bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 491: Endoglin suppresses prostate cancer invasion through two distinct type II TGF-β receptors
Authors: Breen Michael J. , Moran Diarmuid M. , Bergan Raymond C.
Published: August 2012

Prostate cancer (PCa) is the most common cancer of American men and the second leading cause of cancer-related death. Death from PCa results from the development of metastatic disease, yet the processes underlying progression from localized to invasive and ultimately metastatic disease remain poorly understood. Our group has previously shown that endoglin, an auxiliary TGF-β superfamily receptor, is lost with PCa progression. Restoration of endoglin expression inhibits PCa cell migration, invasion, and metastasis in pre-clinical models. Endoglin-mediated suppression of PCa invasion (EMSI) is mediated through the type I TGF-β receptor ALK2 and the downstream effector Smad1. Given that TGF-β signaling minimally requires both a type I and a type II TGF-β receptor (RII), we sought to determine the RII(s) involved in EMSI. We now show that silencing of either the type IIA activin receptor (ActRII) or the type II bone morphogenic protein receptor (BMPRII) abrogates endoglin's invasion suppressive effects. Surprisingly, ActRII and BMPR2 have opposite effects on downstream Smad1 signaling: ActRII promotes basal and endoglin-mediated Smad1 transcriptional activity dependent on its kinase domain, while BMPR2 suppresses Smad1 transcriptional activity independent of its kinase domain but dependent on its cytoplasmic tail. Moreover, we show that engagement of distinct BMP-responsive R-Smads (i.e. Smad1, Smad5, & Smad8) does not account for differential signaling and confirm that Smad1 is the main mediator downstream of endoglin. We posit the existence of two parallel pathways that are required for EMSI: an ActRII / ALK2 / Smad1 pathway and a second, as-yet-uncharacterized pathway involving BMPR2.

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 491. doi:1538-7445.AM2012-491
Abstract 4919: Pathway profiling of head and neck cancer cell lines
Authors: Zuo Zhixiang , Braegelmann Johannes , Keck Michaela , Shen Wanda , Dinali Mohamed El , Vokes Everett E. , Seiwert Tanguy Y.
Published: August 2012

Introduction: Cell lines retain key genetic aberrations of the originating tumors, which frequently correlate with sensitivity to specific inhibitors. We performed genetic and pathway based profiling of 40 head and neck cancer (HNC) cell lines using three publicly available methods for pathway profiling based on expression and copy number data. Methods: 40 HNC cell lines were analyzed for expression using expression arrays (Agilent), and copy number using array comparative hybridization (aCGH) and/or Nanostring methodologies. Integrative genomic analysis was performed to determine pathway activity using pathway analysis techniques previously described by Gatza et al. (BFRM), Pe'er et al (CONEXIC), Vaske et al. (PARADIGM). Results: Frequent pathway activation was identified in >10 well established signalling pathways for HNC including TP53, PI3K-AKT, TP63/SOX2, Cyclin D1, MYC etc, as well as several - for HNC previously unknown - signalling pathways. Cell lines could be associated with expression-based biologic subtypes in HNC tissues suggesting that specific cell lines should be used preferentially for modelling and therapeutic evaluation for HNC subtypes (including HPV(+) cell lines with characteristics of HPV(+) tumors). The three pathway analysis platforms identified a large number of pathways with some overlap in particular between BFRM and CONEXIC, whereas PARADIGM profiled a much wider set of pathways. Both CONEXIC and PARADIGM employed copy number data, whereas BFRM relied solely on expression data. Conclusion: Pathway alterations characteristic of head and neck cancers were identified in virtually all HNC cell lines. Pathway based classification of cell lines was achieved and correlated with pathway activity in HNC tumor tissues. Three pathway-profiling approaches provided a large set of pathway activity with some significant overlap that may have translational relevance. Validation studies are currently on-going.

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 4919. doi:1538-7445.AM2012-4919
Abstract 4923: Understanding cancer invasion by the systems biological analysis of collective cell migration in 3D tissue models
Authors: Grabe Niels , Safferling Kai , Westphal Kathi , Guziolowski Carito , Kittas Aristotelis , Ernst Claudia , Halama Niels , Jaeger Dirk
Published: August 2012

Collective migration is essential for morphogenesis and wound repair in healthy tissue as well as for tissue invasion in cancer. In such migration cells move in supracellular, cadherin mediated units opposed to isolated ameoboid or mesenchymal movements. Understanding collective migration in healthy epithelia is a prerequisite for dissecting and analyzing invasion in carcinoma. We have set up a novel, easily reproducible 3D in vitro wound model of epidermal regeneration. The model is based on commercial tissue cultures and can thus be reproducibly manufactured in larger quantities. We used our model for a systematic analysis of wound reepithelialization by measuring cytokines and mRNA expression. Using virtual microscopy we could quantitatively capture the cellular intra-tissue streams during reepithelialization. We integrated our data in a systems biological multi-scale model. Our results uncover a sequence of different types of collective epithelial migration which occur during wound healing in an orchestrated manner. In cancer invasion these mechanisms are hijacked by the tumor in an emergent malignant exploit of the intrinsically healthy processes of epithelial morphogenesis and repair.

