bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-85: Damage-inducible intragenic demethylation activates transcription of an alternative intronic promoter in TP53-wildtype but not mutant human cells and tumors
Authors: Blackburn James , Ng Robert , Roden Daniel , Wu Jianmin , Epstein Richard J. 
Published: May 2015

Abstract
Unlike the well-known effects of promoter methylation, the functional significance of altered intragenic (gene body) CpG methylation remains unclear, particularly in genes such as the TP53 tumor suppressor which lack a 5′ CpG island. Here we show that CpG-specific demethylation of TP53 exon 5 in normal human and mouse cells is inducible by X-irradiation; this is accompanied by co-expression of a 5′-truncated TP53 isoform, raising the possibility that demethylation permits transcription from the known alternative promoter (P2) in intron 4. Consistent with this, in vivo expression of fully pre-methylated TP53 exonic constructs is associated with reduced basal and damage-inducible expression of both full-length and truncated TP53. In contrast, virally TP53-reconstituted Caco-2 and PC-3 human cancer cell lines respond to damage by upregulating expression of full-length TP53 and reducing expression of the truncated RNA isoform; CDKN1A expression varies directly with P2 isoform expression but inversely with the P1 transcript in these cells, suggesting that the isoform mediates downstream transactivation. 450K methylation analysis of adjacent normal and TP53-mutated human pancreatic cancer tissues suggests a mutation-specific decrease of intragenic TP53 methylation in intron 1 near P1 (p &lt; 0.02 ) and a reciprocal increase in intron 4 near P2 (p &lt; 0.01). Archival TP53 database analysis indicates that CpG-specific mutation frequency in human tumors is inversely associated with damage-inducible demethylation at the same sites in vitro (Spearman coefficient -7.1 ), consistent with methylation-dependent downregulation of transcription-coupled repair. We conclude that intragenic alterations of TP53 methylation are both physiologically inducible and functional, and hypothesise that tumor progression is drivable by either (i) intragenic hypermethylation affecting P1 as a field defect in TP53-wt tumor or adjacent normal tissues, or (ii) damage-inducible repression of P2 isoform expression associated with defective intron 4 demethylation, together with overexpression of full-length p53, in TP53-mutant tumors and cells.
Citation Format: James Blackburn, Robert Ng, Daniel Roden, Jianmin Wu, Richard J. Epstein. Damage-inducible intragenic demethylation activates transcription of an alternative intronic promoter in TP53-wildtype but not mutant human cells and tumors. [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 LB-85. doi:10.1158/1538-7445.AM2014-LB-85
Abstract PL04-02: The breast epithelial hierarchy and its implications for tumor heterogeneity
Authors: Visvader Jane E. , Rios Anne , Fu Naiyang , Nolan Emma , Lindeman Geoffrey 
Published: May 2015

Abstract
Breast cancer is a highly heterogeneous disease at both the molecular and pathological levels. To understand this heterogeneity and ‘cells of origin’ of breast cancer, it is important to dissect the normal mammary epithelial hierarchy. Discrete populations of mouse and human mammary epithelial cells can be isolated on the basis of cell surface marker expression. To date, subpopulations that are highly enriched for mammary stem (MaSC), luminal progenitor and mature luminal cells have been identified. Notably, these are functionally analogous across human and mouse and share highly conserved transcriptomes.
Lineage tracing is an important strategy for assessing the stem cell hierarchy as it allows stem and progenitor cell fate to be studied in situ in the context of development, tissue maintenance and disease. We have combined lineage tracing with a novel three-dimensional (3D) imaging strategy to explore the relative contributions of stem and progenitor cells to post-natal mammary gland development and tissue homeostasis. Cell lineage tracing studies also provide the current gold standard for identifying ‘cells of origin’ in cancer. Towards this end, we are utilizing newly generated transgenic strains harboring lineage-specific gene regulatory regions to direct the expression of specific mammary oncogenic lesions to discrete epithelial cell types. In terms of human breast cancer, the interrogation of molecular profiles has provided insight into potential ‘cells of origin’ in preneoplastic tissue for basal-like cancers arising in BRCA1 mutation carriers. Finally, the identification of deregulated genes/pathways in these crucial target cell populations may enable earlier detection of malignancies and lead to preventative therapies for individuals at high risk of developing breast cancer.
Citation Format: Jane E. Visvader, Anne Rios, Naiyang Fu, Emma Nolan, Geoffrey Lindeman. The breast epithelial hierarchy and its implications for tumor heterogeneity. [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 PL04-02. doi:10.1158/1538-7445.AM2014-PL04-02
Abstract SY12-04: Regulation of normal and cancer stem cell self renewal and senescence by USP16
Authors: Clarke Michael F. 
Published: May 2015

