bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1496: MicroRNA signature associated with poor outcome of glioblastoma patients
Authors: Sana Jiri , Lakomy Radek , Fadrus Pavel , Smrcka Martin , Slampa Pavel , Kren Leos , Hermanova Marketa , Svoboda Marek , Slaby Ondrej 
Published: May 2015

Abstract
Background: Glioblastoma multiforme (GBM) is the most frequently occurring primary malignant brain tumor with very poor prognosis, varying therapeutic response. Therefore, it is very important to find new biomarkers which can predict a clinical outcomes and help in treatment decisions. MicroRNAs (miRNAs) are small, non-coding RNAs that function as post-transcriptional regulators of gene expression and play key role in pathogenesis of wide range of cancer, including GBM. Aim of our study is to identify miRNA signature associated with the more aggressive phenotype of GBMs, which will enable sensitive prediction of clinical outcome in GBM patients under standard therapeutic protocols.
Methods: We determined the expression profile of 667 miRNAs in tumor tissues of 58 patients with primary GBM with completed concomitant chemoradiotherapy with temozolomide according to standard Stupp protocol and 12 non-malignant brain tissues obtained from patients with drug-resistant anteromedial temporal lobe epilepsy. Methylation status of MGMT promoter (methylation-specific HRM), isocitrate dehydrogenase (IDH1) status (immunohistochemistry) and co-deletion of 1p/19q (FISH) was also evaluated.
Results: We have confirmed frequencies of commonly used prognostic biomarkers in GBM patients (MGMT, IDH1, 1p/19q deletion), and observed significant correlation of MGMT methylation status, response to chemoradiotherapy with temozolomide and survival of GBM patients. We have identified specific signature of miRNAs diferentially expressed between GBM tissue and non-tumoral brain tissue from epilepsy surgeries (28 miRNAs, p&lt;10-10). We have confirmed some previous observations (e.g. up-regulation of miR-21, miR-155, down-regulation of miR-128a, miR-23a) and also identified miRNAs deregulated in GBM tissue which were observed for the first time (e.g. miR-220, miR-328, miR-888, miR-504). More importantly we have found miRNA signature (miR-224, miR-31, miR-454, miR-672, miR-885-5p, miR-432) significantly associated short progression-free survival (p&lt;10-6) and overall survival (p&lt;10-6).
Conclusions: These findings indicate that miRNAs play an important role in GBM pathogenesis and may serve not only as promising predictors of therapeutic outcome but also as potential therapeutic targets in GBM patients.
This work was supported by Grant NT13549-4/2012, NT13860 4/2012, NT11214-4/2010 and NT13514-4/2012 of the Czech Ministry of Health, MH CZ - DRO (MMCI, 00209805).
Citation Format: Jiri Sana, Radek Lakomy, Pavel Fadrus, Martin Smrcka, Pavel Slampa, Leos Kren, Marketa Hermanova, Marek Svoboda, Ondrej Slaby. MicroRNA signature associated with poor outcome of glioblastoma patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1496. doi:10.1158/1538-7445.AM2014-1496
Abstract 1503: Rapid detection of somatic mutations in cancer genes
Authors: Powell Michael J. , Pastor Larry , Diaz Rachel , Chen Lily , Wu George , Li Claudia , Zhang Aiguo 
Published: May 2015

