bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2121: High-resolution melting for detection of KRAS and EGFR mutations in tumors of the alimentary system
Authors: Li Mei , Liu Lina , Zhou Luming , Liu Zhimin , Feng Lu , Zhang Qiuping , Wang Zhaohui , Lu Shen 
Published: February 2011

Abstract
The EGFR/Ras/Raf/MAPK pathway is one of the most important signal transduction pathways in cells. Dysregulation of this pathway is a common event in many cancers, including cancers of the alimentary system. EGFR and KRAS are two common genes in which mutations caused abnormal activation of the pathway. EGFR mutations are closely associated with a favorable response to treatment with tyrosine kinase inhibitors. KRAS mutations are associated with unresponsiveness to EGFR inhibitors. EGFR and KRAS mutation detection is important for carcinogenesis research and clinical therapy. Tumor tissue samples included 13 esophagus cancer, 52 gastric cancer and 67 colon cancer from a Chinese population. These were obtained from Dalian Medical University collection. High resolution melting (on a LightScanner™) was used to scan the mutations of KRAS exon 2, EGFR exon 19 and exon 21. All mutations detected by HRM were sequenced to identify the genotype. We found KRAS mutations in 5 (9.6%) patients with gastric cancer (2 with G12D; 1 with G12V; 2 with G13D) and 19 (28.4%) patients with colon cancers (11 with G12D, 3 with G12V, 4 with G13D; 1 with G13V). No KRAS mutations were found in esophagus cancer patients. The frequency of KRAS mutations in colon cancer was significantly higher than those in esophagus and gastric cancer (P&lt;0.01). In 19 colon cancer patients with KRAS mutations, there were 6 (20.7%, 6/29) cases in the right colon (ascending colon and proximal 2/3 transverse colon) and 13 (34.2%, 13/38) cases in the left colon (distal 1/3 transverse colon, sigmoid colon and rectum). There is no significant difference in KRAS mutation frequencies between the right and the left colon. KRAS mutations were not associated with genders, ages, the invasive depth, lymph node metastasis and histopathological types in gastric and colon cancers. There were no EGFR exon 19 mutations found in any cases. EGFR exon 21 mutations were found in 2 gastric cancer patients (1 with L858R; 1 with G863D). In cancers of the alimentary system, KRAS mutations were more common than EGFR mutations, and KRAS mutations could be associated with the original tissues in the embryonic development. Namely, KRAS mutations were more common in cancers of organs from the midgut and hintgut than of those from the foregut, while EGFR mutations were all found in organs from the foregut. High resolution melting was a valuable method both in research and clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2121.
Abstract 2122: KRAS mutation detection using high resolution melting analysis and its prognostic value in archival colorectal cancer tissues
Authors: Deschoolmeester Vanessa , Boeckx Carolien , Wuyts Wim , Marck Eric Van , Vermeulen Peter , Pauwels Patrick , Peeters Marc , Lardon Filip , Vermorken Jan B. , Baay Marc 
Published: February 2011

Abstract
Introduction: The development of targeted therapies has created a pressing clinical need for the rapid and robust molecular characterization of cancers. High resolution melting analysis (HRMA) provides a valid approach to efficiently detect DNA mutations. In the current study, HRMA was validated and implemented for screening of 164 colorectal cancer (CRC) patients to detect hot spot mutations (codon 12/13) in the KRAS oncogene. Direct sequencing was used to confirm and characterize HRMA results. In addition, the prognostic potential of KRAS in CRC was evaluated.
Materials and Methods: Initially, the HRMA sensitivity was established using a cell line dilution model, enabling us to detect 3% mutant DNA in a background of wildtype DNA. Next, HRMA was validated on 7 cell lines with or without a known KRAS mutation. All mutations were readily detectable using HRMA. Subsequently, inter- and intravariation was analyzed.
Results: HRMA revealed abnormal melting patterns in 57/164 (34.8%) CRC samples with G12D substitution the most prevalent type. However, only 50/164 (30.5%) samples could be confirmed by sequencing. The presence of KRAS mutation was associated with proximal location, advanced stage and microsatellite stability (MSS). Kaplan-Meier survival analysis revealed a significantly shorter overall and disease free survival for CRC patients harboring a KRAS mutation, especially for the G12C substitution. In Cox regression, KRAS mutation was still found to be a negative predictor of survival, however, significance was lost.
Conclusions: In conclusion, HRMA was found to be a fast, efficient and reproducible screening method for KRAS mutation detection by which degraded DNA from formalin-fixed, paraffin-embedded tissues can be tested. Additionally, accurate detection of KRAS mutations in CRC shows potential as a prognostic marker and evidence is accumulating that poor outcome could be linked to specific mutations. These results might have an impact on patient selection for adjuvant treatment.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2122.
Abstract 2123: Novel integration sites for Friend murine leukemia virus
Authors: Haeri Mehran , Ben-David Yaacov 
Published: February 2011

