bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5056: A glimpse into the somatic mutation landscape of melanoma through exome sequencing of 121 tumor-normal pairs
Authors: Hodis Eran , Watson Ian , Theurillat Jean-Philippe , Zou Lihua , Place Chelsea , Nickerson Elizabeth , Auclair Daniel , Cibulskis Kristian , Sivachenko Andrey , Kryukov Gregory , Stransky Nicolas , Ramos Alex H. , Voet Douglas , Lawrence Michael S. , Stojanov Petar , Saksena Gordon , McKenna Aaron , Carter Scott L. , Pugh Trevor , Noble Michael , Lin Pei , Lichtenstein Lee , Zupko Robert , Sougnez Carrie , Guiducci Candace , Onofrio Robert C. , Ambrogio Lauren , Fennell Timothy , Chong Kelly , Winckler Wendy , Ardlie Kristin , Lander Eric S. , Golub Todd , Meyerson Matthew , Gabriel Stacey B. , Getz Gad , Wagner Stefan , Schadendorf Dirk , Hoon Dave S. B. , Chin Lynda , Garraway Levi A. 
Published: August 2012

Abstract
Melanoma is an aggressive skin cancer of melanocytic origin characterized by high metastatic potential and mutation rate. Affording a survey of the wide breadth of genomic lesions found in melanoma, we present here an analysis of the somatic mutations discovered in the sequenced exomes of 121 melanoma tumor-normal pairs. We identify frequent genomic alterations both in genes previously implicated in melanoma (BRAF, NRAS, TP53, CDKN2A, PTEN) as well as in several genes whose role in melanoma tumorigenesis has not yet been established and thus are of particular interest. To do so we implement a novel method to increase the identification of genes that are significantly recurrently mutated in melanoma in the setting of its exceptionally high mutation rate. A preponderance of C&gt;T transitions (∼85%) in the observed mutational profile reflects a history of DNA damage due to UV radiation, though the majority of somatic mutations in known melanoma genes are not C&gt;T events. Our study broadens understanding of the genomic lesions involved in melanoma tumorigenesis, and we expect our analysis approach to inform future genomic studies of cancer lineages with similarly high mutation rates.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5056. doi:1538-7445.AM2012-5056
Abstract 5084: Functional genomic classification of breast cancer using pooled lentivirus shRNA screens
Authors: Marcotte Richard , Brown Kevin , Sayad Azin , Haider Maliha , Ketela Troy , Moffat Jason , Neel Benjamin G. 
Published: August 2012

Abstract
Targeted therapies for most breast cancers are lacking because our knowledge of essential genes driving tumor proliferation is still primitive for each subtype. Although ongoing intensive efforts to genetically characterize large numbers of breast tumors are providing a plethora of new data on genomic abnormalities (e.g., amplifications, deletions, somatic mutations), it can be difficult to access which of these actively drive pathogenesis. Even if an oncogene or tumor suppressor is identified, these often are not amenable to targeted therapy (eg. KRAS, c-MYC, p53, etc). However, unanticipated gene/pathway dependencies can arise as a consequence of these genetic abnormalities in cancer cells (“synthetic lethality”). The recent development of lentiviral-based shRNA libraries enables genome-wide screening of cultured cancer cells in a pooled format, facilitating the identification of genes necessary for cancer cell proliferation and survival in cell culture as well as potential synthetic lethal interactions. The overall objective of this project was to identify subtype-specific targets for human breast cancer using a genome-wide shRNA screen, as well as to compare “functional genomic” and genomic classification schemes. We screened a panel of 53 breast cancer lines using an 80,000 lentiviral shRNA library targeting 16,000 genes in a pooled format. We identified several classes of gene “dropouts,” including general essential genes, which are required for survival or growth in more than 70% of all cell lines, irrespective of subtype. Most of these were enriched in housekeeping functions, although several genes involved in cellular signal transduction also were identified, including mTORC1, RAPTOR, TGFBR2, DDR1 and DDR2. In addition, we observed several “subtype-specific” genes, whose essentiality is restricted to a defined subtype. Furthermore, unsupervised and supervised clustering of our functional screening results identified potential “drivers” unique to each subtype. These include amplified/overexpressed genes such as ERBB2, ERBB3, FOXA1, SPDEF, TFAP2C, and CCDN1 known to be specific to the luminal and HER2 subtypes, respectively. Finally, integration of gene expression, copy number variation, and functional screening results identified potential synthetic lethal interactions with common genetic changes. Our study represents an extensive functional genetic survey of three major breast cancer subtypes, reveals complexities between genomic and functional genomic results, and uncovers several unexpected gene dependencies and potential novel therapeutic target for each subtype.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5084. doi:1538-7445.AM2012-5084
Abstract 5089: Evaluation of BMP4 and BMP7 induced gene expression changes in breast cancer cells reveals time-dependent transcription patterns and a common synexpression group of genes
Authors: Rodriguez-Martinez Alejandra , Alarmo Emma-Leena , Saarinen Lilli , Ketolainen Johanna , Nousiainen Kari , Hautaniemi Sampsa , Kallioniemi Anne H. 
Published: August 2012