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 4923. doi:1538-7445.AM2012-4923
Abstract 493: Endothelin-1 induces activation of vascular endothelial growth factor receptor-3 and modulates cell migration and vasculogenic mimicry in melanoma cells
Authors: Spinella Francesca , Caprara Valentina , DiCastro Valeriana , Rosanò Laura , Cianfrocca Roberta , Natali Pier Giorgio , Bagnato Anna
Published: August 2012

Phenotypic and genotypic analyses of cutaneous melanoma have identified endothelin B receptor (ETBR) as tumor progression marker, thus representing a potential therapeutic target. We previously reported that the binding of ET-1 to ETBR stimulates angiogenesis and lymphangiogenesis directly and by stimulating vascular endothelial growth factor (VEGF)-A and VEGF-C production. In this study we investigated as to whether in melanoma cells ET-1 axis may interact with VEGF-A and VEGF-C signaling pathways to heighten cellular responsiveness. We found that in primary and metastatic melanoma cell lines, ET-1 increased VEGF-A, VEGF-C and its selective receptor VEGFR-3, at mRNA and protein level. Following ET-1 stimulation, VEGF-A and VEGF-C were upregulated, VEGFR-3 was rapidly phosphorylated and downstream signaling intermediates, such as p42/44 MAPK and Akt, were activated through ETBR. Inhibition of c-Src activity by PP2, reduced ET-1-induced VEGFR-3 phosphorylation, demonstrating that ET-1 transactivates VEGFR-3 through an intracellular mechanism mediated by c-Src. Stimulation with ET-1 in combination with VEGF-A or VEGF-C increased p42/44 MAPK and AKT phosphorylation, and resulted in a greater degree of melanoma cell migration compared to a single factor. Furthermore, this combination significantly enhanced the ET-1-induced vasculogenic differentiation of melanoma cells in capillary-like structures, vasculogenic mimicry, indicating that crosstalk between ET-1/ETBR axis with VEGFR-3/VEGF-C system may enhance cancer cell motility and invasiveness and contributes to the promotion of cancer metastasis. Finally, in melanoma xenografts, ETBR antagonist suppressed tumor growth and neovascularization-related effectors, indicating that targeting ETBR related signalling cascade may represent a novel treatment of melanoma by impairing the crosstalk between ET-1 axis and VEGF in melanoma. Supported by AIRC

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 493. doi:1538-7445.AM2012-493
Abstract 4930: Integrative analysis of genome-wide methylation and expression profiles for metastatic colorectal cancer
Authors: Midorikawa Yutaka , Tsuji Shingo , Nagae Genta , Takayama Tadatoshi , Sugiyama Yasuyuki , Aburatani Hiroyuki
Published: August 2012

In colorectal cancer (CRC) care, treatment decisions depend on efforts to estimate the metastatic potential of tumors. The liver is one of the most common metastatic sites of CRC and prognosis of CRC patients often reflects metastases to distant sites. However, the molecular mechanisms for further development of CRC with metastasis to the liver, lung, brain, bone and lymph nodes are unknown. The aim of this study was to stratify patients based on DNA methylation status and identify not one biomarker gene, but functional motif for metastatic potential of CRC. Using Illumina HumanMethylation 27 harboring approximately 27,000 CpG loci, we performed genome-wide methylation analysis for 74 CRC samples including 36 patients with liver metastasis and 38 without any distant metastasis. As a control, their corresponding colorectal mucosa was used. Consistent with our previous data, using non-negative matrix factorization and consensus clustering analysis, samples were clustered into three groups; high-, intermediate-, and low-methylation epigenotypes. Next, tumor samples were classified based on gene expression profile in each methylation cluster. Gene Set Enrichment Analysis was applied for expression data, which could identify that Rhodopsin kinase was activated in CRC samples with liver metastasis. Then genes included in this kinase were analyzed by Network Hidden Key molecule miner (NetHike) algorithm. NetHike, which we recently developed as network analysis, demonstrated that CXCR4 was one of key molecule for liver metastasis of CRC. In NetHike algorithm, several information such as methylation status and gene expression was inputted which would be integrated on known signaling pathways. In CXCR4 and its neighbors as a functional motif of CRC metastasis, CXCL12 was methylated without gene expression aberration. On the other hand, CXCR4, CCR5, and ARRB2 were not methylated, of which expression was increased, suggesting that integration and mapping of some gene information effectively identify activated gene pathways in some clusters, and may be missed only by conventional analyses. Taken together, network-based analysis could find the potential functional motif and integration of various gene expression aberrations and methylation status also could stratify CRC patients with liver metastasis and without metastasis. We plan to make an exhaustive exploration to discover the some novel functional topologies that have both expression and methylation aberrations and might be related to the mechanism of CRC metastasis.