Abstract
In the context of personalized cancer treatment, tumor mutational analysis by DNA sequencing has been described frequently as the “gold standard”, yet DNA sequencing is one of the least sensitive methods for characterizing mutation. At least 10-20% of a DNA population must be mutant for the mutation to be detected by standard DNA sequencing. Implicit acceptance that this level of sensitivity is sufficient to characterize tumor mutations only makes sense if one assumes that tumors are monoclonal and that all the critical driver mutations will be present in the bulk of the tumor. Yet these are incorrect assumptions. In fact, it has become clear that most if not all colon tumors are polyclonal and heterogeneous. Consequently, tumor driver mutations may not be detectable using standard DNA sequencing methods. In order to rapidly detect these low frequency mutations in tumor derived DNA we have developed a new technology that allows the detection of tumor driver and drug resistance somatic mutations at &lt;0.1% sensitivity using quantitative PCR (qPCR) without the need for digital PCR or droplet digital PCR (ddPCR) methodology. We utilize xeno-nucleic acid (XNA) clamping probes that are specific for the target gene wild-type template and allow only the selective amplification of mismatched mutant templates. Direct detection of driver and drug resistance mutations within 2 hours of obtaining samples in KRAS, NRAS, BRAF, EGFR and JAK2 utilizing real-time qPCR with interchelating fluorescence dye detection. As well as a new end-point post-PCR microtiterplate based target gene mutant amplicon capture format that utilizes colorimetric or chemiluminescence detection will be described.
Citation Format: Michael J. Powell, Larry Pastor, Rachel Diaz, Lily Chen, George Wu, Claudia Li, Aiguo Zhang. Rapid detection of somatic mutations in cancer genes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1503. doi:10.1158/1538-7445.AM2014-1503
Abstract 1517: Detection of SMAD4, MAP2K4, RB1 and CDKN2A gene deletions in human tumor cells by multiplex qPCR
Authors: Woo Cora , Wilde Joyce , Patel Sunali 
Published: May 2015

Abstract
Gene duplications and deletions are critical to understanding cancer biology. Deletion in SMAD4, MAP2K4, RB1 and CDKN2A genes are known to play important roles in certain types of cancer or cancer states. Characterization of such mutations in different tumor cells provide insight into the study of novel biomarkers of cancer susceptibility, initiation, progression and metastases and help identify them as risk factors for various types of cancer. We demonstrated a quantitative method to detect multiple gene deletions in human tumor cells by multiplex PCR. We designed four TaqMan® Copy Number Assays to interrogate common deletion mutations in SMAD4, MAP2K4, RB1 and CDKN2A genes and performed multiplex PCR alongside with endogenous controls on representative human tumor and normal cells in different tissues. Since the detection of multiple deletion targets were performed in one single reaction, we were able to profile multiple deletion mutations in one single sample. This method can potentially be applied to the study of Copy Number Variations (CNV) on biological samples with limited quantity such as FFPE samples, as well as enables the characterization of multiple targets on samples in exactly the same condition and state.
Citation Format: Cora Woo, Joyce Wilde, Sunali Patel. Detection of SMAD4, MAP2K4, RB1 and CDKN2A gene deletions in human tumor cells by multiplex qPCR. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1517. doi:10.1158/1538-7445.AM2014-1517
Abstract 1526: Integrative and comparative genomic analysis of East-Asian lung squamous cell carcinomas
Authors: Kim Youngwook , Hammerman Peter S. , Kim Jaegil , Getz Gad , Meyerson Matthew , Park Keunchil 
Published: May 2015

Abstract
Purpose
Lung squamous cell carcinoma (SqCC) is the second most prevalent type of lung cancer. Currently, no targeted-therapeutics are approved for treatment of this cancer, largely due to a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SqCC, we probed somatic genome alterations of lung SqCC cases from Korean patients.
Patients and Methods
We performed whole-exome sequencing of DNA from 104 lung SqCC samples from Korean patients and matched normal DNA. In addition, copy number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated.
Results
This cancer cohort is characterized by a very high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of cigarette-smoke exposure. Seven genes demonstrated statistical enrichment for mutation (TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2 and PIK3CA). Comparative analysis between Korean and North American lung SqCC demonstrated similar spectrum of alterations in these two populations, in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SqCC.
Conclusion
These findings provide new steps towards the identification of genomic target candidates for precision medicine in lung SqCC, a disease with a significant unmet medical need.
Note: This abstract was not presented at the meeting.
Citation Format: Youngwook Kim, Peter S. Hammerman, Jaegil Kim, Gad Getz, Matthew Meyerson, Keunchil Park. Integrative and comparative genomic analysis of East-Asian lung squamous cell carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1526. doi:10.1158/1538-7445.AM2014-1526
Abstract 1547: Identification of somatic mutations and copy number alterations in metastatic high-grade ovarian cancer
Authors: Lee Jung-Yun , Yoon Jung-Ki , Bang Duhee , Song Yong-Sang 
Published: May 2015

