bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 767: RalGTPase regulation of p53 and its contribution to malignant transformation.
Authors: Tecleab Awet , Zhang Xiaolei , Sebti Said M. 
Published: August 2014

Abstract
The regulation of the tumor suppressor p53 by Ral GTPases and its contribution to malignant transformation are not known. Here we demonstrate that the expression of K-Ras, Ral A and Ral B, but not Akt1/2 and c-Raf, is required for maintaining low levels of p53 in human cancer cells that harbor mutant K-Ras and wild type p53. Depletion of Ral A and Ral B increases p53 protein levels by increasing its stability and this results in p53-dependent up regulation of p21waf and mdm2. Furthermore, depletion of Ral A and / or Ral B leads to a p53-dependent decrease in the proportion of cells in the S-phase of the cell cycle, inhibition of anchorage-independent growth and suppression of invasion. Thus, expression of Ral proteins is critical to maintaining low levels of p53, and this appears to be critical to the ability of Ral GTPase to induce malignant transformation.
Citation Format: Awet Tecleab, Xiaolei Zhang, Said M. Sebti. RalGTPase regulation of p53 and its contribution to malignant transformation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 767. doi:10.1158/1538-7445.AM2013-767
Abstract 774: RECK silencing enhances hyperplastic phenotypes in epithelial cells through c-Myc and HIF-2α.
Authors: Lee You Mie , Lee Keun Byeol , Lee Sun Hee , Phuong Nguyen Minh 
Published: August 2014

Abstract
Downregulation of the tumor suppressor, RECK is induced by hypoxia (Lee et al., 2010). However, the role of RECK silencing in tumorigenic hyperplastic phenotype is largely unknown. Exposure of various normal epithelial cells to hypoxia resulted in significantly increased cell proliferation. Hypoxia increased diploid S phase cells, cell cycle kinase proteins such as cyclin D1 and c-Myc involved in G1/S transition. Hypoxia promoted phosphorylation of Rb protein (p-pRb), but decreased p21cip1, p27kip1 and p16ink4A. The knockdown of RECK by small interfering (si) RNA (RECKsi) promoted cell proliferation under normoxic conditions. Furthermore, siRECK produced the same expression patterns of cell cycle kinase proteins, c-Myc, and p-pRb observed under hypoxic conditions. MMP-2, MMP-9, and MT1-MMP were activated by hypoxia, and an MMP inhibitor significantly suppressed hypoxia-induced proliferation. In addition, the siRECK-transfected cells formed larger and more numerous colonies than the control cells in vitro tumorigenic assays. Nude mice injected with stably shRECK-transfected cells developed larger tumors more rapidly than those injected with control shRNA-transfected cells. Expression of HIF-2α as well as NFκB and STAT1 was significantly increased both under hypoxic conditions and in RECK-knockdown cells. Knockdown of HIF-2α diminished hypoxia-induced proliferation of epithelial cells. Taken together, these results suggest that hypoxia-induced RECK silencing increases epithelial transformation and tumorigenicity via HIF-2α activation, in which increased metalloproteinase activity may play a role. In conclusion, the suppression of RECK may be a crucial event for achieving a hyperplastic characteristics to favor early tumorigenesis by hypoxic stress.
Citation Format: You Mie Lee, Keun Byeol Lee, Sun Hee Lee, Nguyen Minh Phuong. RECK silencing enhances hyperplastic phenotypes in epithelial cells through c-Myc and HIF-2α. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 774. doi:10.1158/1538-7445.AM2013-774
Abstract 776: Functional analysis of BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) in melanoma.
Authors: Kumar Raj , Njauw Ching-Ni , Ji Zhenyu , Miao Benchun , Taylor Michael , Rajadurai Anpuchchelvi , Udayakumar Durga , Tsao Hensin 
Published: August 2014