Abstract
Background: Friend murine leukemia virus (F-MuLV), a type C retrovirus, induces erythroleukemia when injected into certain strains of mice. The Induction of erythroleukemia is associated with viral integration into Friend leukemia integration site-1 (Fli-1). In some F-MuLV-infected mice we did not observe viral integration into Fli-1 region by Southern blot analysis. We hypothesize that induction of leukemia in these mice is due to insertion of F-MuLV into a novel integration site distinct from Fli-1.
Methods: The genomic DNA of F-MuLV-induced leukemic cells is digested by StuI restriction enzyme. DNA sequences of about 50 base pairs in length, termed adaptors, are then ligated to both ends of the digested fragments. Using primers for the adaptors and F-MuLV sequences, we performed PCR, followed by nested PCR to amplify those fragments that contain F-MuLV sequence. The PCR product is gel purified, cloned into a TA vector and sequenced. The sequences are compared to mouse genome databank to determine the F-MuLV flanking sequences.
Results: We identified seven novel integration sites for F-MuLV. Three of these sites are located inside genes and the remaining four do not interrupt any genes. We performed PCR to check if any of these integration sites were also targets of F-MuLV in twenty other tumors of the same type. We found that one of these integration sites which is close to Myb gene occurred in twenty five percent of the tested tumors in an area 1 kb in length.
Conclusion: We identified seven novel F-MuLV integration sites for F-MuLV. We showed that the integration site on chromosome 10 close to the Myb gene occurs in 25% of F-MuLV- induced tumors and is therefore a common integration site.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2123.
Abstract 2126: Quantitative trait locus analysis of tumor morphology in a mouse model of human colorectal cancer
Authors: Bautz David J. , Uronis Joshua M. , Threadgill David W. 
Published: February 2011

Abstract
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Early detection has frequently been cited as contributing to a favorable outcome. However, detection of CRC is impacted by tumor morphology, with the classical polypoid lesions being detected at a much higher rate than flat lesions. Recently, mouse models of CRC that consistently and almost exclusively develop flat lesions have been developed, indicating that specific host genetic modifiers exist that influence tumor morphology. Using the azoxymethane (AOM) model of human CRC we find that I/LNJ mice develop approximately 85% flat tumors while KK/HlJ mice develop approximately 85% polypoid tumors. To determine what genetic factors contribute to these phenotypic differences, we established an F2 genetic cross between these two mouse strains consisting of 119 animals. After a standardized AOM treatment regimen, these mice developed approximately 40% flat tumors. The mice were genotyped at 80 SNP's evenly spaced across the genome. Statistical analysis revealed two suggestive QTL for tumor morphology, one located on chromosome 12 (LOD 3.45) and the other on chromosome 9 (LOD 2.67). Follow up work has begun to fine map and identify candidate genes at these QTL through high dense SNP genotyping in an additional 300 F2 animals and eQTL analysis of normal colon tissue. These results indicate that tumor morphology is controlled by host genetic factors and we anticipate future studies focusing on the identification of these factors for development of therapeutic interventions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2126.
Abstract 2132: Cigarette smoking increases copy number alterations in non-small cell lung cancer
Authors: Huang Yen-Tsung , Lin Xihong , Chirieac Lucian R. , McGovern Ray , Wain John C. , Heist Rebecca S. , Skaug Vidar , Zienolddiny Shanbeh , Haugen Aage , Su Li , Christiani David C. 
Published: February 2011