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 4930. doi:1538-7445.AM2012-4930
Abstract 4933: Novel insight into hallmark switch in cancer metabolism using the Interrogative Biology™ discovery platform
Authors: Narain Niven R. , Vishnudas Vivek , Grund Eric , Lee Arleide , Alonzo Judith , Agarwal Shiuli , Caprice John , Khalil Iya , Akmaev Slava , Hill Colin , Sarangarajan Rangaprasasd
Published: August 2012

Cancer metabolism is an intergrative ensemble of disrupted enzyme kinetics and dysregulated metabolite utilization leading to loss of normal cellular function that is the result of a multi-factorial yet coordinated breakdown in vascular, immune, cell cycle, apoptotic, and ECM components. In actively metabolizing cancer, the switch from mitochondrial OXPHOS to anaerobic glycolysis is very well characterized and understood. Global cellular changes in response to metabolic switch have either been overlooked or not been primary interest or relevance to cancer metabolism. We describe a novel systems biology/engineering approach encompassing cell models that are conditioned under various oncogenic perturbations or environments and then coupled with functional bioenergetic read out such as employing the XF24 Seahorse Bioscience analyzer, ATP assays, and ROS production. The OCR and ECAR measurements generated by XF24 analyzer enabled quantifying the switch from aerobic to the anerobic mode of energy metabolism. Cellular profiles were captured in the form of multi-omic (proteomic, genomic, proteomic) signatures using high-throughput mass spectrometry based protocols. Analyses were performed on oncogenic breast, prostate, liver, pancreatic, skin (melanoma, squamous cell carcinoma) and were compared to normal fibroblasts, keratinocytes, hepatocytes, kidney cells, adipocytes, and human aortic and endothelial cells. High throughput data cascades from various cancer states were integrated with the metabolic data from the XF24 analyzer using an AI-based data mining platform to generate causal network based on bayesian models (REFS™ model). The output enables the understanding of differential mechanisms that drive glycolysis and mitochondrial OXPHOS in a cancer versus normal environment. Further validation of prominent hub of activity as they partake as key drivers of metabolic end points by siRNA knockdown experiments followed by measurement using the XF24 analyzer confirmed the relevance of these hubs in cancer metabolism and their relevance as potential therapeutic targets and biomarkers for diagnostics development. The data output presented herein strongly suggest that the Interrogative Biology® platform is a key tool in deciphering differential network analysis pertinent to disease pathophysiology and bioenergetics.

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 4933. doi:1538-7445.AM2012-4933
Abstract 4946: Control of cellular proliferation by ERK: A quantitative analysis in single cells
Authors: Albeck John G. , Mills Gordon B. , Brugge Joan S.
Published: August 2012

The EGF-stimulated ERK/MAPK system is a key conduit for physiological growth signals. We have used a combination of live and fixed single-cell measurements to determine the quantitative operating principles of this pathway under long-term stimulation by physiological levels of EGF, revealing three essential properties of the network. First, the extracellular concentration of EGF is encoded, at different points in the network, by distinct frequency- and amplitude-modulated responses. Second, control of cellular proliferation is controlled predominantly by the lower end of the pathway's dynamic range, necessitating nearly complete inhibition of the pathway to elicit growth arrest. Third, the diverse phenotypic outputs of the pathway are controlled by different segments of the overall dynamic range, with distinct molecular targets engaged at different thresholds. These properties have direct relevance to strategies for therapeutic inhibition of the ERK/MAPK network.

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 4946. doi:1538-7445.AM2012-4946
Abstract 4947: Analysis of structural mutations in cancer genomes
Authors: Woo Xing Yi , Menghi Francesca , Inaki Koichiro , Gong Min , Hillmer Axel , Sherbaf Faranak , Liu Edison
Published: August 2012

In our group, we have extensively sequenced various cancer genomes (breast cancer, ovarian cancer and melanoma) using a range of genome-wide sequencing approaches, including DNA-PET, RNA-SEQ and exome-capture sequencing. Taking each tumor as a system of its own, we aim to integrate the different outputs of these technologies to explore the composite of hard-wired changes that drive tumorgenesis in different cancers. One type of hard-wired changes is copy number alterations, where the cancer genome tends to gain oncogenes and lose tumor suppressors by DNA amplifications and deletions respectively. While copy number variation data are now a standard output of the DNA-PET pipeline, the accurate prediction of copy number gains and losses is further complicated by several issues, including normal tissue contamination, tumor heterogeneity and aneuploidy. I will present my current work to deconvolute the contribution of these factors to the copy number profile. I will also discuss the classification of our sequenced cancer genomes into various chromotypes based on their unique copy number signatures. I will show how different chromotypes are enriched in specific types of structural variations, which may underlay alternative mechanisms of genomic instability promoting cancer evolution.

