bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 479: Targeting tumor initiating cells inhibits tumor growth and serial transplantation ability in soft-tissue sarcomas
Authors: Wei Qingxia , Wang Chang Ye Yale , Zheng Feifei , Zhang Phil , Wang Weishi , Wunder Jay S. , Alman Benjamin A. 
Published: June 2012

Abstract
Tumors contain heterogeneous cell populations. There is a subpopulation of cells enriched for tumor initiating potential in sarcomas, which excludes Hoechst dye, and resides in the “side population” when subjected to flow cytometry (SP cells). These cells possess multi-potent differentiation potential, and as such they behave as “cancer stem cells” (CSCs), while the remainder of tumor cells act as “transient amplifying” cells. Because traditional cancer therapies may not target these tumor initiating cells, the persistence of SP cells could be responsible for relapse or a failed response to therapy. To detect signaling pathways that are differentially regulated in SP cells versus the remainder (non-SP) of the cells, we used gene profiling by microarray to compare their differences. RNA expressions were compared between these two cell populations from six malignant fibrous histiocytoma (MFH) samples using microarray. Differentially regulated genes were then analyzed by compiling a list of genes that showed a fold change greater than 1.25 in at least five of the six samples all in the same direction, and identifying if the list is enriched for genes involved in common molecular pathways, using Genespring® analysis tool. Two of the differentially regulated pathways detected were the Hedgehog signaling pathway and the Notch signaling pathway. Differential target gene expression for both pathways was verified using quantitative PCR. Triparanol (an agent that inhibits hedgehog signaling) and DAPT (an agent that inhibits Notch signaling) were used to treat eight primary MFH xenografts established in NOD-SCID mice. The xenografts produced visible tumors six weeks after subcutaneous transplantation, after which the mice were treated with one of the agents or a carrier as a control. At the end of the treatment, the tumors were harvested; their growth and SP% were assessed and compared; and the cells harvested from the treated xenografts were again implanted into mice to study the rate of re-growth upon secondary transplantation. Both triparanol and the Notch blocker DAPT treatment suppressed these pathways in tumor cells, depleted the abundance of SP cells, and reduced tumour growth. Intriguingly, treatment substantially inhibited the tumour-initiating potential of the treated sarcoma cells upon secondary transplantation. The data provides support that SP cells act as tumour initiating cells in sarcomas and shows that targeting the SP (in this case by targeting the Hh and Notch pathways) is an enticing approach for sarcoma therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 479. doi:10.1158/1538-7445.AM2011-479
Abstract 4793: Aberrant methylation of CDH1 correlates with poor prognosis in patients with head and neck squamous cell carcinoma
Authors: Rivera-Peña Bianca L. , Baez Adriana 
Published: June 2012

Abstract
Objective: CDH1 codes for E-cadherin, a key adhesion molecule of epithelial cells, whose loss of expression has been associated with carcinogenesis in several types of cancer. Promoter hypermethylation of CDH1 results in loss of expression of E-cadherin and may be involved in the development of metastasis and a poorer prognosis. The purpose of this study was to determine the methylation profile of CDH1 in a cohort of HNSCC patients and evaluated its association with clinicopathological parameters.
Methods: CDH1 methylation status was determined using the Methylight assay in a cohort of 59 patients that had CDKNA (p16) methylation status assessed previously. Correlations between clinical parameters and methylation profiles were statistically analyzed using Fisher's exact test and chi-square test when appropriate.
Results: Aberrant methylation of CDH1 was detected in 78% of the cases analyzed. In 33% of the patients had also CDKN2A aberrantly methylated. Most patients (69%) with CDH1 aberrantly methylated were in advanced stages of the disease (III/IV). They also had a poorer survival rate. No statistically significant association was found between CDH1 hypermethylation and gender, age, risk factors and staging.
Conclusion: CDH1 aberrantly methylated was detected at early and late stages of the disease. These results suggest that CDH1 hypermethylation may have a role in the initiation and in progression of HNSCC and potentially reduce the survival of HNSCC patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4793. doi:10.1158/1538-7445.AM2011-4793
Abstract 4795: The epigenetic regulation of HPP1 expression in colon cancer
Authors: Wang Jian , Elahi Abul , Hernandez Jonathan , Clark Whalen , Achille Alex , ED Seto , Shibata David 
Published: June 2012