Abstract
In the US alone, 44,250 men and 32,000 women are expected to be diagnosed with melanoma in 2012. Metastatic melanoma is the leading cause of skin cancer-related deaths worldwide. In the metastatic cutaneous melanoma (CM), anti-BRAF and anti-MEK agents have recently been shown to attenuate progression of the disease, though durable responses are still rare (NEJM articles). For metastatic ocular melanoma (OM), there is currently no established treatment strategy. Thus, one major unmet need in the field is the identification of novel “driver” physiologies which underpin the progression of disease and which can be leveraged for therapeutic gain. One new component in the ubiquitination pathway that has been recently implicated in the biology of both CM and OM is BRCA1 associated protein-1 (BAP1). Preliminary data from our laboratory showed that germline inactivating mutations of BAP1 predispose individuals to both CM and metastatic OM along with other neoplasms. In this study we examined the effects of BAP1 knockdown and overexpression on melanoma cell lines and primary melanocytes. BAP1 gene is mutated in melanoma and reported to be tumor suppressor, however suppression of BAP1 led to paradoxical growth inhibition, suggesting that the effects of BAP1 may be context dependent. Currently we are performing global gene expression and allele specific functional studies in an effort to identify novel substrates and other pathways impacted by BAP1. These findings may provide mechanistic insight into the role of BAP1 in melanoma pathogenesis.
Citation Format: Raj Kumar, Ching-Ni Njauw, Zhenyu Ji, Benchun Miao, Michael Taylor, Anpuchchelvi Rajadurai, Durga Udayakumar, Hensin Tsao. Functional analysis of BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 776. doi:10.1158/1538-7445.AM2013-776
Abstract 779: ARF activation is responsible for the tumor-suppressing function of p53 in basal cell carcinomas (BCCs) in Ptch1+/- mice.
Authors: Wang Grace Y. , Wood Carla , Wang Joy , Wang Lynn , Libove Eileen , Epstein Ervin 
Published: August 2014

Abstract
Basal cell carcinomas (BCCs) are the most common cancer among people of European ancestry. Aberrant activation of hedgehog (HH) signaling plays a pivotal role in BCC carcinogenesis. Besides mutations in genes encoding HH pathway components, mutations in the p53 gene frequently are found in human BCCs. Consistently, our previous studies have found that the loss of p53 can dramatically accelerate BCC formation in ionizing radiation (IR)-treated Ptch1+/- mice. It remains elusive how p53 is activated in BCC development. DNA damage response (DDR) and oncogenic induced stress (OIS) are two essentially independent pathways leading to p53 activation although limited evidence suggests crosstalk between these pathways. In response to OIS, ARF is activated and leads to p53 activation, functioning as a tumor suppressor, in many cancers. However, the loss of ARF, unlike loss of p53, failed to affect the development of medulloblastoma in Ptch1+/- mice (Wetmore C., et al, 2001). In the present study, we investigated whether ARF affects BCC development in the same mice.
To address this, we bred ARFGFP/GFP mice, in which ARF function is disabled and GFP is expressed under the control of the endogenous ARF promoter, with our Ptch1+/- mice to generate Ptch1+/- ARFGFP/GFP (designated as ARF mice) for comparison with Ptch1+/- K14CreER2 p53fl/fl (PF) mice. Following our standard protocol of tamoxifen injection at age 7.5 weeks to delete p53 specifically in K14-expressing keratinocytes (for PF mice) and treating both ARF and PF mice with ionizing radiation at age 8 weeks, we compared BCC development between the above 2 lines.
We find that at age 5 months, ARF mice formed numbers of microscopic BCCs comparable to those in PF mice though the latter exhibited greater mouse-to-mouse variation. More importantly, both mouse lines developed initial visible BCCs at age 5 to 7 months, which is dramatically earlier than the age 9 to 18 months for the Ptch1+/- mice (ARF+/+ and p53+/+). In addition, ARFGFP/GFP mice responded to IR-induced DNA damage in a pattern essentially similar to ARF+/+ mice, indicating an intact DDR pathway as reported in the literature.
In conclusion, our data demonstrate that ARF is involved in BCC carcinogenesis as a tumor suppressor, probably playing the major, perhaps the exclusive, role in activating p53 in this process.
Citation Format: Grace Y. Wang, Carla Wood, Joy Wang, Lynn Wang, Eileen Libove, Ervin Epstein. ARF activation is responsible for the tumor-suppressing function of p53 in basal cell carcinomas (BCCs) in Ptch1+/- mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 779. doi:10.1158/1538-7445.AM2013-779
Abstract 783: Mutational status of the p53 tumor suppressor gene is associated with expression of GSTP1 allelic variants in human GBM..
Authors: Antoun Gamil R. , Ali-Osman Francis 
Published: August 2014