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 4947. doi:1538-7445.AM2012-4947
Abstract 4954: The expression of X-linked inhibitor of apoptosis in human oral squamous cell carcinoma and its relationship with clinical factors
Authors: Tamatani Tetsuya , Takamaru Natsumi , Uchida Daisuke , Nagai Hirokazu , Fujisawa Kenji , Miyamoto Youji
Published: August 2012

[Background] X-linked inhibitor of apoptosis (XIAP) is a member of the inhibitor of apoptosis protein family, which is associated with cell survival by blocking caspase-mediated apoptosis. XIAP is expressed in various malignant tumors. The overexpression of XIAP has been reported to be a poorer prognostic factor in various malignancies. However, the prognostic value of XIAP expression in patients with oral cancer is not still cleared. [Purpose] The aims of present study were to evaluate the expression of XIAP protein in oral squamous cell carcinoma (OSCC) and to elucidate the relationships among the XIAP expression, clinical stages, histological differentiation and classification of invasion mode. [Materials and Methods] Four human OSCC cell lines, B88, CAL27, HNt, and HSC3 cells were used in this study. Normal gingival epithelial cells served as control. XIAP expression of cultured cells was detected by western blot. Tissue specimens were obtains from 85 patients with OSCC after surgery or biopsy. XIAP expression was detected by an immunohistochemical method. [Results] The expression of XIAP was detected in all cancer cells, but not in normal cells. Immunohistochemical analysis of 85 cases of OSCC showed that 73 (86%) cases expressed XIAP. There was no relationship between XIAP expression and clinical stages, or classification of invasion mode. There were significant differences between XIAP expression and histological differentiation. Most of non-staining and weakly staining of cancer was well differentiated. In contrast, intense and extensive staining was frequently found in poorly differentiated cancer. [Conclusions] These findings suggested that the expression of XIAP in OSCC could be related to histological differentiation.

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 4954. doi:1538-7445.AM2012-4954
Abstract 4964: Mutations of cysteine residues in Bcl-2 suppress hydrogen peroxide-induced apoptosis of human lung cancer cells through ERK1/2 interaction
Authors: Luanpitpong Sudjit , Wang Liying , Rojanasakul Yon
Published: August 2012

Bcl-2 is an essential antiapoptotic protein of the mitochondrial death pathway whose expression is highly associated with apoptosis resistance in cancer cells. Hydrogen peroxide is a signaling molecule mediating apoptosis to various stimuli, e.g. cisplatin and lipoic acid, in lung cancer cells. Direct treatment of the cells with hydrogen peroxide induced oxidative stress and a concomitant increase in apoptosis of human lung cancer H460 cells. Cysteine residues are likely targets of oxidative modifications of proteins; however, their effects on apoptosis and mechanisms of regulation are not known. To determine the role of cysteine residues, we constructed Bcl-2 mutant plasmids replacing the two cysteine residues Cys158 and Cys229 with alanines (Bcl-2-DM). Overexpression of Bcl-2-DM strongly suppressed the apoptosis induced by hydrogen peroxide in H460 cells as compared to that in control cells overexpressing wild-type Bcl-2. We further found that Bcl-2 directly interacts with MAP kinase ERK1/2 and that hydrogen peroxide disrupts such interaction. However, hydrogen peroxide treatment had a minimal effect on Bcl-2 and ERK1/2 interaction in Bcl-2-DM overexpressing cells, suggesting that Cys158 and Cys229 are required for the oxidative signaling. These findings identified a novel mechanism of oxidative regulation of apoptosis via cysteine modifications of Bcl-2.

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 4964. doi:1538-7445.AM2012-4964
Abstract 4966: The anti-apoptotic activity of caspase-2 short isoform is regulated by XPC protein
Authors: Wang Qi-En , Han Chunhua , Wani Altaf A.
Published: August 2012