Abstract
Background: Tumors often are associated with aberrant epigenetic gene silencing. HPP1, a tumor suppressor gene, is epigenetically silenced by promoter methylation in a number of tumor types including colon cancer however, the contribution of histone acetylation is not clear. Moreover, c-myc interaction with the HPP1 promoter is thought to suppress expression. The purpose of this study is to examine the interplay between c-myc, DNA methylation and histone acetylation in the epigenetic regulation of HPP1 expression.
Methods: The HPP1-negative cell line, HCT-116, was treated with the DNA methylation inhibitor 5-aza-2’-deoxycitidine (5-aza-DC) and/or HDAC inhibitors, including sodium butyrate (SB), Vorinostat (SAHA), trichostatin A (TSA), and valproic acid (VPA). Knockdowns of c-Myc and HDAC-3 were performed using siRNA. Protein and mRNA expression of HPP1 were determined by Western Blot and RT-PCR respectively. HPP1 promoter methylation was assessed by real-time methylation-specific PCR. Furthermore, Chromatin immunoprecipitation (ChIP) experiments were used to demonstrate the binding of c-Myc to the HPP1 promoter.
Results: 5-aza-DC (0.4uM) as well as the HDAC inhibitors, SB (5mM), TSA (200nM), SAHA (5uM) and VPA (2mM), increased the expression of HPP1 in HCT-116 cells. The treatment of 5-aza-DC in combination with individual HDAC inhibitors resulted in a synergistic effect on increasing HPP1 expression as detected by both RT-PCR and Western blotting. We found that SAHA reduced the expression of HDAC-3 and c-Myc. Concordantly, knockdown of c-Myc and HDAC-3 by siRNA significantly enhanced HPP1 expression. We have also confirmed that c-Myc binds to the HPP1 promoter and its knockdown results in a reduction of HPP1 promoter methylation.
Conclusions: These results indicate that c-Myc- and HDAC-3-associated promoter methylation and histone deacetylation contribute to HPP1 epigenetic silencing. Colon cancer cells treated with DNA methylation and HDAC inhibitors can re-express the cancer suppressor gene HPP1. This study supports the conept that 5-aza-DC and HDAC inhibitors represent potentially promising classes of anticancer drugs for the future treatment of colon cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4795. doi:10.1158/1538-7445.AM2011-4795
Abstract 48: Detecting and controlling for physical contamination in next-generation sequencing cancer studies
Authors: Cibulskis Kristian , McKenna Aaron , Fennell Tim , Getz Gad 
Published: June 2012

Abstract
All large-scale cancer genome characterization efforts rely on the unprecedented throughput of massively parallel sequencing technologies, such as Illumina/Solexa, ABI/SOLiD, Roche/454, and others to generate short sequence reads. In turn, this has spurred the development of novel algorithms for sequence alignment and detection of DNA alterations. Particularly in cancer genome studies, these detection algorithms must be exceedingly sensitive since the events of interest are present in just a fraction of the observed data due to stromal contamination and tumor ploidy. At the same time they must be very specific, since the events are also extremely rare.
Little has been published on tools to measure and control the quality of such data and in particular tools for identifying contamination of the sequenced DNA with DNA originating from different individuals than intended. In the case of cancer genome studies, contamination of this kind can lead to seemingly somatic events.
We have developed and made available a novel tool, called ContEst, for estimating the level of contamination in next generation sequencing data of human samples. We demonstrate ContEst's accuracy across a range of contamination levels, sources and read depths using sequencing data that were mixed in-silico at known concentrations.
Finally, we will show the effect of physical contamination by different individuals with regard to somatic mutation detection, and present strategies for compensating in the contaminated data.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 48. doi:10.1158/1538-7445.AM2011-48
Abstract 4802: Cat eye syndrome chromosome region, candidate 1 (CECR1) is overexpressed and hypomethylated in salivary gland adenoid cystic carcinoma
Authors: Shao Chunbo , Tan Marietta , Glazer Chad A. , Bhan Sheetal , Chang Xiaofei , Uemura Mamoru , Kim Myoung S. , Moskaluk Christopher , Sidransky David , Califano Joseph A. , Ha Patrick K. 
Published: June 2012