Abstract
Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta superfamily of growth factors. They are well-known for their key roles in the regulation of various developmental processes and bone formation, but in recent years, evidence has also accumulated of their crucial contribution in tumor biology. In particular, BMP4 and BMP7 have been implicated in breast cancer pathogenesis. However, little is known about BMP target genes in the context of tumor cells. Here, we used whole-genome microarrays to explore the effects of BMP4 and BMP7 treatment on global gene expression levels in seven breast cancer cell lines during a 6-point time series. Several complementary methods, including hierarchical clustering of differentially expressed genes, gene ontology enrichment analyses and model based clustering of temporal data, were used for data analysis. Both BMP ligands had a strong influence on gene expression levels, although the response to BMP4 treatment was more pronounced as compared to BMP7. As might have been expected, the cellular functions most strongly affected by the stimulation of BMP signaling were regulation of transcription and development. The observed transcriptional response, as well as its functional outcome, followed a temporal sequence, where the regulation of gene expression and signal transduction was followed by changes in transcripts involved in metabolism and cell proliferation. Hierarchical clustering analysis revealed distinct differences in the response of individual cell lines to BMPs, but also underlined a common synexpression group of genes for both ligands. Remarkably, the majority of the genes within these synexpression groups were shared by the two ligands, and thus these genes are likely to represent the core molecular responses common to BMP4 and BMP7 signaling pathways. Taken together, our data demonstrate that BMP signaling has a substantial effect on gene transcription in breast cancer cells and that the cellular functions affected follow a logical temporal pattern. Our results also reveal components of the cellular transcriptional response that are common to BMP4 and BMP7. Finally, our study provides a list of putative novel BMP target genes relevant in breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5089. doi:1538-7445.AM2012-5089
Abstract 5105: Genetic alterations of the metastatic lesions in ovarian carcinoma
Authors: Malek Joel , Mery Eliane , George Binu , Martinez Alejandra , Thiery Jean-Paul , Huang Ruby , Querleu Denis , Rafii Arash 
Published: August 2012

Abstract
Background: Ovarian cancer is the most deadly gynecological cancer. The high rate of mortality is due to the large tumor burden with extensive metastatic lesion of the abdominal cavity. There are few studies on genetic alterations and their consequences in peritoneal metastatic tumors when compared to their matched ovarian primary tumors. Our hypothesis is that differences between the metastatic and primary lesions might be the cause of residual disease and, most importantly may have a role in post-chemotherapeutic recurrences. Methods: We conducted integrated genomics analysis on matched primary and metastatic tumors from 9 patients. In the papers presented here we analyze genome-wide Copy Number Variations (CNVs) using SNP Arrays targeting peritoneal metastasis differences, Gene expression differences using Microarrays also targeting peritoneal metastasis differences, and for some patients, Single Nucleotide Polymorphisms (SNPs) in genes through Exome sequencing. Results: Here we show that CNVs vary significantly between primary and metastatic tumors and include genes that have been considered potential chemotherapeutic targets based on primary tumor only data. Gene expression differences, while minor, showed highly statistically significant enrichment of genes in ovarian cancer critical pathways. In agreement with findings in other cancers, exome sequencing data revealed very few SNP differences of which most metastasis enriched SNPs were present at very low levels in the primary tumor. The results presented here should allow better design of therapies to target residual ovarian cancer disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5105. doi:1538-7445.AM2012-5105
Abstract 5142: Up-regulation of glutamine synthetase attenuates the oncogenicity of wnt/β-catenin signaling in hepatocellular carcinoma
Authors: Sohn Bo Hwa , Kim Sang-Bae , Park Yun-Yong , Park In Young , Jeong Mi-Ra , Lee Ju-Seog 
Published: August 2012