Caspase-2 (casp-2) is the most conserved caspase across species. The casp-2 gene produces several alternative splicing isoforms. The inclusion of exon 9 leads to the inclusion of an in-frame stop codon in casp-2 short isoform (casp-2S) mRNA, thus producing a truncated protein that inhibits cell death, whereas the exclusion of exon 9 results in casp-2 long isoform (casp-2L) mRNA, whose protein product induces cell death. Earlier it has been reported that casp-2 is required for stress-induced apoptosis. However, that study could not have separated the roles of casp-2L and casp-2S, since the siRNA used in their experiments actually targeted both casp-2 isoforms. We have reported that targeted RNAi-mediated down-regulation of casp-2S enhanced the UV-induced apoptosis in XPC-deficient but not in XPC-proficient cells. However, by using the siRNA targeting both casp-2L and casp-2S, we failed to find any influence of casp-2 down-regulation on UV-induced apoptosis in these fibroblasts. Similarly, casp-2 specific inhibitor z-VDVAD was unable to reduce UV-induced apoptosis. In addition, the expression of casp-2S, but not casp-2L is regulated by XPC protein. To gain insight into the mechanism by which XPC down-regulates casp-2S, we examined the casp-2S promoter activity and the enrichment of XPC protein on casp-2S promoter. Our data clearly demonstrated that XPC protein can inhibit casp-2S promoter through binding to the promoter region. Furthermore, our cellular fractionation study demonstrated that casp-2L exclusively resides in cytoplasm, while casp-2S can be detected in both cytoplasm and nucleus. UV irradiation reduced the amount of nuclear casp-2S in XPC-proficient cells, while this reduction is not prominent in XPC-deficient cells, indicating that XPC protein facilitates the depletion of nuclear casp-2S upon UV irradiation. This finding provides an additional mechanism by which XPC facilitates DNA damage-induced apoptosis. (Supported by NIH grants CA151248 to QEW and ES12991 to AAW.)

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 4966. doi:1538-7445.AM2012-4966
Abstract 4967: Altholactone induces caspase dependent and independent apoptosis of human colorectal cancer cells
Authors: Mhaidat Nizar M.
Published: August 2012

Resistance of colorectal cancer (CRC) to the available chemotherapy reveals the demand for identification of new anticancer agents. We evaluated the antitumor potential of altholactone, a naturally occurring bioactive compound isolated from Goniothalamus spp. (Annonaceae) hooks, against CRC cells. Antitumor activity of altholactone was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the propidium iodide method. Apoptosis mediators involved were assessed using biochemical inhibitors and Western blotting analysis. Results revealed that altholactone induced varying degrees of apoptosis in CRC cells but not in normal fibroblasts. Dissection of the altholactone-induced apoptotic signalling pathway revealed that altholactone activated caspase-dependent and -independent apoptotic pathways. Activation of caspase-4 appeared to be the initiating event in the caspase-dependent apoptotic pathway. Pre-treatment of CRC cells with the antioxidant N-acetylcysteine (NAC) significantly inhibited activation of caspase-4 and altholactone-induced apoptosis. These results indicate that altholactone induces selective cytotoxicity against colon carcinoma cells and warrants further clinical evaluation.

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 4967. doi:1538-7445.AM2012-4967
Abstract 5042: A-AS1, a long non-protein coding RNA overexpressed in esophageal adenocarcinoma, influences cancer cell proliferation and apoptosis
Authors: Wu Wenjing , Song Jee Hoon , Cheng Yulan , Meltzer Stephen J.
Published: August 2012

Esophageal adenocarcinoma (EAC) is one of the fastest-growing cancers in the Western world. 95% of EACs occur without any antecedent diagnosis of Barrett's esophagus (BE). In these 95% of EAC patients, 5-year survival is only 15%. The rising incidence and poor prognosis of EAC have intensified research efforts into earlier methods to detect this disease. The majority of the human genome is transcribed and generates mostly non-coding (nc)RNAs that do not encode protein information. Long non-coding RNAs (lncRNAs) are emerging as a novel class of ncRNAs, but knowledge about these ncRNAs is limited. Recently, dysregulation of lncRNAs has been shown in various types of cancer, suggesting that lncRNAs may be involved in tumorigenesis or tumor progression. In the present study, we report that a number of lncRNAs are differentially expressed in EAC tissues and cell lines relative to normal esophageal tissues and cell lines. One of these lncRNAs, A-AS1 is derived from the antisense strand of the A gene locus and is overexpressed in EACs relative to matched normal esophagus (NE). Cell proliferation and colony formation assays revealed that A-AS1 siRNA-mediated knockdown reduces cell proliferation and colony-forming ability. In vitro scratch assays, migration and invasion assays in vitro also demonstrated decreased migration and invasion induced by A-AS1 siRNA knockdown. Moreover, we found that inhibition of A-AS1 expression results in increased apoptosis in EAC cell lines. Taken together, these results suggest that the elevated expression of A-AS1 observed in EACs may have contributed to their development or progression.