Abstract
BACKGROUND and PURPOSE: Salivary gland adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary glands. It is characterized by a heterogeneous morphology, perineural invasion, and a variable clinical course. The molecular mechanisms underlying ACC are still unknown. We previously developed a high-throughput integrative epigenomic screening method to discover novel proto-oncogene candidates in ACC. With this screening method, we found that cat eye syndrome chromosome region, candidate 1 (CECR1) was a promising oncogene candidate for ACC. CECR1 encodes a member of a subfamily of the adenosine deaminase protein family and acts as a growth factor through its adenosine deaminase activity. No previous studies have correlated CECR1 in human cancers. In the current study, we validated several features of CECR1 in primary ACC samples, including promoter methylation status and expression levels.
METHODS and RESULTS: Bisulfite genomic sequencing was first employed to analyze the DNA methylation levels in the promoter of CECR1 in four ACC samples and four normal salivary gland tissues. Decreased methylation in CECR1 was found in three out of four ACC samples compared to zero out of four normal tissues. Secondly, quantitative methylation specific PCR (qMSP) was performed in a larger ACC cohort including 15 ACCs and 18 normal tissues. Consistent with the bisulfite genomic sequencing results, significant demethylation of CECR1 was detected in ACC samples (methylation levels ranged from 0.1 to 300.1; median, 19.8) compared to normal tissues (range from 10.2 to 600.0; median, 235.6), p &lt; 0.05. Thirdly, we induced global demethylation in an ACC cell line, ACC83, by 5-aza-2′-deoxycytidine/ trichostatin A (5 Aza dC/TSA) treatment. Quantitative reverse transcription PCR (qRT-PCR) showed that CECR1 was significantly re-expressed in 5 Aza dC/TSA treated cell lines. Lastly, we analyzed the expression levels of CECR1 by qRT-PCR in the same ACC cohort. We found significant overexpression of CECR1 in ACCs compared to normal salivary tissue, p &lt; 0.05.
CONCLUSIONS: This is the first study to associate elevated CECR1 levels with salivary gland ACC. The transcription of CECR1 appears to be upregulated by promoter demethylation. Both overexpression and promoter hypomethylation of CECR1 are hallmarks of ACC. CECR1 might play an important role in salivary gland ACC.
FUTURE DIRECTIONS: Functional studies of CECR1's role(s) in the carcinogenesis of salivary gland ACC are underway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4802. doi:10.1158/1538-7445.AM2011-4802
Abstract 4810: Utility of promoter hypermethylation for differentiating malignant and benign effusions in liquid-based cytology specimens
Authors: Kim Ga-Eon , Lee Ji-Shin , Kim Jin-Sook , Bae Woo-Kyun , Lee Ji-Hee , Hwang Jun-Eul , Lee Jae-Hyuk 
Published: June 2012

