bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4816: Overexpression of thymosin β10 gene is not mediated by DNA methylation in non-small cell lung cancer
Authors: Lee Su Man , Lee Ji Yun , Kim Mi Jin , Yoon Ghil Suk , Park Jae Yong , Kim Dong Sun 
Published: June 2012

Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide and is usually associated with a late diagnosis and a poor prognosis. Thymosin β10 (TMSB10) is monomeric actin sequestering protein to regulate actin cytoskeleton organization. The aberrant TMSB10 expression has been implicated in the pathogenesis of human cancers. However, its role in carcinogenesis is still controversial. To better understand the role of TMSB10 in lung tumorigenesis and its regulatory mechanism, we have examined the methylation status and expression of the TMSB10 gene in non-small cell lung cancers (NSCLCs) using methylation-specific PCR (MSP) and immunohistochemistry (IHC), respectively. MSP analysis showed that TMSB10 promoter was almost unmethylated in tumor tissues and became to be hypomethylated in 7 out of 139 (5.0%) NSCLCs. However, there is no significant association of TB10 demethylation with clinicopathologic features. IHC showed that TMSB10 protein was strongly expressed in the cytoplasm of malignant cells and its overexpression was detected in 15 of 30 (50.0%) the tumor tissues compared to normal tissues. Moreover, TMSB10 overexpression was frequently observed in sqaumous cell carcinomas compared to adenocarcinomas with border line significance (P = 0.072), but its overexpression was not associated with the methylation status of TMSB10 gene. Collectively, these results suggest that TMSB10 overexpression may be a frequent event in the progression of NSCLC, but DNA methylation may not involve in TMSB10 overexpression. However, further studies with a large number of cases are needed to confirm our findings.
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 4816. doi:10.1158/1538-7445.AM2011-4816
Abstract 4819: Wolf-Hirschhorn syndrome candidate 1, a histone lysine methyltransferase, is involved in human carcinogenesis
Authors: Hamamoto Ryuji , Yoshimatsu Masanori , Toyokawa Gouji , Cho Hyun-Soo , Nakamura Yusuke 
Published: June 2012

Abstract
A number of histone methyltransferases have been identified and biochemically characterized, but the pathological roles of their dysfunction in human diseases like cancer are not well understood. Here, we demonstrate that Wolf-Hirschhorn syndrome candidate 1 (WHSC1) plays an important role in human carcinogenesis. Transcriptional levels of this gene are significantly elevated in various types of cancer including bladder and lung cancers. Immunohistochemical analysis using a number of clinical tissues confirmed significant up-regulation of WHSC1 expression in bladder and lung cancer cells at the protein level. Treatment of cancer cell lines with small interfering RNAs targeting WHSC1 significantly knocked down its expression and resulted in the suppression of proliferation. Moreover, knockdown of WHSC1 decreased the cell population of cancer cells at S phase and increased that at G2/M phase through the regulation of genes involved in the Wnt signaling pathway. Furthermore, we found WHSC1 to be interacted with some proteins related to the Wnt pathway including β-catenin. As expression levels of WHSC1 are significantly low in normal tissues, it may be feasible to develop the inhibitors targeting these enzymes as anti-tumor agents which have a minimal risk of adverse reaction.
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 4819. doi:10.1158/1538-7445.AM2011-4819
Abstract 4820: Whole methylome explorations of paired tumor and non-tumor clinical samples using HELP
Authors: Mullapudi Nandita , Shi Miao , Suzuki Masako , Spivack Simon 
Published: June 2012