Abstract
Background: The extent to which metastatic tumors further evolve by accumulating additional mutations is unclear and has yet to be systematically addressed using next-generation sequencing in high-grade serous ovarian cancer.
Methods: During cytoreductive surgery prior to chemotherapy, 11 spatially separated tumor samples from primary tumor and associated metastatic sites with 2 normal samples were obtained. Whole exome sequencing and copy number analysis were performed and multiplex PCR followed by ultra-deep resequencing was used for validation. Especially, omental samples were sequenced with high depth of coverage (∼200x).Phylogenetic tree was built to explore the evolutionary relationship between samples.
Results: Only 6% of all somatic mutations were present in every sample of a given case with TP53 gene as the only known mutant gene consistently present in all samples. Two non-spatial clusters of primary samples (cluster 1 and 2), and a cluster of metastatic samples (cluster M) were identified. The patterns of mutations indicate that cluster M was originated from cluster 1, and that cluster 2 was diverged from a portion of right fimbriae in cluster 1 at the early phase of tumorigenesis. No significant metastatic sample-specific mutations or copy number changes were detected.
Conclusion: Our results showed that high level of intratumor heterogeneity was evident in a high-grade serous ovarian cancer. Moreover, we showed that transcoelomic metastasis arises with little accumulation of somatic mutations or copy number alterations.
Citation Format: Jung-Yun Lee, Jung-Ki Yoon, Duhee Bang, Yong-Sang Song. Identification of somatic mutations and copy number alterations in metastatic high-grade ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1547. doi:10.1158/1538-7445.AM2014-1547
Abstract 1550: Differential angiogenic roles of serum amyloid A 1 (SAA1) isoforms in esophageal squamous cell carcinoma (ESCC)
Authors: MAN ON YING , Lung Maria , Lung Hong Lok 
Published: May 2015

Abstract
Esophageal Caner (EC), a highly metastatic and fatal cancer, is ranked the eighth in mortality rate in Hong Kong cancer patients (Hong Kong Cancer Registry, Hospital Authority, 2010). Esophageal Squamous Cell Carcinoma (ESCC) is the predominant type comprising more than 90% of EC. Using a functional complementation approach, SAA1 was identified as one of the tumor suppressor gene candidates. SAA1 is located at chromosome 11p15.1 and is expressed as a secretary protein in liver, human cultured smooth muscle cells, monocyte-macrophage cell lines, and in histologically-normal human epithelial tissues. Genetic polymorphisms of SAA1 have been identified as a risk factor of diseases such as amyloidosis. Three SAA1 isoforms with two single nucleotide polymorphisms at exon three (SAA1.1, 1.3, and 1.5) were observed in the ESCC patients and healthy individuals.
The SAA proteins contain the functional YIGSR-like and RGD-like motifs, proteins with these motifs can inhibit angiogenesis, cell adhesion to ECM, growth and metastasis. To understand the anti-tumorigenic and anti-angiogenic roles of the three SAA1 isoforms in ESCC progression, both recombinant proteins and secreted proteins from the conditioned media of lentiviral-infected ESCC cell lines were used for functional assays. For the vascular endothelial cell tube formation assay, the treatments with SAA1.1 and 1.3 proteins showed suppression of tube formation, whereas no significant effects could be observed in the treatment with the SAA1.5. Suppression of cell proliferation and induction of cell death were observed when the endothelial cells were cultured with SAA1.1 and 1.3 proteins. To further elucidate the differential effects among the three SAA1 isoforms in anti-angiogenesis, the cytoskeleton arrangement of the vascular endothelial cells was studied. The SAA1.1 and SAA1.3 proteins could abolish the endothelial cell adhesion by disturbing the formation of stress fibers and focal adhesions. As a conclusion, the present data has shown the variation in anti-angiogenic potential of the three SAA1 isoforms.
We acknowledge the financial support of the Food and Health Bureau of the Hong Kong Special Administration Region, China, grant number HMRF 01120886 to HLL.
Citation Format: ON YING MAN, Maria Lung, Hong Lok Lung. Differential angiogenic roles of serum amyloid A 1 (SAA1) isoforms in esophageal squamous cell carcinoma (ESCC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1550. doi:10.1158/1538-7445.AM2014-1550
Abstract 1551: p53 mutant regulates a network of cellular anoikis through activation of AKT and suppression of BMF
Authors: Tan Boon Shing , Tiong Kai Hung , Yap Ivan Kok Seng , Rosli Rozita , Cheong Soon-Keng , Leong Chee-Onn 
Published: May 2015