Abstract
Down syndrome (DS) is a complex clinical syndrome associated with multiple pathological conditions including deficits in motor skills and learning. DS has also been associated with early onset and higher incidence of aging-related phenomena such as Alzheimer's disease. Recently, it has been proposed that the aging process is correlated with an impaired or exhausted ability of stem cells to self-renew. we show that in Ts65Dn mice, trisomic for 132 genes homologous to HSA21, triplication of Usp16 reduces self-renewal of hematopoietic stem cells and expansion of mammary epithelial cells, neural progenitors, and fibroblasts. Moreover, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. Usp16 can remove ubiquitin from H2AK119, a critical mark for the maintenance of multiple somatic tissues. Downregulation of Usp16, either by mutation of a single normal USP16 allele or by shRNAs, largely rescues all these defects. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and post-natal neural progenitors while downregulation of USP16 partially rescues the proliferation defects of DS fibroblasts. Taken together, these results suggest that USP16 plays an important role in antagonizing the self-renewal and/or senescence pathways in Down syndrome and could serve as an attractive target to ameliorate some of the associated pathologies. Down syndrome patients also have a decreased incidence of solid tumors including breast cancer. The potential role of USP16 in human breast cancer will be discussed.
Citation Format: Michael F. Clarke. Regulation of normal and cancer stem cell self renewal and senescence by USP16. [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 SY12-04. doi:10.1158/1538-7445.AM2014-SY12-04
Abstract SY20-04: Mechanisms of malignant progression
Authors: Weinberg Robert A. 
Published: May 2015

Abstract
Metastasis is responsible for ∼90% of cancer-associated mortality, but we still have an incomplete understanding of its underlying mechanisms. Thus, we don't understand why certain primary tumor cells have a predilection to disseminate while others do not; why disseminated cancer cells can thrive in certain distant tissues but not in others; what adaptations disseminated cancer cells originating in one type of primary tumor must undergo in order to thrive in the microenvironment of a distant and potentially inhospitable tissue; and why certain indolent disseminated micrometastatic deposits suddenly erupt after great delay, generating life-threatening disseminated metastatic diseases. These and related issues will be examined in this session.
Citation Format: Robert A. Weinberg. Mechanisms of malignant 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 SY20-04. doi:10.1158/1538-7445.AM2014-SY20-04
Abstract SY24-01: A SAGA of GCN5 and USP22 in stem cells and cancer
Authors: Dent Sharon Y. R. , Atanassov Boyko , Hirsch Calley , Koutelou Evangelia , Coban Zeynep , Lan Xian Jiang , Wang Li 
Published: May 2015