Abstract
Introduction: Gene silencing by promoter methylation is common in carcinogenesis. In lung cancer, hypermethylation of specific gene promoters has been found to occur during the earliest histologic stages of the cancer. Thus far surveys of methylation in lung tumors have focused on specific gene panels (5 – 10 genes). A few large scale studies have reported selection of longer gene lists or focused on larger sets of CpG islands.
Methods: We have adapted an approach to survey genome-wide methylation events in tumor and adjacent non-tumor tissue from clinical lung resection samples using the HELP (HpaII tiny fragment Enrichment by Ligation mediated PCR) assay. This assay, based on the generation of restriction enzyme libraries generated by methylation sensitive (HpaII) and methylation insensitive (MspI) isoschizomers yields information on 1.2 million HpaII fragments throughout the genome. Each HpaII fragment corresponds to two CpG sites. The assay lends itself to low starting amounts of DNA (3 ug) and robust assessment of methylation status by comparing ratios of HpaII- generated- fragments to MspI- generated fragments co-hybridized to a Nimbelgen custom high-density microarray.
Summary of results: In a pilot set of three paired tumor and non-tumor tissue samples, we identified 1504 fragments (corresponding to two CpG sites each) that were hypermethylated in tumor versus non-tumor in all three pairs. Of these, 165 fragments were located within gene promoters. In the opposite direction, 2907 fragments were found to be hypermethylated in non-tumor versus tumor. Of these, 81 were located within gene promoters. We could identify both known and novel regions of the genome as well as specific gene-promoters that are hypermethylated in tumor versus non-tumor. We will discuss selected methylation events in further detail.
Conclusion: The HELP assay is a powerful approach to interrogate methylation status of individual HpaII fragments across the whole genome, offering a large sample size of 1.2 million HpaII fragments. We are able to discover individual methylation events common across different clinical specimens and are currently expanding our sample set, and planning correlations with transcriptome-wide studies.
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 4820. doi:10.1158/1538-7445.AM2011-4820
Abstract 4823: Single cell analysis of head and neck squamous cell carcinoma cells isolated from primary tumors and matched metastases
Authors: Sproll Karl C. , Behrens Bianca , Hollinger Andrea , Baldus Stephan E. , Kübler Norbert R. , Knoefel Wolfram T. , Brakenhoff Ruud H. , Stoecklein Nikolas H. 
Published: June 2012

Abstract
Background: Genetic heterogeneity is a hallmark of cancer and significant evolution occurs locally and at metastatic sites with disease progression. This heterogeneity might contribute significantly to therapy resistance. Since systematic in depth analyses are lacking in head and neck squamous cell carcinomas (HNSCC), we established and tested a protocol that enables comprehensive single cell analyses of cancer cells from primary tumors and metastasis.
Material and Methods: From matched primary tumors and lymph node metastases of two HNSCC patients, single cell suspensions were generated and sedimented on positively charged glass slides at low density. Epithelial tumor cells were identified with double-immunofluorescence staining for CD44v6 and CK5/14. Twelve to 14 double-positive cells were isolated via micromanipulation from each tumor and an adapter-linker PCR was used for whole genome amplification of single cells. Sequencing of TP53 was performed on genomic DNA from primary tumors as well on single cell amplification products. An allele-drop-out experiment was performed to control for artificial allelic loss. Fluorescence-in-situ-hybridization (FISH) was used to determine the copy number of chromosome 17 and TP53-gene loci, respectively.
Results: Two different heterozygous TP53 mutations were detected in both cases. On the single cell level, we observed an unexpected variation of wild-types, heterozygous mutations and homozygous mutations on the investigated mutation sites. This mutational distribution was significantly different from the allele-drop-out experiment (drop-out rate: 8%). In one we found an expansion of mutated clones in metastasis, and in the other patient a transmission of the genetic changes between the primary tumor and the lymph node metastasis. Interestingly, our preliminary data indicate a polyclonal origin of the metastasis. Conclusion: Our protocol is feasible to study comprehensively genetic heterogeneity between primary tumors and metastases on a single-cell level. The single cell amplification products tested for TP53 mutations can be used for several other genetic studies, including genome-wide methods such as CGH. Our initial data revealed an unexpected intratumoral genetic heterogeneity in primaries and metastases of HNSCC.
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 4823. doi:10.1158/1538-7445.AM2011-4823
Abstract 483: CXCR6, a newly defined biomarker of tissue-specific stem cell asymmetric self-renewal, identifies more aggressive human melanoma cancer stem cells
Authors: Taghizadeh Rouzbeth , Noh Minsoo , Huh Yang Hoon , Arosio Beatrice , Sherley James , LaPorta Caterina AM 
Published: June 2012