Abstract
Background : The cytologic differentiation between benign and malignant effusions can be difficult. Because promoter hypermethylation of tumor suppressor genes is a frequent epigenetic event in many human cancers, it could serve as a marker for the diagnosis of cancer. The aim of this study was to investigate the feasibility of promoter hypermethylation as a diagnostic tool for the differentiation between malignant and benign effusions in liquid-based cytology samples. Methods : A multiplex, nested, methylation-specific polymerase chain reaction analysis was used to examine promoter methylation of 4 genes (RAR-β, APC, Twist and HIN-1) in malignant (n=85) and benign (n=31) liquid-based cytology samples. Results : The frequencies of hypermethylation of RAR-β, APC, Twist and HIN-1 were significantly higher in malignant effusions than in benign effusions (p&lt;0.001 for each). In receiver-operating characteristic analysis, the area under the curve (AUC) for APC was the highest. The AUC for the best two-gene combination (APC/HIN-1) was not statistically different from the best individual tumor suppressor gene (APC). Conclusions : This study suggests that promoter methylation analysis on residual liquid-based effusion samples may be a feasible approach to detect malignant effusions, and that APC is the best marker for differentiating malignant and benign effusions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4810. doi:10.1158/1538-7445.AM2011-4810
Abstract 4813: Aberrant promoter methylation of TMS1 gene in patients with colorectal carcinoma in Saudi Arabia
Authors: Uddin Shahab , Siraj Abdul K. , Al-Rasheed Maha , Husain Azhar , Bavi Prashant , Al-Sanea Nasser , Abduljabbar Alaa , Homoud Samar Al , Ashari Luai , Dayel Fouad Al , Al-Kuraya Khawla S. 
Published: June 2012

Abstract
Gene silencing associated with aberrant methylation of promoter region CpG islands is an acquired epigenetic alteration. It serves as an alternative to genetic defects in the inactivation of tumor suppressor and other genes in human cancers. Several genes have been shown to be epigenetically inactivated in a wide range of tumors. TMS1 is a tumor suppressor gene which encodes for a CARD (caspase recruitment domain) containing regulatory protein and has been shown to be hyper-methylated in various cancers. Therefore, we studied the methylation status of TMS1 using a panel of colorectal cell lines and 15 CRC cases. Methylation status of the promoter region of TMS1 gene was determined using methylation specific PCR in colorectal cancer cell lines. Seven out of 13 colorectal cell lines showed to be methylated for TMS1 gene (54%). Initial analyses with 15 clinical colorectal cases demonstrated 53% methylation. Real time PCR and western bolt analysis was employed to assess the expression levels. 5-AZA-2′-deoxycytidine was used to demethylate colorectal cancer cell lines. Four out of 7 methylated colorectal cell lines were completely methylated and 3 out of 7 showed partial methylation for TMS1 gene resulting in loss of TMS1 expression. Treating methylated colorectal cell lines with the methyltransferase inhibitor, 5-aza-2’ deoxycytidine alone resulted in partial demethylation and re-expression of TMS1 gene, suggesting the role of methylation in silencing the gene. TMS1 gene has shown tumor suppressive effects after demethylation in thyroid cancer cell. Additionally the oncogenic role of TMS1 has been demonstrated in different cancers. We will further evaluate the role of TMS1 gene after demethylation for apoptosis. After demethylation of TMS1 gene with 5-aza-2’ deoxycytidine we will treat our colorectal cancer cell lines with increasing doses of TRAIL and will evaluate its response by Annexin/PI dual staining and western blot analysis.
Our results demonstrated that TMSI gene is methylated in colorectal cancer cells and repression of methylation by 5-Aza-2′-deoxycytidine restored the expression of TMS1 gene. In conclusion, methylation of TMS1 may prove to be a useful prognostic marker and/or predictor of patient survival in colorectal and can be utilized for targeted therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4813. doi:10.1158/1538-7445.AM2011-4813
Abstract 4826: Identification of low prevalence somatic mutations in heterogeneous tumor samples
Authors: Harismendy Olivier , Kotsopoulos Steve , Bao Lei , Amorese Doug , Stapleton Mark , Olson Jeff , Nakano Masakazu , Cairn Brian , Pond Stephanie , Messer Karen , Chen Pengchin , Sementchenko Victor , Schwab Richard , Chee Mark , Link Darren , Frazer Kelly A. 
Published: June 2012