Abstract
BACKGROUND: Cigarette smoking is a well-established risk factor of lung cancer. How smoking induces oncogenesis in lung remains not fully understood. We conducted a genome-wide study of copy number and smoking pack-years in a large collection of non-small cell lung cancer (NSCLC) tumors on three different scales: whole genome, chromosome and focal region.
METHODS: Genome-wide analyses of copy number and pack-years of cigarette smoking were performed on NSCLC tumors (n=264), which was randomly divided into a discovery set (n=134) and a validation set (n=130). Copy numbers were inferred from the dense single nucleotide polymorphisms array by dChip. On the scales of whole genome and chromosome, four indices were proposed to test large-scale copy number alterations (CNAs) patterns between heavy and light smokers: total CNAs events, continuous CNAs pattern, discrete CNAs pattern, and selecting effect with respect to gene locations. On the scale of focal region, genome-wide association (GWA) analyses of focal copy number and smoking pack-years were performed on 256,554 loci.
RESULTS: On the whole genome scale, heavy cigarette smokers (&gt;60 pack-years) have significantly more copy number gains than non-/light smokers (≤60 pack-years) (p=2.46×10−4). Copy number losses tend to occur away from genes in non-/light smokers (p=5.15×10−5) but not in heavy smokers (p=0.52). Smoking-associated copy number gains are most significant on chromosomes 8 (p=1.19×10−5), 10 (p=4.81×10−4) and 12 (p=3.31×10−3). For the focal region, GWA analyses show six loci with strong association of copy number and cigarette smoking pack-years, including four neighboring loci at 12q23.2 (p=1.79×10−8 to 6.17×10−7) where IGF1 (insulin-like growth factor 1) is located. All above analyses were tested in the discovery set and confirmed in the validation set.
CONCLUSIONS: Heavy smokers have more copy number gains and less selection of gene locations in copy number losses. Copy number increases in 12q23.2 where IGF1 is located are positively associated with cigarette smoking pack-years.
Supported by US National Institutes of Health Grants No. CA092824, CA074386, CA090578; and the Norwegian Cancer Society
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2132.
Abstract 2133: Identification of driver genes for amplification of the narrow amplicon at 2q11 present in oral cancers and pre-cancers
Authors: Lin Mauting , Snijders Antoine M. , Bhattacharya Aditi , Paquette Jesse , Jordan Richard C. K. , Schmidt Brian L. , Albertson Donna G. 
Published: February 2011

Abstract
Genome-wide analysis of copy number aberrations in oral squamous cell carcinoma (SCC) and oral epithelial dysplasia, a pre-malignant lesion, by array CGH has revealed that the genomes of these cancers and pre-cancers frequently harbor narrow (∼3 Mb) regions of amplification. These amplicons are recurrent, but rare, being present in &lt;10% of cases. Nevertheless, candidate driver genes in the amplicon are often up-regulated in tumors without amplification. Thus, these narrow amplicons highlight genes/pathways that are de-regulated in oral cancer. A narrow amplicon at 2q11 has been observed in 3/44 oral dysplasia cases, in 1/89 oral SCC and one primary oral SCC cell line. In one patient with synchronous mild and moderate dysplasia lesions, the 2q11 amplicon was uniquely present in moderate dysplasia, suggesting that the amplified and overexpressed gene(s) at 2q11 contributed to progression. The 2q11 amplicon spans 3.5 Mb and includes 43 genes. Examination of two independent head and neck cancer gene expression datasets retrieved from the NCBI Gene Expression Omnibus database revealed up-regulation of 11 of these genes in one or both datasets. All 11 genes are overexpressed in oral SCC lines SCC4, SCC9 and HSC3. Knockdown of individual genes in a panel of eight oral SCC cell lines was performed with one or more siRNA's targeting each of the genes. These studies revealed that cellular proliferation and morphology were significantly disrupted in cells transfected with siRNA to two of the genes, suggesting there are two potential driver genes for the 2q11 amplicon.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2133.
Abstract 2138: Functional characterization of the 19q12 amplicon in grade 3 breast cancers
Authors: Natrajan Rachael C. , Wetterskog Daniel , Lambros Maryou BK , Felipe Geyer , Mackay Alan , Vatcheva Radost , Palacios Jose , Reis-Filho Jorge 
Published: February 2011