Abstract
Histone modifying enzymes are important creating and maintaining epigenetic programs that regulate cell identity and growth. Our lab uses genetic approaches to define the full spectrum of functions for these enzymes. For example, we have created a series of mutations in the mouse Gcn5 (KAT2A) gene in order to define the functions of this histone acetyltransferase (AT) in a mammalian system. Gcn5 is the catalytic subunit of the SAGA and ATAC complexes. Deletion of Gcn5 led to early embryonic death and to telomere dysfunction. We are now defining the role of Gcn5 and SAGA in maintenance of pluripotency in mouse ES cells and ES cell differentiation. Our data indicate that Gcn5 is an important cofactor for both Myc and E2F family transcription factors, predicting a role for Gcn5 not only in self renewal of ES cells but also in Myc-driven cancers. Our latest studies are defining the functions of the SAGA deubiquitinase module, and these are revealing new information about SAGA composition and function during mouse development and in human diseases.
Citation Format: Sharon Y. R. Dent, Boyko Atanassov, Calley Hirsch, Evangelia Koutelou, Zeynep Coban, Xian Jiang Lan, Li Wang. A SAGA of GCN5 and USP22 in stem cells and cancer. [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 SY24-01. doi:10.1158/1538-7445.AM2014-SY24-01
Abstract SY35-01: Unexpected results of prolonged EZH2 inhibition in an in vivo model for glioblastoma
Authors: Lohuizen Maarten van 
Published: May 2015

Abstract
Repressive Polycomb-group (Pc-G) protein complexes and the counteracting Trithorax-group (Trx-G) of nucleosome remodeling factors are involved in the dynamic maintenance of proper gene expression patterns during development, acting at the level of chromatin structure. As such, they are important controllers of cell fate and differentiation. When deregulated, these master switches of gene expression are strongly implicated in formation of a diverse set of cancers. Examples are the Pc-G gene Bmi1 and Ezh2 which are overexpressed in many cancers including glioblastoma. However, recently Ezh2 has also been found to be mutated/inactivated in other forms of cancer, suggesting a highly context-dependent role as either an oncogene or tumor suppressor. An outstanding question is how to identify among the many Pc-G bound genes the cancer-relevant ones. Hereto we have recently successfully combined stringent ChIP-seq with custom shRNAi library screening in in vivo models for glioblastoma. As Ezh2 is associated with poor prognosis and metastasis in many cancer settings there is an increasing interest for development of selective Ezh2 inhibitors as potential new ways for epigenetic cancer therapy. We have developed conditional shRNAi inhibition in mouse models for aggressive glioma to study the effects of Ezh2 inhibition on tumor initiation and maintenance. Whereas initial tumor regression upon Ezh2 inhibition was observed in vivo, prolonged Ezh2 inhibition caused unexpected profound changes in tumor plasticity, differentiation status with important consequences for tumor progression and treatment options, which will be discussed.
Selected references:
1. Sophia W.M. Bruggeman, Danielle Hulsman, Ellen Tanger, Tessa Buckle, Marleen Blom, John Zevenhoven, Olaf van Tellingen and Maarten van Lohuizen. Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 2007, 12, 328-341.
2. Gargiulo G, Cesaroni M, Serresi M, de Vries N, Hulsman D, Bruggeman SW, Lancini C, van Lohuizen M. In vivo RNAi screen for BMI1 targets identifies TGF-β/BMP-ER stress pathways as key regulators of neural- and malignant glioma-stem cell homeostasis. Cancer Cell. 2013 May 13;23(5):660-76
Citation Format: Maarten van Lohuizen. Unexpected results of prolonged EZH2 inhibition in an in vivo model for glioblastoma. [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 SY35-01. doi:10.1158/1538-7445.AM2014-SY35-01
Abstract SY35-03: Novel anti-tumor activity of targeted LSD1 inhibition
Authors: Kruger Ryan G. 
Published: May 2015