Abstract
p53 is the most frequently mutated tumor suppressor gene in human cancers. Unlike other tumor-suppressor genes, p53 mutations mainly occur as missense mutations within the DNA-binding domain, leading to the expression of full-length mutant p53 protein. Mutant p53 proteins not only lose their tumor suppressor function, but may also gain new oncogenic function and promote tumorigenesis through transactivation of new target genes. By using an RNA interference (RNAi) approach, we show that silencing of endogenous p53 R273H contact mutant in MDA-MB-468 cells induced massive apoptosis while no apoptosis was observed in the silencing of the p53 R175H structural mutant in SKBR3 cells. Further analysis shows that the apoptotic effects of mutant p53 knock-down involved activation of caspase-9 and mitochondria depolarisation, suggesting a role for mutant p53 in suppressing the intrinsic apoptotic pathway. Indeed, a BCL-2 family member, BCL-2 modifying factor (BMF), was reproducibly up-regulated following knock-down of mutant p53 in MDA-MB-468 cells while no significant changes was observed in other BCL2 family members. Furthermore, we show that p53 R273H contact mutant, but not p53 R175H conformation mutant, suppressed anoikis by down-regulation of BMF expression. Anoikis is a form of apoptosis induced by cell detachment and is a major mechanism to prevent metastasis. Further analyses using microarray gene profiling and connectivity map analysis show that silencing of mutant p53 in MDA-MB-468 cells generates gene expression signatures characteristic of PI3K inhibitors, suggesting that apoptotic effects of mutant p53 knock-down involved dephosphorylation of AKT, a direct substrate of PI3K. Ectopic expression of the activated form of AKT in MDA-MB-468 completely abrogated the apoptotic effects of mutant p53 knock-down. In summary, our results demonstrate that R273H mutant p53 promotes anoikis resistance in breast cancer cells that express it through suppression of BMF expression by the constitutively activated AKT pathway.
Citation Format: Boon Shing Tan, Kai Hung Tiong, Ivan Kok Seng Yap, Rozita Rosli, Soon-Keng Cheong, Chee-Onn Leong. p53 mutant regulates a network of cellular anoikis through activation of AKT and suppression of BMF. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1551. doi:10.1158/1538-7445.AM2014-1551
Abstract 1554: Identification of BRCA1 and BRCA2 somatic mutations in breast cancer tumors with loss of BRCA1 nuclear expression
Authors: Alvarez Carolina , Wiener David , Gajardo Patricia , Fernandez Wanda , Cornejo Valeria , Gamboa Jorge , Carvallo Pilar 
Published: May 2015