Abstract
Background- A fundamental problem in cancer research is identifying the cell type that is capable of sustaining neoplastic growth and its origin from normal tissue cells. Recent investigations of a variety of tumor types have shown that phenotypically identifiable and isolable subfractions of cells possess the tumor-forming ability. In the present paper, using two lineage-related human melanoma cell lines, primary melanoma line IGR39 and its metastatic derivative line IGR37, two main contributes are reported. The first one is the first phenotypic evidence to support the origin of melanoma CSCs from mutated tissue-specific stem cells and the second one is the identification of a more aggressive subpopulation CXCR6+ in melanoma.
Methods/Findings- We defined CXCR6 as a new biomarker for tissue-specific stem cell asymmetric self-renewal. Thus, the relationship between melanoma formation and ABCG2 and CXCR6 expression was investigated. Consistent with their non-metastatic character, unsorted IGR39 cells formed significantly smaller tumors than unsorted IGR37 cells. In addition, ABCG2+ tumors gave a 2-fold greater mass than tumors from unsorted cells or ABCG2- cells. Furthermore, CXCR6+ cells produced more aggressive tumors. These findings show that CXCR6 identifies a more discrete subpopulation of cultured human melanoma cells with a more aggressive melanoma cancer stem cell phenotype than cells selected on the basis of ABCG2, and CXCR6+/ABCG2+ expression.
Conclusions/Significance- The association of more aggressive tumor phenotype with asymmetric self-renewal phenotype reveals a previously unrecognized aspect of tumor cell physiology. Namely, the retention of some tissue-specific stem cell attributes, like the ability to preserve self-phenotype, impacts the natural history of human tumor development. Knowledge of this new aspect of tumor progression may provide new targets for cancer prevention and treatment.
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 483. doi:10.1158/1538-7445.AM2011-483
Abstract 4833: A genomic portrait of tumor progression using next-generation sequencing
Authors: Johansson Peter , Wei Jun S. , Chen Qingrong , Bowden Nikola , Badgett Tom C. , Song Young K. , Wen Xinyu , Holman Catherine , Yeh Susan , Khan Javed 
Published: June 2012

Abstract
Genetic alterations are thought to enable cancers to proliferate and survive more effectively or to resist cytotoxic therapies. However, the molecular basis of tumorigenesis and progression is not fully understood. In order to understand the genetic aberrations underlying tumor progression in refractory neuroblastoma, we performed next-generation sequencing on the whole exomes of three sequential tumor samples taken from a high-risk stage 4 neuroblastoma patient at diagnosis, after cytotoxic therapies, and at death, paired with a germline DNA sample from the same patient. Each genomic DNA sample was first partitioned using SureSelect whole human exome kits targeting ∼38Mb of genomic regions, then subjected to sequencing. Each exome sequencing experiment yielded approximately 240 million mappable reads representing 12 billion base pairs. We used DiBayes to identify single nucleotide variants (SNVs). After filtering away the low-quality SNVs, we identified approximately 18,000 high-quality SNVs in each sample, of which ∼7500 are within the protein coding regions. Using the frequencies of the SNVs derived from the sequencing experiments, we discovered a shared LOH signature at the chromosome level among all three tumors indicating they originate from a common cancer progenitor. When we examined the germline DNA, we found about 97% of SNVs for each tumor sample were also found in the germline DNA, and each tumor had more than 300 unique somatic SNVs. These data showed that despite of the shared LOH pattern, tumor genomes are highly unstable at the single nucleotide level. Furthermore, we also found that the three tumor samples shared 64 SNVs which may be potential driver mutations. Twenty of those common 64 SNVs, located on 7 genes, are predicted to be damaging mutations by SIFT algorithm. These mutations are currently being validated using Sanger sequencing, and further RNA-seq in the same tumor samples to investigate for pathway disruption that may lead to chemo-refractory disease.
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 4833. doi:10.1158/1538-7445.AM2011-4833
Abstract 4835: Gonosome-linked expression of PPP2R3B in cutaneous melanoma correlates with distant metastasis free survival
Authors: Spatz Alan , van Kempen Leon C. , Job Bastien , Richon Catherine , Barrois Michiel , Dessen Philipe , Lazar Vladimir , Michiels Stefan , Helbling-Leclerc Anne , Dumay Anne , Petrella Teresa , Batist Gerald , Stas Marguerite , Schadendorf Dirk , van den Oord Joost , Feunteun Jean 
Published: June 2012