Abstract
Wnt/β-catenin signaling has been known to be involved in many cellular processes including cell proliferation, migration, and survival. Aberrant activation of Wnt/β-catenin signaling has been widely reported in many cancers and associated with poor outcome after treatments. However, activation of Wnt/β-catenin signaling in hepatocellular carcinoma (HCC) has been known to be significantly associated with favorable outcome. In this study, we identified 82 genes as a β-catenin signature by analyzing expression data from tumor tissues of patients with HCC and liver tissues from active β-catenin mutant transgenic mice. HCC patients with the β-catenin signature have significantly better prognosis in both overall survival and recurrence-free survival than those without the signature. Further analysis of β-catenin signature revealed over-expression of glutamine synthetase (GS), liver-specific β-catenin target gene, and shift of glutamine metabolism. Cell growth rate were highly dependent on GS expression levels. Cell proliferation rate was increased by GS knockdown using shRNAs but decreased by GS overexpression in HCC cell lines. Intracellular glutamate concentrations were severely decreased by GS overexpression. GS overexpression in HCC cells also led to decrease intracellular α-ketoglutarate levels impeding TCA cycle, and intracellular glutathione levels accumulating high reactive oxygen species (ROS). In conclusion, we found GS up-regulation in HCC cells inhibited cell growth by glutamate depletion and thereby lower anaplerotic metabolic activity and higher ROS levels. Our results present molecular mechanisms for the favorable outcome in HCC patients with CTNNB1 mutations and importance of glutamine metabolism in cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5142. doi:1538-7445.AM2012-5142
Abstract 5147: Glutamine addiction: Recognizing and harnessing the pathometabolic potential of Ras-mediated macropinocytosis
Authors: Commisso Cosimo , Soydaner-Azeloglu Rengin G. , Bar-Sagi Dafna 
Published: August 2012

Abstract
Oncogenic mutations in Ras-encoding genes are found in approximately 30% of all human tumors and are most prevalent in carcinomas of the pancreas, colon, lung and bladder. Oncogenic forms of Ras are trapped in a constitutively active state and, as a consequence, promote the persistent stimulation of effector pathways that control cell growth, survival and proliferation. A prominent phenotypic feature associated with oncogenic Ras expression is the stimulation of macropinocytosis, an endocytic process that mediates the uptake of extracellular fluid via large, heterogeneous vesicles known as macropinosomes. While in amoeboid organisms this process has been linked to nutrient internalization, the functional significance of oncogenic Ras-mediated macropinocytosis is unknown. We have found that cancer cells harboring oncogenic Ras utilize macropinocytosis to internalize extracellular albumin, a major constituent of extracellular fluids and a potentially rich source of amino acids. Furthermore, we have established that tumor cells harboring oncogenic Ras mutations display robust macropinocytosis in vivo. Utilizing cell biological approaches and amino acid quantification, we determined that extracellular albumin that is internalized via oncogenic Ras-stimulated macropinosomes is targeted for degradation leading to the intracellular production of albumin-derived amino acids. Cancer cells display a heightened dependence on glutamine due to their need to sustain rapid proliferation, bioenergetics and macromolecular biosynthesis. We have observed that in cells expressing oncogenic Ras, the adverse effects of glutamine deprivation on cell growth can be rescued by macropinocytosis-mediated uptake of extracellular albumin. Moreover, the capacity of macropinocytic inhibition to diminish this growth advantage is dependent on both glutamine and glutamine-derived metabolites. These results indicate that macropinocytosis may serve as a glutamine supply mechanism that is particularly critical under conditions where free glutamine is limiting. Together, these data implicate oncogenic Ras-mediated macropinocytosis in the regulation of cancer cell metabolism and point to the possibility of exploiting this process in the design of anti-cancer therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5147. doi:1538-7445.AM2012-5147
Abstract 5149: CYLD downregulation induces aerobic glycolysis via mTOR pathway in human oral squamous cell carcinoma cells
Authors: Nakamura Takuya , Shinriki Satoru , Hayashi Mitsuhiro , Yamamoto Yutaka , Ibusuki Mutsuko , Sueyoshi Takanao , Ota Tomoko , Shinohara Masanori , Ando Yukio 
Published: August 2012