Abstract
High throughput sequencing enables the digital measurement of each allele in a DNA sample. This provides an ideal method to interrogate mutations present in heterogeneous samples such as solid tumors in which clonal selection or contamination with stroma can hinder the identification of important somatic mutations. We developed an ultra-deep targeted sequencing (UDT-Seq) assay to screen 46 cancer genes via microdroplet PCR (RainDance Technologies) and direct sequencing of the amplicons on the Illumina GA. This UDT-Seq library interrogates ∼86 kb of DNA located in cancer mutational hotspots (87% of all COSMIC mutations) and ∼29 kb located in exons sequenced in HapMap samples for the assay calibration and performance evaluation. We devised a statistical filtering of the mutations by using both experimental estimation and statistical modeling of the sequencing error rate. We measured the performance of our assay by processing 4 blends of 4 HapMap samples, interrogating 160 SNPs with known prevalence in each blend. The sensitivity and specificity of our method is &gt;90% and &gt;99% respectively for variants present at 5% prevalence or greater. We next interrogated 4 cancer samples (xenografts, 2 of which with matching primary samples) from 4 different tissues. We were able to detect low-prevalence somatic mutations in all samples of which some are well-known driver mutations. Interestingly, the mutational profile from primary to xenograft is conserved for one sample but different for another. Finally, we analyzed the robustness of the detection and prevalence measurement after performing whole-genome amplification on DNA extracted from fresh frozen and FFPE tissue using Single Primer Isothermal Amplification technology (SPIA® -NuGEN Technologies). Featuring a streamlined sample preparation to interrogate a large number of bases, this assay is well suited for clinical applications to study clonal selection in cancer progression or treatment with sub-optimal heterogeneous cancer samples.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4826. doi:10.1158/1538-7445.AM2011-4826
Abstract 4827: Loss of 11p in primary breast cancer and brain metastases
Authors: Wikman Harriet Anna-Liisa , Lamszus Katrin , Sielaff-Frimpong Bettina , Wiztel Isabell , Westphal Manfred , Pantel Klaus 
Published: June 2012

Abstract
Metastatic breast cancer remains essentially incurable, with mortality being especially high in patients who develop brain metastases. Approximately 15% of all epithelial tumors metastasize to the brain, with incidence rates highly dependent on the primary tumor type. Apparently, the brain microenvironment is specifically permissive for the out-growth of tumor cells from some carcinomas but not others.
In a previous study we screened by array CGH primary breast tumors and brain metastases. A 10MBp loss at 11pter-p15.4 was found in 70 % of the brain metastases whereas only 15% of the early stage primary tumors showed loss of 11p. In this study the aberration pattern of 11p was verified by microsatellite analysis in primary breast tumors and brain metastases. Six markers with an average spacing of 2 MBp were analyzed at 11p15.5-p15.4. Allelic imbalance (AI) at 11p was found in 26% (11/42) of the primary tumors whereas 71.4% (15/21) of brain metastases showed AI (p=0.001). In primary tumors the occurrence of AI was associated with high grade (p=0.03) and positive lymph node status (p=0.02). Interestingly, primary tumors with a brain relapse showed an equally high AI rate (75%) as the brain metastases (71%) in contrast to primary tumors without a relapse (26%). Furthermore, two matched pairs of primary tumors and brain metastases showed equal aberrations patterns and the third matched pair showed an enlarged AI of 11p, indicating that loss of 11p is defining a specific subgroup of breast cancer patients with a high risk of brain relapse.
In summary, these results indicate an accumulation of chromosomal imbalances during the carcinoma-metastasis sequence and the possible involvement of loss of 11p in brain metastasis formation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4827. doi:10.1158/1538-7445.AM2011-4827