V) and BRAF (V600E) that effect senescence through p16 dependent and p16 independent pathways, respectively. Alternatively, loss of tumor suppressor gene function can also induce senescence. In malignant rhabdoid tumors (MRTs), SNF5 behaves as a tumor suppressor and its re-expression in MRT cell lines results in growth arrest via the RB pathway. Paradoxically, when we knocked out SNF5 in normal human fibroblasts (NHF-1), we also observed senescence. We therefore hypothesize that perturbation of the SWI/SNF complex (e.g. knocking down SNF5) results in cellular senescence in most normal tissues. This suggests an epigenetic mechanism of senescence occurring through a p16 independent pathway, as previous publications have demonstrated a critical role for SNF5 in p16 expression. Additionally, in BRAF induced senescence, changes in levels of CD44, phospho-MEK1/2, and p16 are observed. However, we do not find these changes during SNF5 loss. Our findings suggest a relationship between SWI/SNF's chromatin remodeling activity and the regulation of cellular senescence. Importantly, our studies will identify the key signaling pathways that allow MRTs to escape cellular senescence after SNF5 loss. These results will further elucidate the role of SNF5 loss in MRT development and provide new targets for clinical intervention.
Acknowledgement:
We thank the members of the Weissman lab for their help, advice, and support and R01CA91048 (B.E.W.) , T32ES007126 (D.W.), UNC Dissertation Completion Fellowship (D.W.) for financial support.
Citation Format: Darmood Wei, HoYoon Chung, Dennis A. Simpson, William K. Kaufmann, Bernard E. Weissman. Mechanism of replicative senescence induced by SNF5 loss. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2245. doi:10.1158/1538-7445.AM2014-2245
Abstract 2246: Senescence as a result of impaired ribosome biogenesis
Authors: Lessard Frédéric , Bourdeau Véronique , Deschênes-Simard Xavier , Igelmann Sebastian , Montero Marinieve , Ferbeyre Gerardo 
Published: May 2015

Abstract
Senescence is a stable arrest of cell proliferation in which the cells remain viable and metabolically active but display a constitutive activation of the DNA damage response and of the tumor suppressors p53 and RB. The senescent phenotype can be induced by multiple stresses including short telomeres and oncogenes. We have shown that senescence, involves the ERK-dependent degradation of selective proteins involved in cell cycle progression and tumorigenesis. We call this process senescence associated protein degradation (SAPD) and it involves many nucleolar proteins that play a role in ribosome biogenesis. Using tritium pulse labelling we found a strong decrease of rRNA synthesis in senescent cells indicating that the degradation of nucleolar proteins is functionally relevant. Because we know how exactly the human 47S precursor rRNA is processed, it was possible to design primers on both sides of some processing sites and study their maturation by QPCR. In this way we showed defects in the processing of rRNA in senescent cells. Knocking down some of the nucleolar proteins degraded in senescence was sufficient to trigger the process indicating that a decrease in ribosome biogenesis is causal to cellular senescence. Mechanistically, the degradation of nucleolar proteins during senescence involves the ubiquitin-proteasome system suggesting that E3 ligases link the oncogenic stress that trigger senescence to nucleolar proteins degradation. We will discuss ongoing efforts to identify these enzymes.
Citation Format: Frédéric Lessard, Véronique Bourdeau, Xavier Deschênes-Simard, Sebastian Igelmann, Marinieve Montero, Gerardo Ferbeyre. Senescence as a result of impaired ribosome biogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2246. doi:10.1158/1538-7445.AM2014-2246
Abstract 2247: Histone H3 cleavage via Cathepsin L drives a cellular senescence program
Authors: Duarte Luis F. , Young Andrew R. , Wu Hsan-Au , Panda Taniya , Wang Zichen , Maia Alexandre G. , Hasson Dan , Kapoor Avnish , Narita Masashi , Bernstein Emily 
Published: May 2015

Abstract
Oncogene-induced senescence (OIS) is characterized by irreversible loss of proliferative capacity. It has been proposed that OIS functions as a tumor suppressor mechanism, and several studies have demonstrated induction of senescence markers in pre-malignant lesions. In addition to profound morphological changes, significant alterations in chromatin structure occur during senescence including formation of senescence-associated heterochromatin foci (SAHF). We have used well-characterized senescence models in human primary lung fibroblasts and melanocytes to study how chromatin alterations contribute to the senescence phenotype. We discovered that the N'-terminal tail of histone H3 is proteolytically cleaved by the lysosomal protease Cathepsin L1 (CTSL1). We show that CTSL1 is induced during senescence both at the mRNA and protein levels, and that it is present in the chromatin fraction of senescent cells. Chemical and shRNA-mediated inhibition of CTSL1 activity effectively block H3 tail cleavage and leads to a SAHF formation defect. We identified two distinct cleaved forms of H3 in senescent cells, which are associated with chromatin and incorporated into nucleosomes. Using antibodies directed against specific post-translational modifications (PTMs) of the histone H3 tail, we have mapped the approximate locations of the cleavage sites. Furthermore, overexpression of flag-tagged cleaved versions of H3, but not the full-length histone, trigger robust senescence in IMR90 cells accompanied by a modest induction of SAHFs. Interestingly, we also detect cleaved H3 in chromatin extracted from benign nevi tissue samples, providing evidence of H3 tail cleavage in senescence models in vivo. Collectively, our results suggest that H3 tail cleavage may contribute significantly to the senescence phenotype, potentially through transcriptional regulation of key senescence target genes. This area of investigation is currently ongoing.
Citation Format: Luis F. Duarte, Andrew R. Young, Hsan-Au Wu, Taniya Panda, Zichen Wang, Alexandre G. Maia, Dan Hasson, Avnish Kapoor, Masashi Narita, Emily Bernstein. Histone H3 cleavage via Cathepsin L drives a cellular senescence program. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2247. doi:10.1158/1538-7445.AM2014-2247