Abstract
The tumor suppressor and transcription factor, p53, regulates the transcription of a large number of genes that control key cellular functional, such as, cell cycle arrest, DNA repair, senescence and apoptosis, and its mutational inactivation of p53 has been implicated in tumor development and progression. Mutation in p53 is a common genetic abnormality in GBM and other cancers and several studies have associated wild type p53 with high tumor drug resistance. Our laboratory previously reported that the polymorphic human GSTP1 gene is a transcriptional target of and is activated by p53 via a canonical p53 binding motif located in intron 4 of the GSTP1 gene. The ability of the p53 wild type to transcriptionally activate the GSTP1 gene, thus, defines a novel mechanism of protecting the genome and enhancement tumor drug resistance. The ability of the different GSTP1 alleles to protect against the toxicity of anticancer agents plays an important factor in this GSTP1-mediated tumor drug resistance. In a previous study, we showed that p53 mutations in GBM spanned the entire p53 gene, with the majority of the mutations in the DNA binding domain and that GSTP1 expression correlated, in most cases with wild type p53. In the present study, we examined the relationship between p53-dependent GSTP1 gene activation genetic polymorphism and expression in human GBM. We sequenced the p53 gene in 52 primary human GBMs, genotyped these tumors for their GSTP1 allelic status and determined the expression of the GSTP1 gene transcripts by quantitative PCR. The results showed the GSTP1*A allele to most highly (40%) expressed in the tumors and of these 27% harbored wild-type p53. In contrast, GSTP1*C allele was not only the least prevalent allele but also had the least association with wild-type p53. GSTP1*B, as well as, heterozygous GSTP1 alleles were intermediate in their association with p53 mutational status of the tumors. The level of expression of the individual genes also correlated with the presence of wild-type p53 in inversely with mutant p53. These results demonstrate a significant impact of p53 mutational status, not only in mediating the level of GSTP1 gene expression but also that it is related to the specific allelic form of GSTP1 that is expressed. This suggest that p53 mutational status and both GSTP1 expression and allele polymorphism may interact together to mediate glioma drug resistance.
Citation Format: Gamil R. Antoun, Francis Ali-Osman. Mutational status of the p53 tumor suppressor gene is associated with expression of GSTP1 allelic variants in human GBM. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 783. doi:10.1158/1538-7445.AM2013-783
Abstract 786: Genomic and functional characterization identify different manifestations of p53 pathway in 17p13 deletion cases of multiple myeloma.
Authors: Teoh Phaik Ju , Yan Junli , Chng Wee Joo 
Published: August 2014