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 5042. doi:1538-7445.AM2012-5042
Abstract 5052: MicroRNA alterations following radiation in melanoma
Authors: Walston Steve A. , Gordon Nicolaus , Chakravarti Arnab , Palanichamy Kamalakannan
Published: August 2012

Purpose: Melanoma only accounts for 4% of skin cancer while causing 75% of cancer related deaths. Also, the incidence is increasing with the annual percent change in the United States reported as 2.4% for the period 1986-2006 and currently increasing faster than any other cancer worldwide. Moreover, patients who develop locally advanced or metastatic melanoma have limited treatment options with 5-year survival rates of 65% and 16%, for regional disease and metastatic disease, respectively. Historically, melanoma was regarded as resistant to radiation therapy (RT), however, recently the utility of RT has been re-explored in the adjuvant setting with fractionated radiotherapy (FRT) and also in the oligometastatic setting with stereotactic radiotherapy (SBRT), and does show increase in local control in appropriately selected patients. The importance of microRNA (miRNA) in cancer continues to be elucidated and in melanoma they are extensively reported as having significant roles in melanoma transformation, progression, invasiveness, metastasis, and outcome/prognosis. However, there are no reports of melanoma miRNA profiling and RT. miRNA expression profiles change as a consequence of RT in several tumor types. Experiments show delivery of miRNA in vivo appears both feasible and tolerable in murine models. Additionally, correcting miRNA deregulation has been shown to mitigate the tumorigenic phenotype and also induce radiosensitivity in vitro and in vivo. Materials/Methods: We cultured more than a dozen melanoma cell lines and sequenced for mutations in key genes such as B-RAF, N-RAS, etc. to group them. Next we isolated their miRNA of untreated and treated with 6 Gray dose of radiation isolated at 5 days. The miRNA expression was quantified using RT-qPCR of TaqMan Low Density Arrays (TLDA) cards. The data is reported using hierarchical clustering and those miRNAs significantly deregulated have been delineated. Results/Discussion: We have characterized the miRNA expression profiles of melanoma cell lines when comparing untreated and those treated with radiation. Our data indicate that miRNA profiles done pre and post RT are significantly different. To this end we have identified clusters of miRNA associated with RT sensitivity/resistance. Thus, these miRNAs could be important factors in response to RT and their differential expression may be linked to resistance to RT. Consequently, it is conceivable that these miRNA and/or their mRNA targets could be used in the future as targets for drug development to radiosensitize melanoma and thus further improve outcomes.

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 5052. doi:1538-7445.AM2012-5052
Abstract 5054: Inferring mutational chronology in breast cancer by deep-sequencing tumor subpopulations
Authors: Navin Nicholas E. , Wang Yong , Waters Jill , Chen Ken , Hall Ira , Malhotra Ankit , Quinlan Aaron
Published: August 2012

Heterogeneous breast carcinomas often contain nuclei with multiple distributions of ploidy, each representing a distinct genomic subpopulation. We present an approach called Ploidy-Seq that combines flow-sorting and next-generation sequencing to isolate tumor subpopulations and deep-sequence the nuclei at high coverage (80-100X) to identify somatic mutations. We applied Ploidy-Seq to a triple-negative (ER-, PR-, Her2-) ductal carcinoma that showed three major tumor subpopulations and one stromal subpopulation. In order to distinguish germline from somatic mutations, we first identified all of the SNPs in the 2N stromal cells. We then studied the evolution of different molecular clocks within the breast tumor, including single nucleotide variations (SNVs), indels, structural rearrangements, copy number changes and translocations. By applying set theory operations, we compared the three tumor subpopulations to identify early mutations (present in all subpopulations), intermediate events (shared between two subpopulations) and late mutations (exclusive to each subpopulation). Overall we identified 101 nonsynonymous point mutations of which 31 had occurred early and were present in all tumor subpopulations. Many of the early mutations occurred in cancer genes including THSD7B involved in TGFβ signaling, the CDH26 cadherin-like 26 gene, and the kinesin gene KIF2B. Early mutations were further studied by single-cell sequencing, which showed evidence of clonal expansions within the tumor, suggesting that they provided a major selective advantage. These early mutations are of considerable interest for therapeutic targeting since they are present in all of the tumor subpopulations, and are likely to be driving the growth of the 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 5054. doi:1538-7445.AM2012-5054
Abstract 5058: Application of a high throughput cancer mutation profiling platform to clinical research
Authors: Garcia Elizabeth P. , Shivdasani Priyanka , Sharaf Nematullah , Crosby Lauren , Byrne Mark N. , Wade Jacqueline E. , Joshi Ruchi , Ducar Matthew , Palescandolo Emanuele , Hummelen Paul Van , Lindeman Neal I. , Kuo Frank C. , Longtine Janina A. , MacConaill Laura E.
Published: August 2012