Abstract
Lysine specific demethylase 1 (LSD1) is a histone H3K4me1/2 demethylase found in various transcriptional co-repressor complexes. These complexes include Histone Deacetylases (HDAC1/2) and Co-Repressor for Element-1-Silencing Transcription factor (CoREST). LSD1 mediated H3K4 demethylation can result in a repressive chromatin environment that silences gene expression and has been shown to play a role in development. LSD1 can interact with pluripotency factors in human embryonic stem cells and is essential for decommissioning enhancers in stem cell differentiation. Beyond embryonic settings, LSD1 is also critical for hematopoietic differentiation. LSD1 dysregulation plays a key role in cancer and LSD1 is overexpressed in multiple tumor types, including acute myeloid leukemia (AML). Recent literature suggests inhibition of LSD1 reactivates the all-trans retinoic acid differentiation pathway in AML. Together, these observations suggest LSD1 is an important regulator of the epigenome that modulates gene expression through post-translational modification of histones and its presence in transcriptional complexes.
The current study describes the anti-tumor effects of a novel LSD1 inhibitor (GSK2879552). GSK2879552 is a potent, selective, mechanism-based irreversible inhibitor of LSD1 currently in clinical development. Screening of over 150 cancer cell lines revealed that while many tumor types appear resistant to LSD1 inhibition, specific tumor types were uniquely sensitive. For example, AML cells have a distinct requirement for LSD1, and LSD1 inhibition results in a prodifferentiation effect in this setting. Preclinical characterization of the anti-tumor activities of GSK2879552 both in vitro and in vivo in AML as well as the solid tumor setting will be discussed.
All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed.
Citation Format: Ryan G. Kruger. Novel anti-tumor activity of targeted LSD1 inhibition. [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 SY35-03. doi:10.1158/1538-7445.AM2014-SY35-03
Abstract 12: Germline BRCA mutations in an unselected cohort of patients with pancreatic adenocarcinoma
Authors: Holter Spring , Borgida Ayelet , Dodd Anna , Narod Steven , Akbari Mohammad , Moore Malcolm , Gallinger Steven 
Published: May 2015

Abstract
This is the first prospective study to determine the frequency of BRCA1 and BRCA2 germline mutations in an unselected series of patients with pancreatic adenocarcinoma.
Patients with histologically or clinically confirmed pancreatic adenocarcinoma were approached at a single cancer centre to enroll in the IRB-approved Ontario Pancreas Cancer Study. Patients provided informed consent and cancer family history data was obtained. Blood was collected and analyzed by Sanger sequencing and MLPA for germline variants in BRCA1 and BRCA2. All predicted deleterious germline variants were confirmed by a clinical laboratory on an independent blood sample.
Pathogenic germline mutations were identified in 12/234 (5%) of unselected incident pancreatic adenocarcinomas. BRCA1 mutations accounted for 1.2% (3/234) and BRCA2 accounted for 3.8% (9/234) cases. For the cohort, average age of pancreatic adenocarcinoma diagnosis was 65 years (27-91) and 46% were female. Previous primary cancer was reported in 24% of cases and 12% were of Ashkenazi Jewish descent. A family history of breast and/or ovarian cancer was reported in 25% of cases; however, of these with a family history, 1/3 did not meet NCCN guidelines to warrant germline BRCA analysis. Pancreatic cancer in another relative was reported in 12% of cases. A personal history of a previous primary cancer diagnosis and a family history of breast and/or ovarian cancer were significantly associated with germline BRCA mutations.
Previous studies of BRCA mutations in pancreatic adenocarcinoma have been limited to retrospective case series and incomplete germline analysis. Our study shows that germline BRCA mutations account for a significant proportion of pancreatic adenocarcinoma, regardless of family history of breast and ovarian cancer. Increased identification of patients with germline BRCA mutations and pancreatic adenocarcinoma may allow for tailored chemotherapy through the use of platinum agents or PARP inhibitors.
Citation Format: Spring Holter, Ayelet Borgida, Anna Dodd, Steven Narod, Mohammad Akbari, Malcolm Moore, Steven Gallinger. Germline BRCA mutations in an unselected cohort of patients with pancreatic adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 12. doi:10.1158/1538-7445.CANSUSC14-12
Abstract 18: Molecular characterization of Brazilian patients suspected for Lynch syndrome
Authors: Silva Felipe C. , Torrezan Giovana T. , Figueiredo Márcia CP , Ferreira Jose Roberto O. , Santos Érika M. , Nakagawa Wilson T. , Aguiar-Junior Samuel , Rossi Benedito M. , Ferreira Fabio O. , Carraro Dirce M. 
Published: May 2015