Abstract
Multiple myeloma (MM) is an incurable hematologic malignancy. p53, being one of the most commonly mutated tumor suppressor gene in human cancer, is found to be wild type (WT) in almost 90% of MM. Nevertheless, the frequency of p53 abnormalities is more prevalent in the advanced stage of MM, suggesting its crucial role in the disease progression. Of paramount importance, hemizygous deletion of 17p13 (17p13(del)), which harbours the TP53 gene, has been identified in more than 30% of MM patients and is significantly associated with poor prognosis. To date, there is no conclusive evidence that p53 is the critical gene. Essentially, the integrity of p53 pathway in 17p13(del) cases remains obscure. This study utilized three human myeloma cell lines (HMCL) which harbour 17p13(del) encompassing TP53, as study models. Concurrently, HMCLs with various different p53 status (WT, mutation and null) were recruited as reference model. We have identified a spectrum of unique protein expression profile amongst cells with different p53 status upon induction of the pathway. Genotoxic and non-genotoxic stress confer an intact p53 pathway in WT/WT p53 cells; whereas, p53 mutant cells and p53 null cells demonstrated a defective p53 activity, indicating that functional p53 is exclusively required in triggering the downstream response. Using the WT/WT and the mutant/null profile as reference, the three 17p13(del) cell lines exhibited distinctive phenotypes. XG6, which have basal p53 expression half of that of the WT/WT cell line, displayed a partially compromised p53 pathway. Differentially, KMS18, which has a very low level of basal p53, and JJN3 which has a complete absence of basal p53, displayed a virtual abrogation of p53 response, as evidenced by defective transcriptional activities of p53 as well as resistance to growth arrest and apoptosis. Physiological investigations revealed that the remaining single copy of p53 was likely to be negatively regulated by MDM2 overexpression and epigenetic factors. In conclusion, this study has identified different behaviors in the p53 pathway in 17p13(del) cases. p53 appears to possess haploinssufficiency properties whereby hemizygous p53 loss is sufficient to render a partially defective p53 response. p53 basal level was shown to be the critical determinant of the integrity of the pathway. This has significant clinical implications as this finding can be manipulated to identify patients with different outcome and treatment response.
Citation Format: Phaik Ju Teoh, Junli Yan, Wee Joo Chng. Genomic and functional characterization identify different manifestations of p53 pathway in 17p13 deletion cases of multiple myeloma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 786. doi:10.1158/1538-7445.AM2013-786
Abstract 803: Genomic sequencing of meningiomas reveals oncogenic SMO and AKT1 mutations.
Authors: Brastianos Priscilla , Horowitz Peleg M. , Santagata Sandro , Jones Robert T. , McKenna Aaron , Getz Gad , Ligon Keith , Van Hummelen Paul , Ducar Matt , Raza Alina , Sunkavalli Ashwini , MacConaill Laura , Stemmer-Rachamimov Anat , Louis David N. , Hahn William C. , Dunn Ian , Beroukhim Rameen 
Published: August 2014

Abstract
Meningiomas are the most common primary brain tumor in the US. While many Grade I meningiomas are cured by surgery, 20% recur and are minimally responsive to systemic therapy. Meningiomas of higher grades are particularly challenging to treat and are associated with a poor prognosis. Though the tumor suppressor gene NF2 has been linked to meningiomagenesis, the spectrum of genetic changes in meningiomas remains poorly understood, particularly in the large subset of tumors without NF2 alterations. We performed whole-exome or whole-genome sequencing on 17 meningiomas and focused sequencing using a 645 gene-set on an additional 48 tumors. The majority of meningiomas exhibited simple genomes, with fewer copy-number alterations, mutations, and rearrangements compared to other adult tumors. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors. A subset of NF2-wildtype meningiomas harbored recurrent oncogenic mutations in AKT1 and the Hedgehog pathway regulator SMO. Tumors with these mutations varied histologically from their NF2-mutated counterparts, and exhibited immunohistochemical evidence of pathway activation. These results begin to define the spectrum of genetic alterations in meningiomas. Our findings of known driver oncogenic mutations including AKT1 and SMO have immediate therapeutic potential.
Citation Format: Priscilla Brastianos, Peleg M. Horowitz, Sandro Santagata, Robert T. Jones, Aaron McKenna, Gad Getz, Keith Ligon, Paul Van Hummelen, Matt Ducar, Alina Raza, Ashwini Sunkavalli, Laura MacConaill, Anat Stemmer-Rachamimov, David N. Louis, William C. Hahn, Ian Dunn, Rameen Beroukhim. Genomic sequencing of meningiomas reveals oncogenic SMO and AKT1 mutations. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 803. doi:10.1158/1538-7445.AM2013-803
Abstract 817: Genomic evolution landscape of patient tumor derived xenograft of gastric cancer.
Authors: Yu Kun , Wong Swee Seong , Ting Jason C. , Doman Thompson N. , Yue Yong , aggarwal Amit , Donoho Gregory P. , Krumbach Rebekka , Feibig Heiner H. , kong Seong-Ho , Kim Woo-ho , Yang Han-kwang , Reinhard Christoph 
Published: August 2014