Detection of critical cancer gene mutations in tumor samples may result in improved care, treatment and outcomes for patients. It has become clear that for specific cancer types there is a high association between mutations in a defined set of oncogenes or tumor suppressors some of which are actionable. While it has become common practice to screen for specific mutations in specific cancer types, to date broad mutation screening has not been practical. We report here the first large scale screening initiative between the Dana Farber Cancer Institute and Brigham and Women's Hospital that allows adult cancer patients the option to have their tumor tissue screened for genetic mutations implicated in cancer. OncoMap is a high throughput mutation profiling platform developed to detect 471 genetic mutations across 41 known oncogenes and tumor suppressor genes. The goal is to utilize OncoMap to identify genetic mutations in cancerous tissue across all tumor and tissue types. Because there is no bias as to which cancers are screened for specific mutations our aim is to identify new trends and associations between cancer types, mutational status and patient outcome. OncoMap has been analytically validated under CLIA guidelines as recommended by the Clinical Laboratory Standards Institute. Our findings show that OncoMap detects somatic mutations that are present at an allele frequency of 7.5% with 95% confidence. Precision and reproducibility studies were performed using 30 distinct formalin-fixed paraffin embedded tumor samples from various tissue types known to harbor somatic mutations in KRAS, BRAF or exon 19 deletions in EGFR. Further concordance studies demonstrate that OncoMap shows ninety-six percent sensitivity with respect to detection of codon 12 and 13 mutations in KRAS, detection of BRAF V600E mutations and JAK2 V617F mutations. Using the OncoMap cancer genetic profiling platform we anticipate that ∼10,000 individual tumors from adult cancer patients will be screened on a yearly basis enabling the identification of newly discovered associations between cancer tissues, their mutational status and patient outcome.

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 5058. doi:1538-7445.AM2012-5058
Abstract 5063: International Cancer Genome Consortium (ICGC)
Authors: Hudson Thomas J. , Jennings Jennifer L.
Published: August 2012

The International Cancer Genome Consortium (ICGC) was established to bring together researchers from around the globe to comprehensively analyze the genomic, transcriptomic, and epigenomic changes in 50 different tumor types or subtypes that are of clinical and societal importance across the globe. (International network of cancer genome projects (Nature 464, 993-998 (15 April 2010)). As of November 2011, the ICGC has received commitments from funding organizations in Asia, Australia, Europe and North America for 43 project teams in 13 jurisdictions to study over 18,000 tumor genomes. The genomic analyses of tumors conducted by ICGC members in Australia and Canada (pancreatic cancer), Japan (liver cancer), Spain (blood cancer), the UK (breast, lung and skin cancer) and the USA (blood, brain, breast, colon, kidney, lung, ovarian, rectal, stomach and uterine cancer) are now available through the Data Coordination Center housed on the ICGC website at www.icgc.org. The ICGC's informed consent and ethical oversight policies state that cancer patients enrolled in an ICGC-related study should be informed that their participation is voluntary, that their clinical care will not be affected by their participation and that data obtained from analyses using their samples will be made available to the international research community. Ultimately, over 25,000 tumor genomes will be sequenced worldwide. This will provide a comprehensive catalogue of genomic abnormalities associated with cancer, a collection of data that will reveal the repertoire of mutations that cause this wide-ranging disease and help define clinically relevant subtypes of cancer. The data will also provide a rich resource for the world's researchers who are working to develop new treatments to make patient care move forward.

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 5063. doi:1538-7445.AM2012-5063
Abstract 5069: Genomic profiles of primary non-small cell lung cancer (NSCLC) xenograft tumors identify distinct gene signatures associated with histological subtypes
Authors: To Christine , Strumpf Dan , Panchal Devang , Li Ming , Pham Nhu-An , Xie Wing , Yanagawa Naoki , Bandarchi Bizhan , Chui Michael Herman , Der Sandy , Shepherd Frances A. , Kislinger Thomas , Moran Michael , Jurisica Igor , Muthuswamy Lakshmi , Tsao Ming-Sound
Published: August 2012

Xenografts established directly from patient tumors mirror closely the histology of the primary tumors. Therefore, primary tumor xenografts (PTXG) may serve as important preclinical models to evaluate novel anti-cancer drugs. We previously reported that the ability of resected tumors to engraft in NOD-scid mice is a strong predictor of relapse after surgery and poorer prognosis in NSCLC patients, and thus may represent biologically more aggressive cancers (Clin Cancer Res 2011;17:134-41). Genomic characterization of PTXG would help identify genetic aberrations that drive malignant oncogenic pathways in NSCLC. We characterized the somatic copy number alterations (CNA) of 36 PTGX, consisting of 15 adenocarcinoma (ADC), 18 squamous cell carcinoma (SCC), 2 large cell neuroendocrine carcinoma (LCNEC) and 1 large cell carcinoma (LC), along with 34 patient normal samples as controls using Illumina Omni-1 Quad SNP arrays. The gene expression profiles of the 36 PTGX were analyzed using Illumina Omni-1 Quad HT-12 v4 arrays. Histology-specific recurrent regions of CNA observed in PTGX are concordant with the published and publicly available primary NSCLC CNAs. We identified 1053 genes with somatic copy number gains and 932 genes with somatic copy number losses that distinguish between SCC and ADC. From integrative analysis of mRNA expression and somatic CNAs, we identified 325 genes specific to ADC and 2232 specific to SCC that are well correlated. Gene candidates that are deregulated in ADC include WRN, STK35, SIX1; and genes that are over-expressed in SCC include SOX2, RNF13, WNK1, PIK3CA, TFRC, TP63, PAK2 suggesting there is differential deregulation of signaling pathways between these two subtypes of lung cancer. We have identified candidate gene signatures that distinguish between ADC and SCC from PTXG, suggesting these xenograft models can provide a valuable resource to study cancer biology and preclinical drug target evaluation in vivo.