Abstract
The hypermetabolic nature of cancer cells and their increased reliance on “aerobic glycolysis,” as originally described by Otto Warburg et al, are considered metabolic hallmarks of cancer cells including oral squamous cell carcinoma (OSCC) cells. However, its precise mechanisms remain unknown. Cylindromatosis (CYLD) is recognized as a tumor suppressor gene whereas little is available about its impact on cancer progression. Our unpublished data showed that lower CYLD expression was associated with poor prognosis in OSCC patients. The objective of our study was to address specific contributions of CYLD to the signature metabolic features of cancer cells, including the so-called “Warburg effect”. We investigated effects of CYLD knockdown by siRNA on aerobic glycolysis in human OSCC cell lines. As the result of CYLD knockdown, both glucose consumption and lactate production significantly increased in several OSCC cell lines with increased expression of LDHA which is known to be important for glycolysis. Consistently, culture medium became more acidic after CYLD knockdown compared with the control. Repression of CYLD expression induced Akt phosphorylation. Importantly, the increase in aerobic glycolysis induced by CYLD repression was completely blocked by an mTOR inhibitor, rapamycin as well as a PIK inhibitor, LY294002. Our study indicats that dysfunction of CYLD contributs to the Warburg effect through Akt-mTOR pathway in OSCC. Further investigation on the advantage of such increased glycolysis and the change in metabolome profiling may lead to development of effective therapeutic strategies for OSCC and other malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5149. doi:1538-7445.AM2012-5149
Abstract 516: Obinutuzumab (GA101): A novel type II glycoengineered CD20 antibody exhibits enhanced cell death against Rituximab-resistant and -sensitive cell lines in B-cell non-Hodgkin lymphoma
Authors: Tiwari Aradhana Awasthi , Ayello Janet , ven Carmella Van de , Cairo Mitchell S. 
Published: August 2012