Abstract
Patient-derived xenograft (PDX) models have emerged as key model systems to understand the efficacy of anti-cancer agents. PDX systems have demonstrated superiority over cell lines with regards to higher histological resemblance to primary tumor, presence of stroma and also in mimicking response to therapeutic agents. However, the genomic evolution landscape of model establishment is not a well studied topic. In order to do that, we systematically collected materials from the first three passages of xenografts derived from eight gastric cancer patients from Seoul National University, Korea from 2008-2011. We subsequently generated comprehensive genomic profiles of the first three passages, parent primary tumor, and matched normal tissues for the eight patients. The genomic profiling data included whole-exome sequencing data (Agilent exome capture, paired-end sequencing on Illumina HiSeq 2000), mRNA expression (Affymetrix U133 Plus2.0), copy number data (Affymetrix SNP6), miRNA expression (Agilent miRNA array v16.0) and DNA methylation data (Illumina HumanMethylation27). The analysis is focused on two types of events: a) Cancer-related genomic changes derived from normal vs. tumor comparison, and their subsequent assessment in early passages; b) Passage-specific genomic changes derived from tumor vs. passages comparison. A further refinement of passage-specific genomic changes is done to differentiate ‘true’ passage-specific events from the ones that appear due to the difference in tumor purity that is lower in primary tumor due to the normal contamination. Overall, we describe the genomic landscape of evolution along xenograft establishment in gastric cancer and provide a comprehensive picture of genetic and genomic similarities (and differences) of xenografts to the primary tumor. This analysis will help us to better interpret the in vivo results emanating from experiments using xenografts and to translate the findings appropriately to the clinic.
Citation Format: Kun Yu, Swee Seong Wong, Jason C. Ting, Thompson N. Doman, Yong Yue, Amit aggarwal, Gregory P. Donoho, Rebekka Krumbach, Heiner H. Feibig, Seong-Ho kong, Woo-ho Kim, Han-kwang Yang, Christoph Reinhard. Genomic evolution landscape of patient tumor derived xenograft of gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 817. doi:10.1158/1538-7445.AM2013-817
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 819: Targeted sequencing to detect somatic mutations, translocations and copy-number variation in human tumors simultaneously.
Authors: Van Hummelen Paul , Ducar Matthew , Jones Robert T. , Raza Alina , Sunkavalli Ashwini , Hanna Megan , Mills Adri , Adusumilli Ravali , Kumar Prateek , Schubert Laura , Breneiser Marc , Cooley Anna C. , Garcia Elizabeth , Scholl Lynette M. , Lindeman Neal I. , Wagle Nikhil , Garraway Levi , Cibulskis Kristian , Carter Scott L. , Lawrence Michael , Getz Gad , Meyerson Matthew L. , Hahn William C. , MacConaill Laura E. 
Published: August 2014

Abstract
The ability to harness the power of next generation sequencing for characterizing the cancer genome would be extremely valuable to the cancer research community and ultimately improve diagnosis and individualized therapy.
We present a targeted approach using massively parallel sequencing to simultaneously detect mutations, translocations and copy-number variations in archived clinical tumor specimen.
Targeted sequencing was achieved by designing RNA baits to capture the exons of 504 genes with relevance to cancer. The bait set was augmented with specific intronic sequences to detect translocations often involved in cancer. The overall performance of the hybrid capture was improved by optimizing the tiling strategy of the baits. These improvements significantly shifted fragments with low or no-coverage closer to the overall mean, resulting in a more uniform coverage distribution.
To validate the targeted gene panel we sequenced tumor samples harboring mutations, translocations and copy-number alterations that were previously identified by clinically approved assays. All the known alterations were confirmed with additional potentially actionable mutations.
The ultimate goal of the targeted panel is to screen cancer patients quickly and economically allowing simultaneous detection of all common genomic alterations in the cancer genome.
Citation Format: Paul Van Hummelen, Matthew Ducar, Robert T. Jones, Alina Raza, Ashwini Sunkavalli, Megan Hanna, Adri Mills, Ravali Adusumilli, Prateek Kumar, Laura Schubert, Marc Breneiser, Anna C. Cooley, Elizabeth Garcia, Lynette M. Scholl, Neal I. Lindeman, Nikhil Wagle, Levi Garraway, Kristian Cibulskis, Scott L. Carter, Michael Lawrence, Gad Getz, Matthew L. Meyerson, William C. Hahn, Laura E. MacConaill. Targeted sequencing to detect somatic mutations, translocations and copy-number variation in human tumors simultaneously. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 819. doi:10.1158/1538-7445.AM2013-819