Abstract
Lynch syndrome (LS), former known as Hereditary Non Polyposis Colorectal cancer (HNPCC), accounts for 3-5% of all colorectal cancers (CRC) and is inherited in an autossomal dominant fashion. This syndrome is characterized by early CRC onset, high incidence of tumors in the ascending colon, excess of synchronous and metachronous tumors, and accelerated transition adenoma-carcinoma (2-3 years). Nowadays, LS is regarded of patients who carry deleterious germline mutations in one of the five Mismatch repair genes, such as MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), post-meiotic segregation increased 1 (PMS1) or post-meiotic segregation increased 2 (PMS2). In order to characterize Brazilian patients suspect for LS, we assessed the frequency of germline point mutations in MSH6, PMS1 and PMS2 in patients negative for point mutations in MLH1 and MSH2 by capillary sequencing. We also assessed chromosomal deletions in MLH1 and MSH2 and MSH6 generating a complete characterization of MMR genes. The analysis of the five MMR genes revealed 46 carriers of pathogenic mutations, including 25 in MSH2 (54%), 16 in MLH1 (35%), 4 in MSH6 (9%) and one in PMS2 (2%) gene In addition, from the 70 negative patients, we selected one mutation negative family that met the stringent Amsterdam criteria (AC) for whole exome sequencing using the SOLID platform. For this family, we selected 5 close blood relatives, including 3 affected and 2 unaffected individuals in order to facilitate the identification of new susceptibility genes with autosomal dominant pattern. The results revealed two candidate genes, c-KIT and WDR27 that segregated with the disease. Additional analysis are under evaluation.
Citation Format: Felipe C. Silva, Giovana T. Torrezan, Márcia CP Figueiredo, Jose Roberto O. Ferreira, Érika M. Santos, Wilson T. Nakagawa, Samuel Aguiar-Junior, Benedito M. Rossi, Fabio O. Ferreira, Dirce M. Carraro. Molecular characterization of Brazilian patients suspected for Lynch syndrome. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 18. doi:10.1158/1538-7445.CANSUSC14-18
Abstract 19: Novel HIF2A mutations disrupting oxygen sensing lead to a new syndrome of multiple paragangliomas and somatostatinomas associated with polycythemia
Authors: Yang Chunzhang , Pacak Karel , Zhuang Zhengping 
Published: May 2015

Abstract
Hypoxia inducible factors (HIFs) control the cellular response to hypoxia and when dysregulated, contribute to tumorigenesis. We identified novel somatic mutations in HIF2A in patients with multiple paragangliomas and somatostatinomas associated with polycythemia, representing a new syndrome found predominantly in female patients. Mutations in HIF2A resulted in an amino acid substitution in the evolutionarily conserved oxygen-dependent degradation (ODD) domain and were found to uniquely disrupt the HIF-2α hydroxylation site recognized by prolyl hydroxylase domain-2 containing protein (PHD2). Disruption of HIF-2α hydroxylation resulted in the stabilization of HIF-2α and increased expression of hypoxia-related genes, dysregulated hematopoiesis, and neuroendocrine tumor formation. These results show for the first time the role of HIF-2α somatic mutations in cancer pathogenesis.
Citation Format: Chunzhang Yang, Karel Pacak, Zhengping Zhuang. Novel HIF2A mutations disrupting oxygen sensing lead to a new syndrome of multiple paragangliomas and somatostatinomas associated with polycythemia. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 19. doi:10.1158/1538-7445.CANSUSC14-19