Abstract
Breast cancer is the first cause of death by cancer in women in Chile as in many countries around the world. Until today, BRCA1 and BRCA2 are the most relevant genes for breast cancer high risk. Moreover, different studies have shown that BRCA1 is under expressed in breast tumors. Our group has found that in a high percentage of hereditary tumors BRCA1 protein have a diminished or null expression, or is mislocalized to the cytoplasm (unpublished data). In this regard, it has become a goal for us to identify if mislocalization and/or loss of expression of BRCA1 and BRCA2 could be related to somatic mutations in the tumors. In this work, we sequenced BRCA1 and BRCA2 in DNA extracted from 14 fresh/frozen tumors. DNA was isolated from each tumor and amplified by PCR in 5 multiplexes (a total of 93 amplicons) considering all exons and intron/exon junctions with approximately 30bp of intronic sequence each side. Multiplexes were then pooled for each patient and processed for sequencing in the GS Junior Roche. All reads were processed with AVA software to detect nucleotide changes in BRCA1 and BRCA2 sequences and analyzed manually to discard misinterpretations. All mutations identified were confirmed by Sanger. From the same tumors we obtained a second section that was formalin fixed and paraffin embedded. This FFPE fragment was cut in 4 μm sections and analyzed by immunohistochemistry and immunofluorescence to assess BRCA1 expression and localization. We found a total of 5 mutations, 3 in BRCA1 and 2 in BRCA2, in 6 tumors. Interestingly, one BRCA1 mutation present in 7 to 20% of reads, was found in 5 tumors. Among those, two tumors presented two different mutations in BRCA2, in addition. The last tumor presented one extra mutation in BRCA1. BRCA1 expression analysis was coherent between immunohistochemistry and immunofluorescence assays. In general 9 tumors showed weak or negative BRCA1 nuclear expression and 5 mainly moderate nuclear staining. In addition 6 tumors presented moderate to strong cytoplasmic expression of the protein, considered abnormal. Considering tumors with weak or negative expression of BRCA1, 40% presents BRCA1 or BRCA2 mutations. The relevance of the absence of BRCA1 expression, or function impairment of BRCA1 and/or BRCA2 due to somatic mutations, relays on the possible treatment with PARP1 inhibitors. Supported by FONDECYT 1120200.
Citation Format: Carolina Alvarez, David Wiener, Patricia Gajardo, Wanda Fernandez, Valeria Cornejo, Jorge Gamboa, Pilar Carvallo. Identification of BRCA1 and BRCA2 somatic mutations in breast cancer tumors with loss of BRCA1 nuclear expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1554. doi:10.1158/1538-7445.AM2014-1554
Abstract 1555: TP53 oncomorphic mutations are associated with resistance to platinum- and taxol-based standard chemotherapy in advanced serous ovarian cancer patients
Authors: Brachova Pavla , Dai Donghai , Carlson Mathew , Goodheart Michael , Thiel Kristina , Devor Eric , Leslie Kimberly 
Published: May 2015

Abstract
Mutations in the tumor suppressor gene TP53 abrogate the tumor suppressive functions of the p53 protein, and some mutations endow the mutant protein with oncogenic activity. These specific mutations we term oncomorphic. Many studies have attempted to correlate p53 mutation status with patient outcomes; however the results have been controversial due to indiscriminate categorization of all TP53 mutations into one group. Using advanced ovarian cancer as a model, our objective was to determine the relationship of oncomorphic TP53 mutations with the development of chemoresistance in advanced serous ovarian cancer patients uniformly treated with platinum and taxol primary chemotherapy. Clinical, genetic, and protein expression data from 264 high-grade serous ovarian cancer patients were downloaded from The Cancer Genome Atlas (TCGA) data portal. Associations between mutation types, chemoresistance, and progression-free survival (PFS) were calculated for patients harboring oncomorphic TP53 mutations, loss of function mutations, or unclassified mutations. Using a large and uniform patient population, we demonstrate the phenomenon of oncomorphic mutations in ovarian cancer. Specifically, patients with oncomorphic TP53 mutations showed significantly worse PFS when compared with patients with unclassified TP53 mutations (Log-rank, p &lt; 0.05). Patients with oncomorphic TP53 mutations displayed higher rates of platinum resistance (X2, p = 0.0024) and an almost 60% higher chance of recurrence (HR=1.59, 95% confidence intervals 1.09, 2.33, p = 0.016). Furthermore, tumors containing oncomorphic TP53 mutations displayed a unique protein expression profile distinct from tumors with LOF or unclassified mutations. Taken together, these data reveal that particular oncomorphic TP53 mutations are highly associated with worse patient outcomes. Importantly, not all TP53 mutations are equal, and future studies should segregate mutations based on functional consequence. These data may have important implications for the future treatment of patients based on which TP53 mutation is present.
Citation Format: Pavla Brachova, Donghai Dai, Mathew Carlson, Michael Goodheart, Kristina Thiel, Eric Devor, Kimberly Leslie. TP53 oncomorphic mutations are associated with resistance to platinum- and taxol-based standard chemotherapy in advanced serous ovarian cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1555. doi:10.1158/1538-7445.AM2014-1555