Abstract
Background: A strong adverse male effect for melanoma incidence and survival has been reported. No biological explanation, including hormonal differences, has been identified so far. We hypothesize that this gender difference in incidence and survival involves X-linked tumor suppressor genes and/or oncogenes whose expression is affected by X-chromosome alterations.
Methods: DNA and RNA were extracted from 49 fresh frozen primary melanomas (32 females, 17 males, distant metastasis free survival (DMFS) &lt;3 years or follow up &gt;3 years) and subjected to array-based comparative genomic hybridization. Supervised and unsupervised cluster analyses were performed. X-inactivation was studied by Xist RNA in situ hybridization and androgen receptor methylation-sensitive PCR. The expression of a candidate X-linked gene was analyzed by quantitative PCR and correlated with DMFS in uni- and multivariate analyses.
Results: Supervised cluster analyses revealed distinct DNA signatures associated with clinical and histopathological characteristics. Unsupervised clustering identified three groups of which one was composed of predominantly female patients (10/13) and associated with the worst DMFS. This group was characterized by loss of one X-chromosome in 7 of the 13 patients. Loss of X correlated with poor DMFS of female patients (logrank p=0.009). Intriguingly, the lost X chromosome was systematically the inactivated copy. Among the 17 males, Y-chromosome loss correlated with DMFS (logrank p=0.015). We found that the PPP2R3B gene, located within one of the pseudoautosomal regions and thus not inactivated on the inactive X in females, is lost from the Y in males. PPP2R3B encodes a regulatory subunit of protein phosphatase 2 that may negatively control cell proliferation via targets such as CDC6 or RB. Quantitative analysis of PPP2R3B mRNA expression in an independent sample set of melanomas revealed a strong correlation between decreased levels of PPP2R3B expression and poor DMFS irrespective of gender in multivariate analysis (p=0.0007).
Conclusion: Our analyses reveal a specific pattern of X and Y chromosome losses that are associated with melanoma progression. PPP2R3B is a potential gonosome-linked tumor suppressor gene, whose loss of expression correlates with poor DMFS.
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 4835. doi:10.1158/1538-7445.AM2011-4835
Abstract 484: Persistent activation of mesenchymal stromal cells (MSCs) and tissue repair in the etiology of desmoid tumors (DT)
Authors: Carothers Adelaide M. , Rizvi Hira , Heit Yvonne , Hasson Rian M. , Davids Jennifer , Bertagnolli Monica M. , Cho Nancy L. 
Published: June 2012