Abstract
Background: Rituximab (RTX), an antibody targeting the B-cell antigen CD20, in combination with chemotherapy, is safe, well tolerated and associated with &gt; 90% EFS in children with advanced mature B-Cell NHL (Cairo M.S. et al, ASCO 2010). However, RTX resistance has evolved as one of the limiting factors of such therapy and the exact cause of this resistance is not well understood. C-terminal deletion mutations of CD20 may be one possible reason such resistance or for relapse (Mishima Y. et al, Blood Cancer Journal 2011). Obinutuzumab (GA101), a novel type II glycoengineered CD20 antibody of the IgG1 isotype, demonstrates superior cell death induction and its glyco-engineered Fc region has shown to cause significant enhanced ADCC (Mössner et al, Blood 2010; Niederfellner G. et al, Blood 2011). The objective of this study was to evaluate the efficacy of GA101 as compared to RTX against RTX resistant cell lines (Raji-2R and Raji-4RH, generously supplied by M. Barth, MD, Roswell Park Cancer Center, Buffalo, NY) in-vitro. Methods: We evaluated the efficacy of GA101 against Raji (Burkitt Lymphoma), a RTX sensitive cell line (RSCL) and RTX resistant cell lines (RRCL), Raji-2R and Raji-4R (Barth M. et al, ASH 2010). All cell lines were cultured in RPMI with 10% FBS and incubated with dose escalation of GA101 (1-100 µg/ml) for 24 hrs. Cell death was evaluated by staining with AnnexinV/7AAD using a standard kit (BD Biosciences) and flow-cytometry. B-Cell Leukemia-Lymphoma (BLL) U-698-M cells (CD20+) (DSMZ, Germany) were used as the positive control; whereas, Loucy cells (CD20−) (T-ALL) (ATCC, Manhass, VA) were used as the negative control. Results: At 100 µg/ml of GA101 when incubated for 24 hrs, Raji and U-698-M demonstrated 26.5±0.42% and 32.4±1.9% cell death, respectively. Cell death of the RRCL, Raji-2R and Raji-4RH, was 16.3±3.4% and 17.5±0.07% respectively, at 100 µg/ml of GA101 at 24 hrs. Significant cell death was demonstrated with RSCL as compared to the RRCL, Raji vs Raji-2R (p&lt;0.05) and Raji vs Raji-4RH (p&lt;0.01). There was no significant change in cell death with any concentration of GA101 with the Loucy cell line. Conclusion: Based on these findings, GA101 is a promising novel CD20 antibody for the treatment of RTX resistant B-Cell Lymphomas and related B-Cell malignancies. Further studies are aimed to identify novel candidates that may increase the efficacy of GA101 against RTX resistant cell lines in-vitro and in-vivo. One such approach is to combine GA101 with activated NK cells or a chemotherapeutic agent.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 516. doi:1538-7445.AM2012-516
Abstract 5162: COX-2 downregulation protects SUM-149 cells following targeting of choline phospholipid metabolism
Authors: Mori Noriko , Stasinopoulos Ioannis , Wildes Flonne , Bhujwalla Zaver M. 
Published: August 2012

Abstract
Enzymes in the choline phospholipid metabolism pathway such as choline kinase (Chk) and phopholipase D1 (PLD1) are being evaluated as novel targets in cancer therapy since these enzymes are overexpressed in aggressive cancers including breast cancer. We have previously shown that single and double downregulation of Chk and PLD1 significantly reduced cell proliferation in breast cancer cells. We also observed a close association between Chk and cyclooxygenase 2 (COX-2), an inducible enzyme that mediates the inflammatory response and plays a role in cancer invasion, angiogenesis and metastasis. COX-2 inhibition is also being considered as a strategy for cancer prevention or treatment. Here we investigated the effect of the COX-2 downregulation combined with PLD1 and Chk downregulation using siRNA, on cell proliferation to achieve improved control and minimize compensatory responses that allow the cell to survive or adapt. The triple negative inflammatory breast cancer cell line, SUM149, was used in this study. Cells were transfected with 25 nM siRNA against COX-2 (siRNA-cox2), PLD1 (siRNA-pld1) or Chk (siRNA-chk) either singly or combined for 48 h. Untreated cells and the transfection reagent (DharmaFECT) treatment were used as negative controls. Immunoblot analysis was done after 48 h transfection using antibodies specific to COX-2, PLD1, Chk-α, and GAPDH (as a loading control). Proliferation/viability of cells was determined using the CCK-8 assay (cell counting kit-8, Dojindo) at day 2 and day 5 after transfection. After 48 h transfection with siRNA-pld1 or siRNA-chk, PLD1 or Chk-α protein were downregulated significantly and COX-2 protein was upregulated. When we combined downregulation of Chk or PLD1 with COX-2 dowregulation, we established significantly lower COX-2 protein levels compared to single knockdown of Chk and PLD1. COX-2 downregulation alone did not significantly reduce proliferation. Downregulation of PLD1 or Chk, however, significantly reduced proliferation compared to untreated cells (PLD1: –75%, Chk: –68%). When we combined COX-2 downregulation with PLD1 or Chk downregulation, cell survival was significantly higher than with just PLD1 or Chk alone (PLD1: –46%. Chk: –28%). These results suggest that COX-2 downregulation rescues cells following downregulation of PLD1 or Chk in SUM149 cells, identifying a different facet of COX-2 in the choline phospholipid pathway. This work supported by R01 CA82337
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5162. doi:1538-7445.AM2012-5162