Abstract
Grade III (GIII) invasive ductal carcinomas of no special type (IDC-NST) comprise up to 60% of all invasive breast cancers and have an aggressive clinical behavior. We have previously identified 19q12 amplification in a subgroup of estrogen receptor (ER)-negative HER2 amplified (4%) and basal-like (16%) subtypes of breast cancer. This amplicon comprises 9 genes, including cyclin E1 (CCNE1), which has been proposed as its driver due to a strong association with gene over-expression. The aims of this study were to identify functionally the genes within the 19q12 amplicon whose expression is required for the survival of cancer cells harboring this amplification. We analyzed a series of 48 micro-dissected GIII IDC-NSTs using high-resolution microarray CGH and mRNA expression arrays and identified 19q12 amplification in 7.6% of ER negative GIII tumors. Of the 9 genes mapping to the smallest region of amplification, UQCRFS1, POP4, C19ORF12, CCNE1 and C19ORF2 were significantly over-expressed when amplified (P&lt;0.05). Breast cancer cell lines with (MDAMB157 and HCC1569) and without (Hs578T, MCF7, MDAMB231 and ZR75.1) 19q12 amplification were screened with an RNAi library targeting the 9 genes mapping to the smallest region of amplification on 19q12. Individual short interfering RNA (siRNA) SMARTpools targeting these genes were plated in 96-well plates and cell viability was assessed after 9 days using CellTiter-Glo Luminescent Cell viability assay. Silencing of POP4, PLEKHF1, ZNF536 and ZNF537 selectively inhibited cell viability in 19q12-amplified cells compared to control cells. CCNE1 silencing was neither selectively lethal to cells harboring 19q12 amplification, nor lethal in all cells with this amplification. Our results demonstrate that expression of POP4, PLEKHF1, ZNF536 and ZNF537 is required for the survival of cancer cells displaying their amplification and suggest that the 19q12 amplicon may harbor more than one ‘driver’.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2138.
Abstract 214: Anticancer effect of Compound A, a novel modulator of the glucocorticoid receptor, in acute leukemia cells
Authors: Lesovaya Ekaterina A. , Kirsanov Kirill I. , Budunova Irina V. , Yakubovskaya Marianna G. 
Published: February 2011

Abstract
Glucocorticoids (GCs) are widely used in chemotherapy of blood cancers, including childhood acute leukemia. The biological effects of GCs are mediated by the glucocorticoid receptor (GR), a well known transcription factor. Therapeutic effects of GCs are mainly mediated via GR transrepression that involves negative interaction between GR and other transcription factors. In contrast, many adverse metabolic effects of glucocorticoids are mediated by GR transactivation that requires GR binding to hormone-responsive elements in gene promoters. Thus, selective GR activators (SEGRA) that modify GR, shift GR functions towards transrepression resulting in improved therapeutic index, hold a great potential for the GR-targeted chemotherapies.
Recently we and others characterized novel non-steroidal GR ligand, 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride or Compound A (CpdA), and showed that CpdA prevents GR dimerization and transactivation, but strongly enhances GR transrepression. We also revealed that CpdA possesses anti-cancer properties: it inhibited growth and viability of prostate cancer cells in GR-dependent fashion.
Here we report that CpdA at concentrations 10−6-10−5M exerted cytostatic (evaluated by MTT test) and cytotoxic (evaluated by FACS analysis of DNA fragmentation as sub-G1 peak in propidium iodide-labeled cells) effects in K564, NB-4 and CEM leukemia cell lines. We found that these cell lines express wild type nonmutated GR. Consequently, these cell lines present a good model system for the further comparative analysis of CpdA and GCs effects. Leukemia cell lines were sensitive to apoptotic effect of both GR ligands: Dexamethasone (Dex) and CpdA. Dex induced apoptosis at the concentrations 10−7 to 10−5M; and CpdA affected cell viability at concentrations 5×10−6−10−5M.
As a first step towards the evaluation of toxicological profile of this promising anti-cancer compound, we assessed its mutagenicity using Ames test. CpdA was not mutagenic either in frameshift or in base-substitution indicator strains, TA98 and TA100, respectively, at the wide range of concentrations (10−9-10−4M).
Overall, our data suggest that novel non-mutagenic GR modulator has a high chemotherapeutic potential. The detailed mechanisms of its anti-cancer effects in leukemia cell lines is under investigation.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 214.
Abstract 2141: Analysis of DNA copy number changes in ovarian cancer data reveals differences in progressive vs. complete response samples
Authors: Soheil Shams , Parman Craig , Gregg Jeffrey 
Published: February 2011

Abstract
Data from The Cancer Genome Atlas (TCGA) project, related to Ovarian Cancer was obtained from the TCGA web site. The data comprised a total of 489 samples hybridized on 2-color oligo-arrays with 244K probes per array. Raw log-ratio data representing DNA copy number values relative to a DNA pool of normal samples were used in the analysis. The raw data was processed using Nexus Copy Number version 5 software (BioDiscovery, El Segundo CA) and regions of copy number change were identified using the built-in FASST algorithm with significance threshold of 5.0 E-6. After applying a QC filter to remove hybridizations with excessive noise, 463 samples remained for further analysis. Of these, there were 214 solid tumors and 242 normal samples (either surrounding tissue or blood from same patient). In our analysis we compared copy number differences from samples with Progressive disease (n=29) and those with Complete response to therapy (n=245). Using a Fisher's Exact test and a maximum p-value of 0.05 we identified significant regions of copy number change covering a genome area composed of a total of 1049 genes. Included were regions of significant increase in the number of DNA copy number gains in the for the Complete response samples as compared to Progressive cases. The most significant of these were in the 6p21.1 − 6p12.1 and 5p14.1 − 5p13.3 regions. Other regions include a number of well-know genes related to apoptosis, such as TNF (on 6p21.33) and RHOB (on 2p24.1) that were also significantly gained in Complete response but showed DNA loss in Progressive samples.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2141.
Abstract 2142: Multifaceted genomic analyses reveal novel glioblastoma candidate genes and microbial DNAs
Authors: Duncan Christopher G. , Killela Patrick J. , Yan Hai 
Published: February 2011

Abstract
The glioblastoma (GBM) genome displays remarkable chromosomal aberrations, which harbor critical GBM specific genes contributing to several oncogenetic pathways. However, deciphering further driver genomic changes from passenger gene alterations remains a daunting challenge. In attempt to identify novel GBM genes, we carried out a multifaceted genome-wide analysis to characterize the most significant aberrations of DNA content occurring in GBM patients. First, we performed copy number analysis using Digital Karyotyping (DK) and Illumina BeadChip technologies and identify genomic loci which consistently present as focal copy number alterations. Next, we overlaid copy number altered loci with the somatic mutation data from our genome-wide coding sequencing analysis. Upon expression analyses of these genes, we identify several previously unrecognized genes which are dysregulated in GBM. Most significantly, we identify grade-specific activation of set of genes potentially involved in chromosomal instability of the GBM genome. Finally, we evaluated the contribution of microbial DNA to the GBM genome using an approach, called DK-MICROBE, which we developed to identify genomic DNA of bacteria and viruses in human disease tissues. Our multifaceted genomic evaluation of GBM establishes several candidate oncogenes, tumor suppressors and caretaker genes and provides insight on the molecular mechanisms and pathways to this deadly disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2142.