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 5069. doi:1538-7445.AM2012-5069
Abstract 5086: Frequent genetic alteration in transitional cell carcinoma of the bladder by large scale exome sequencing
Authors: da Hu Xue
Published: August 2012

Bladder cancer is the ninth most common cancer worldwide, with TCC being the predominant form (90%). We completed a preliminary research that investigated into exomes of 9 TCCs and target genes of additional TCCs, and discovered frequent aberrations of the chromatin remodeling genes. Six genes, including UTX, MLL/MLL3, CREBBP/EP300, NCOR1, ARID1A and CHD6, were identified in 59% of the 97 TCC patients. Here, in order to obtain a more comprehensive genetic overview of TCC, we sequenced both exomes and whole genomes for another 92 TCC samples. For exome sequencing, we had an average coverage of 75.3x for targeted regions encompassing 38M of Refseq census coding sequence, and >92% of the target bases were covered sufficiently for variant calling (≥10×). As for whole genome resequencing, we achieved the average coverage at 3.8x. We analyzed the exome and genome sequencing data of 92 TCC samples together with the 9 TCCs from the preliminary study to identify the somatic mutations and copy number variations (CNVs), and detected 11,143 non-sysnonymous point mutations, 1,041 small Indels in coding regions (<100bp) and 12,034 CNVs. A total of 12,216 genes were found to be affected by these somatic genetic changes. Furthermore, 125 genes that harbored the confirmed non-silent mutations in at least five other tumors types were observed to have a significantly higher (likelihood test, p<0.01) non-silent mutation rate than the background. We also analyzed the biological pathways by Gene Set Enrichment Analysis, and discovered that the MAPK signaling pathway and the pathway of actin cytoskeleton regulation were mutated in 76 and 75 TCC tumor samples, respectively. Our studies gathered a large number of genetic data on Bladder cancer by applying exome and whole genome sequencing, and provided an unprecedented panoramic view of the genetic basis of TCC.

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 5086. doi:1538-7445.AM2012-5086
Abstract 5087: UCSC Cancer Genomics Browser 2.0
Authors: Zhu Jingchun , Craft Brian , Swatloski Teresa , Ellrott Kyle , Goldman Mary , Wilks Christopher , Ma Singer , Szeto Christopher , Collisson Eric , Haussler David
Published: August 2012

As the rate of cancer genomic information production has increased so has the task of managing the computational infrastructure required to host, visualize and analyze that data. The UCSC Cancer Genomics Browser (https://genome-cancer.ucsc.edu) provides a variety of tools to help researchers analyze their data. It includes sortable genomic heatmaps linked to patient clinical attributes that can be explored on demand. A user can run statistical tests between user defined groupings of samples, genomic signature evaluations, and toggle between chromosomal and custom gene sets views. The browser is linked to the UCSC Genome Browser; thus inheriting and integrating the Genome Browser's rich set of human biological and genetic data that enhances the interpretability of the cancer genomics information. UCSC Cancer Genomics Browser 2.0 has been released with drastically enhanced user. Other recent improvements in the Cancer Genomics Browser have been in response to the growing number of collaborative cancer analysis projects. Designed with the privacy issues that come along with patient data in mind, cancer browser accounts provide user-specific sessions, gene sets, genomic profiles, and user-specific data tracks controls. In addition to the public portal, the Cancer Genomics Browser also supports projects that require secured access control. The system hosts results from TCGA, SU2C (Stand Up To Cancer), LINCS (Library of Integrated Network-based Cellular Signatures), GEO (Gene Expression Omnibus) and the ISPY trials along with information from individual labs. Researchers that have been authenticated to multiple projects can see the results from all of their projects in a single page. The other aspect of working with multiple collaborative cancer projects is the issue of properly defining data interchange formats. For the Cancer Genome Browser we have created a specification called cgData, which will be used by UCSC to consolidate various types of information from TCGA. cgData is a designed to provide the variety of file formats that are required to describe the heterogeneous data required for the browser. Formats for defining expression matrices, genomic probe definitions, clinical feature data, mutation information and sample mapping have all been specified to enable rapid integration of new data into the Cancer Genome Browser. This format is being developed in collaboration with partners from SU2C and LINCS, and utilities to convert The Broad Institutes TCGA Firehose analysis and MSKCC cBio portal information have already been developed. The publicly available data is organized into downloadable releases on a monthly basis.

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 5087. doi:1538-7445.AM2012-5087