Abstract
Mesenchymal stromal cells (MSCs) are multipotent cells that can be isolated from various adult tissues and are implicated in a growing list of sarcomas. Desmoid tumors (DTs) have a clonal origin, are linked with wound healing, and mostly arise in the abdomen of patients with familial adenomatous polyposis (FAP) or sporadically. MSCs home to sites of tissue damage and the persistent activation of these cells in a wound healing context combined with deregulated Wnt signaling may lead to neoplasia. To test this idea, we performed immunohistochemistry on 17 sporadic and FAP-associated DTs from different individuals for the expression of multiple MSC markers (CD73, CD90, and Bmi1). While present in differing numbers, all specimens showed positive cells for all markers, and immunofluorescence (IF) showed co-localization of these markers and CD105 in cells within tumors. Matching adjacent normal fascia from a subset was negative for these antigens. A FAP DT-derived cell line was then made that also co-expressed these MSC markers but not CD34, a negative marker. Fluorescence-activated cell sorting analysis of surface antigen profiles confirmed that &gt;90% of the cell population bore MSC positive, but not negative, markers. Although not genotyped, IF for the C- vs. N-termini of APC confirmed that only truncated APC product was expressed in our DT-derived MSC line. Upon growth for 5-6 weeks in differentiation medium, we confirmed by co-expression of CTGF and Sox9 (obligate chondrocyte markers) plus Alcian blue staining, PPARγ and c/EBPα (obligate adipocyte markers) plus Oil Red staining, and OPN and Runx2 (obligate osteocyte markers) plus von Kossa staining that the DT-derived MSCs were tripotent. In conclusion, this study supports the view that DT etiology involves the persistence of MSCs with deregulated Wnt signaling. The differentiation potential of these cells combined with expression of Bmi1, a transcriptional repressor downstream of Hedgehog and Notch signaling, suggest that inhibitors targeting these pathways may provide a rational systemic therapy to prevent primary or recurrent DT in high-risk 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 484. doi:10.1158/1538-7445.AM2011-484
Abstract 4844: Genomics aberrations and BRCA1 silencing in hereditary triple negative breast tumors in Chilean women
Authors: Tapia Teresa , Sanchez Alejandro , Alvarez Carolina , Cornejo Valeria , Fernandez Wanda , Alvarez Manuel , Camus Mauricio , Carvallo Pilar 
Published: June 2012

Abstract
Breast cancer is one of the most common cancers in women worldwide and the second cause of death by cancer among women in Chile. Either sporadic or hereditary breast cancers show a wide variety of tumor phenotypes, leading to individual clinic responses to specific treatments. Among breast cancer tumors, a group named as triple negative breast cancer (TNBC) does not express hormone receptors and HER2 (ER-, PR-, HER2-). For these tumors no specific treatment complementing chemotherapy has been developed yet. Therefore the study of the genes involved in the progression of TNBC tumor may provide a rationale for the future exploration of therapeutic strategies. TNBC is frequently observed in women carrying a germline mutation in the BRCA1 gene and in approximately 30% of non-carrier women with loss of expression of BRCA1 protein. Our aim, is to identify common genomic aberrations among TNBC tumors and to evaluate BRCA1 silencing by hypermethylation of its promoter in TNBC tumors. It has been described that about 80-90% of TNBC tumors belong to the basal-like molecular subtype, constituting a biological and clinical distinct subgroup. To determine the basal-like subtype we evaluated the expression of Cytokeratin 14 (CK14) marker in 22 hereditary TNBC. Our results revealed that a 63% (14/22) of the tumors express CK14, suggesting that these tumors belong to the basal-like subtype. Additionally, we analyzed the methylation status of the BRCA1 promoter and its correspondent protein expression in the tumors. A 77% (17/22) of the tumors had BRCA1 promoter hypermethylation. Of all tumors 32% (7/22) had absent or reduced nuclear expression of BRCA1. Interestingly, we found 54% (12/22) of the TNBC tumors with a cytoplasmic expression of BRCA1. Finally, we also analyzed through array-CGH, 19 hereditary TNBC tumors to identify common genomic aberrations between these tumors. The array-CGH analysis revealed the gain of the genomic regions 7q34, 15q26.1 and 16p13.3 and the deletion of the regions 1q21.1, 9q33.3, 18q22.1-q22.3 and 19q13.41 in more than 30% of the TNBC tumors. In conclusion, we found that 71% of tumors expressing CK14 have absent or reduced expression of the BRCA1. On the other hand, 61% of tumors with promoter hypermethylation of BRCA1 have loss expression of its protein. Interestingly, the region deleted 1q21.1 was found in 94% of the hereditary TNBC tumors. Financed by FONDECYT 1080595 and CONICYT 24091058.
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 4844. doi:10.1158/1538-7445.AM2011-4844