bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2759: Association between genetic variations in DNA damage response pathways and risk for gene methylation in sputum from smokers
Authors: Leng Shuguang , Stidley Christine A. , Willink Randall P. , Liu Yushi , Picchi Maria A. , Berg David Van Den , Gilliland Frank D. , Crowell Richard E. , Belinsky Steven A. 
Published: June 2012

Abstract
The detection of gene promoter hypermethylation in sputum containing exfoliated epithelial cells is a promising biomarker for detecting early incident lung cancer. