bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2107: Deregulation of tumor suppressor miRNAs results in Six1 oncogene overexpression in pediatric and adult human cancers
Authors: Imam J. Saadi , Buddavarapu Kalyan , Lee-Chang Jennifer S. , Hornsby Peter , Chen Yidong , Yoon Kihoon , Rao Manjeet 
Published: February 2011

Abstract
MicroRNAs (miRNAs) are naturally occurring, short non-coding RNAs believed to be involved in many biological processes including normal development and adult cancer. It seems logical that miRNAs would be particularly important in pediatric cancers as these malignancies generally involve perturbations of normal developmental and differentiation processes, yet relatively little is known about the role of miRNAs in pediatric cancers. Here, we show that oncogenesis in Wilms’ tumor - the most common pediatric renal cancer - is mediated by miRNAs. MiRNA microarray analysis identified a cohort of miRNAs that show altered expression in Wilms’ tumors when compared with normal matched control kidney. Our results reveal that several of these miRNAs show similar expression patterns both in Wilms’ tumors and fetal kidney, suggesting that they may play an important regulatory role in kidney development and Wilms’ tumorigenesis. Supporting this notion are our findings that show a number of differentially expressed miRNAs to target genes known to play a role in kidney development and Wilms’ tumorigenesis, including the Six1 homeobox gene, a potent oncogene reported to be overexpressed in several solid tumors. Analyses of primary Wilms’ tumors and ovarian cancer tissues as well as multiple tumor cell lines from breast cancer, ovarian cancer and rhabdomyosarcoma showed decreased expression of miRNAs targeting the Six1 3′UTR, paralleling an increase in Six1 levels. Further investigation revealed a potent tumor suppressor role for Six1 targeting miRNAs, as ectopic expression suppressed the ability of cancer cell lines to form colonies and tumor growth in nude mice. Interestingly, the reduced expression of these miRNAs in Wilms’ tumors was due in part to genomic loss of loci that contain these miRNAs, as revealed by high resolution comparative genomic hybridization analysis. In summary, our findings suggest that miRNAs are integral to the molecular circuitry that plays an important role in Wilms’ tumorigenesis by regulating events during normal kidney development. In addition, our discovery of novel tumor suppressor miRNAs targeting the Six1 oncogene promises to unravel a unique regulatory mechanism for Six1 deregulation in pediatric as well adult tumors.
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 2107.
Abstract 2109: Mir-125b confers the resistance of cancer cells to Taxol through suppression of Bak1
Authors: Zhou Ming , Zhao Yuhua , Ding Yan , Liu Hao , Liu Zixing , Xi Yaguang , Xiong Wei , Li Guiyuan , Lu Jianrong , Fodstad Oystein , Riker Adam I. , Tan Ming 
Published: February 2011

Abstract
Paclitaxel (Taxol) is one of the most effective chemotherapeutic agents for treatment of cancer patients. Despite impressive initial clinical responses, the majority of patients will eventually develop some degree of resistance to Taxol-based therapy. The mechanisms underlying cancer cells resistance to Taxol are not fully understood. microRNA (miRNA) has emerged to play important roles in tumorigenesis and drug-resistance. However, the interaction between the development of Taxol resistance and miRNA has not been previously explored. In this study, we utilized a miRNA array to screen differentially expressed miRNAs, comparing Taxol-resistant and their Taxol-sensitive parental cells, and investigated the role and mechanisms of miR-125b in Taxol resistance of breast cancer cells. We found that miR-125b was up-regulated in Taxol-resistant cells, with its overexpression causing a marked inhibition of Taxol-induced cytotoxicity and apoptosis, and a subsequent increase in the resistance of cancer cells to Taxol. Moreover, we demonstrated that Bak1 is a direct target of miR-125b in breast cancer cells, and down- regulation of Bak1 suppressed Taxol- induced apoptosis and led to an increased resistance to Taxol. Furthermore, restoring the expression of Bak1 by either miR-125b inhibitor or specific siRNA recovered Taxol sensitivity, overcoming miR-125-mediated Taxol resistance. Taken together, our data strongly supports a central role for miR-125b in conferring Taxol resistance through the suppression of Bak1 expression. This finding has important implications in the development of targeted therapeutics for overcoming Taxol resistance in a number of different tumor histologies.
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 2109.
Abstract 2112: COLD-PCR -based deep sequencing identifies novel mutations and intratumor TP53 mutational heterogeneity in lung adenocarcinoma
Authors: Li Jin , Milbury Coren A. , Li Cheng , Makrigiorgos Mike G. 
Published: February 2011

Abstract
TP53 is frequently mutated in lung adenocarcinoma, a major type of lung cancer, and certain TP53 mutations correlate with prognosis and multidrug resistance. Reliable identification of the type and position of TP53 mutations is problematic as the mutations are scattered over numerous codons while their abundance in clinical samples can fall below the sensitivity limits of conventional sequencing methods. Here we employ COLD-PCR, a new form of PCR that selectively amplifies mutation-containing sequences such that the resulting PCR products contain high percentages of mutant alleles. To ensure the highest sensitivity, we adapted the method to employ two consecutive rounds of COLD-PCR followed by Sanger sequencing. Using this highly sensitive new approach for ‘deep-sequencing’ we screened 48 lung adenocarcinoma samples to identify presence and type/position of low-level TP53 mutations. Missense/frame-shift TP53 mutations throughout exons 5-8 were identified in 23 out of 48 (48%) lung adenocarcinoma samples examined, including 8 low-level mutations with an abundance of 1-17% and 3 with an abundance below 1%. 3 novel lung adenocarcinoma mutations were discovered. We identified disruptive mutations that are undocumented in the lung cancer TP53 mutation database and samples harboring low-level (2%-abundance) putative driver mutations concurrently with passenger clonal TP53 mutations (80%-abundance). Our data reveal the presence of widespread intra-tumoral TP53 mutation heterogeneity, and a spectrum of numerous protein-altering mutations at low abundance, that were missed in previous investigations. The implications of using deep-TP53-sequencing as a prognostic/predictive biomarker, evaluation of cancer risk, recurrence, and further understanding of cancer biology are discussed. In addition, we evaluate the use of whole genome-amplification prior to mutation screening in situations when the source of genomic DNA is limited, which can be critical for early cancer detection from biopsy, the assessment of minimal residual disease following surgery, disease staging, and monitoring of cancer progression.
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 2112.
Abstract 2114: Deletions/Duplications detection by MLPA in Chilean families with hereditary colorectal cancer: Lynch syndrome and FAP
Authors: Hurtado Claudia , Orellana Paulina , Alvarez Karin , De la Fuente Marjorie , Wieland Ana María , Pinto Eliana , Heine Claudio , Church James , Kronberg Udo , Carvallo Pilar , López-Kostner Francisco 
Published: February 2011

Abstract
The main variants of colorectal cancer hereditary are Familial Adenomatous Polyposis (FAP) and Lynch Syndrome, which account for approximately 5% of total cases of colorectal cancer. Point mutations in APC and MMR genes are responsible of about 85% and 50% of Chilean FAP (classic phenotype) and Lynch Syndrome (Amsterdam criteria) families, respectively. Different molecular strategies are available for the detection of mutations in these genes. Studies in other populations have identified deletions and duplications of one or more consecutive exons account for around 50% and 10-20% of the total alterations in MMR and APC genes, respectively. The aim of our work was the detection of genomic deletion/duplication through Multiplex Ligation-Dependent Probe Amplification (MLPA) in Lynch Syndrome and FAP patients in Chile. In this study, we analized alterations in MLH1 and MSH2 in 26 Lynch Syndrome families (5 Amsterdam and 21 Bethesda families), and in APC in 10 FAP families (6 classic and 4 attenuated), all of them non carriers of point mutations in these genes. We identified 3 different alterations in the MLH1 in four Amsterdam families, all of them are 0.5 times deletion, which are located: exon 1 in one family, exon 19 in two families, and exons 14 and 15 in one family. In the MSH2, in one Amsterdam family we detected a 0.5 time deletion of exon 2. In the APC, we found 2 different alterations in three classic FAP families: in one family we detected a 0.5 times deletion of the whole gene including promoter region, and in two families we found a 1.5 time amplification of exons 1, 2 and 3. These alterations were confirmed in other relatives of these families and in two independent MLPA analysis. The deletion of exon 19 in MLH1 and the amplification of exons 1, 2 and 3 in APC have not been previously described in other populations. In conclusion, genomic deletions/duplications were only detected in 5 Lynch Syndrome families that fulfilled Amsterdam criteria, and in 3 FAP families with classic phenotype. The detection of different mutations involved in these syndromes, allows the development of prevention strategies of these diseases. Financed by Cleveland Clinic Foundation and Las Condes 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 2114.
Abstract 2115: Increased sensitivity of KRAS mutation detection by High-Resolution Melting analysis of COLD-PCR products
Authors: Daugaard Iben L. , Kristensen Lasse S. , Kjeldsen Tina , Dutoit Stephen Hamilton , Hager Henrik , Hansen Lise Lotte 
Published: February 2011

Abstract
Much effort has been put into the development of sophisticated technologies enabling the detection of clinically significant low-level tumor specific KRAS mutations. The constitutively active KRAS oncogene harbors a mutation hotspot in codon 12 and 13 of exon 2. These mutations are predictors of response to treatment with the monoclonal antibodies panitumumab and cetuximab targeting the epidermal growth factor receptor (EGFR). Therefore, it is crucial to develop robust and sensitive assays targeting these mutations. Coamplification at lower denaturation temperature-PCR (COLD-PCR) is a new form of PCR that selectively amplifies mutation containing amplicons based on the lower melting temperature of heteroduplexes versus homoduplexes. We have developed an assay based on real-time COLD-PCR and high-resolution melting (HRM) targeting codon 12 and 13 for simultaneous detection of the various mutations found in this mutation hotspot. By using mutation containing cell-lines serially diluted into wild-type DNA we have compared the sensitivity of HRM after standard PCR with the sensitivity of HRM after COLD-PCR. We have also analyzed 60 colorectal cancer samples for which KRAS mutation status previously has been evaluated by the DxS kit which is approved by the U.S. Food and Drug Administration. Replacing standard PCR by COLD-PCR increased the sensitivity of the assay by up to 50 fold depending on the specific mutation. Furthermore, we have obtained very similar results when using our COLD-PCR assay as we obtained when using the DxS kit and confirmed the HRM results with Sanger sequencing. In conclusion, applying COLD-PCR to HRM analysis is a simple way of increasing the sensitivity of KRAS mutation detection without adding to the complexity and cost of the experiments.
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 2115.
Abstract 2116: High-sensitivity K-RAS mutation detection using a plant endonuclease-based genotyping method
Authors: Legendre Ben , Shi Yanggu , Wu Grant , Gerard Gary F. , Eastlake Phil , Martin Gerald , Hild David , Kaldjian Eric 
Published: February 2011

Abstract
Newly developed therapeutic agents targeting the epidermal growth factor receptor (EGFR) have proven to be effective against colorectal cancer. However, in certain colorectal cancers these drugs are ineffective. Around 40% of colorectal tumors carry K-RAS gene mutations associated with poor response to EGFR antagonists. K-RAS mutation status can therefore be used to determine whether or not a tumor will respond to anti-EGFR therapy.
SURVEYOR Nuclease is a mismatch-specific plant DNA endonuclease that can scan for known and unknown mutations and polymorphisms in heteroduplex DNA by cleaving DNA with high specificity at sites of base-substitution mismatch and other alterations. This DNA endonuclease cuts both strands of a DNA heteroduplex on the 3’-side of the mismatch site, yielding fragments of smaller size that can be detected by size discrimination technologies. Small insertions/deletions as well as all base-substitution mismatches are recognized; the efficiency of cleavage varies with the sequence of the mismatch. SURVEYOR Scan K-RAS is a research-use-only kit for detecting all sequence variations in exons 2 and 3 of the K-RAS gene.
Studies using plasmid controls have demonstrated detection of all known activating exon 2 mutations in codons 12 and 13, as well as the most common mutation in exon 3, Q61H. Limit of detection experiments have demonstrated that SURVEYOR Scan is highly sensitive, capable of detecting a mixture of 1% mutant in a background of 99% non-mutant DNA. The resulting digestion patterns for codons 12, 13 and 61 are highly specific and recognizable by comparison with controls. In addition, since heteroduplex cleavage is not position specific, mutations outside of these three codons also are detected. SURVEYOR Scan has been used successfully with HPLC (WAVE® HS System) and with automated micro-fluidic capillary electrophoresis (Caliper Lab Chip GX) suitable for high-throughput analyses. Use of SURVEYOR Scan K-RAS can decrease sequencing burden and aid aggressive sequence calling where automated sequencing software fails to definitively resolve the presence of a mutation. This method has also been successfully applied to activating mutations in the BRAF and PIK3CA genes as well. The extension of SURVEYOR Scan to mutation analysis in tumor suppressor genes, such as p53, in which inactivating mutations may be present in multiple exons in numerous locations, is anticipated to be of significant utility, since mutation-specific methods are not practical and sequencing requirements are onerous.
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 2116.
Abstract 2117: Detection of rare mutations in patient samples by comparative allele-specific TaqMan® assay-based PCR (CastPCR)
Authors: Tan Ruoying , Brzoska Pius , Chen Caifu 
Published: February 2011

Abstract
Circulating tumor cells and circulating tumor DNA in the blood of cancer patient may carry cancer-associated mutations. Detection of these mutations directly from the blood of cancer patient is the key to early cancer diagnosis. Here we report a new comparative allele-specific TaqMan® assay-based PCR (CastPCR) method for rare mutation detection. CastPCR combines allele-specific TaqMan® assay with allele-specific MGB-modified blockers to suppress amplification of the wild type allele. We have demonstrated that CastPCR has TaqMan® assay-like sensitivity, linearity and dynamic range; can detect single mutant molecule in the presence of 1 million wild-type molecules; and can detect rare cancer-associated mutations in cancer patient samples. CastPCR will have broad applications in cancer research and in cancer diagnosis.
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 2117.
Abstract 2125: Somatic hypermutations in hairy cell leukemia suggest a canonical process, except in patients with the poor-prognosis VH4-34 variant
Authors: Arons Eugeny , Suntun Tara , Kreitman Robert J. 
Published: February 2011

Abstract
Hairy cell leukemia (HCL) cells express an immunoglobulin (Ig) heavy chain variable (VH) gene with different degrees of somatic mutation. We recently reported that of 82 patients with HCL, 14 expressed VH4-34 and that these patients had a poorer outcome compared to the other 68 patients. Moreover, poor prognosis in the VH4-34 patients was independent of the known poor-prognosis variant of HCL, called HCLv. To confirm these findings, and to more extensively characterize the somatic mutations occurring in the non-VH4-34 patients, we studied mutations from these and an additional 32 patients. A total of 118 rearranged VH sequences from 114 HCL patients were analyzed. Four patients had 2 rearrangements each, none of them VH4-34. Seventeen (15%) of the 114 patients had VH4-34 rearrangements, comprising 10 (38%) of 26 HCLv and 7 (8%) of 88 classic HCL patients (p=0.0005). Sixteen (94%) of 17 VH4-34 rearrangements were unmutated (&gt;98% homologous to germline), compared to 15 (15%) of the other 101 (p=2 × 10-10). Median homology to germline was 99.6% in VH4-34 vs 95.4% in the other rearrangements (p&lt;0.0001). Previous clinical findings that VH4-34+ HCL is associated with high white blood cell count at diagnosis, inferior response and progression-free survival after initial cladribine therapy, and poor overall survival from diagnosis independent of HCLv status, were confirmed. Characterization of the locations of somatic VH mutations in lymphocytic leukemias is rare. One published study reported that in 172 chronic lymphocytic leukemia (CLL) rearrangements, mutations were concentrated in the complementarity determining (CDR) regions, with higher replacement/silent (R/S) mutation ratios for CDRs (4.60) vs framework (FR) regions (1.72) (Blood, 103:3490-3495, 2004). We found that in our 118 HCL rearrangements containing 1385 mutations, R/S was 2.40 overall, 4.29 for CDRs, and 1.83 for FRs, nearly identical to the reported CLL data. Other features reported in CLL, including mutations preferentially in RGYW hot spots and consisting predominantly of transitions rather than transversions, were also observed in HCL. These data suggest that like CLL, VH mutations in HCL result from canonical somatic hypermutation and select for stable antigen receptors, similar to the mutation process taking place in the normal germinal center. However, the origin of VH4-34+ HCL appears different and requires further study.
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 2125.
Abstract 2127: Screening of the PALB2 gene in 57 Chilean patients with hereditary breast cancer
Authors: Alvarez Carolina , Gajardo Patricia , Sánchez Alejandro , Tapia Teresa , Herrera Cristobal , Benavides Felipe , Camus Mauricio , Alvarez Manuel , Carvallo Pilar 
Published: February 2011

Abstract
PALB2 is essential for the nuclear localization and function of BRCA2. Together, these proteins participate in DNA damage repair by Homologous Recombination (HR). It has been described, that women carrying mutations in PALB2 gene have greater susceptibility to develop breast cancer than non-carriers. In order to determine the presence of PALB2 mutations among Chilean breast cancer patients, we analyzed through Single Strand Conformomer Polymorphisms analysis (SSCP) and Direct Sequencing, 57 Chilean families with breast cancer, that are not carriers of BRCA1 or BRCA2 mutations. We found 11 sequence alterations: 8 exonic, 2 intronic, and 1 in 5′UTR region. Among these, 2 are novel and found for the first time in our study: an intronic deletion c.3351-66delT and an exonic silent variant p.G752G. With the purpose of assessing the effect of each aminoacidic variant on PALB2, we use the software Polyphen, showing that the missense variant p.G998E may affect the function and/or structure of PALB2 protein. We also evaluated a possible effect of some silent variants on splicing using the software ESEfinder, finding that the 5′UTR nucleotide substitution c.1-47G&gt;A, and the silent variant p.T1100T affect the binding of SR proteins to Exonic Splicing Enhancer sequences. The 5′UTR variant and two aminoacidic substitutions, p.G998E and p.Q559R, were screened in 200 healthy controls, finding no association to hereditary breast cancer. Our work is the first mutation screening study for PALB2 gene among families with breast cancer in a Latin American population.
Financed by FONDECYT 1080595
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 2127.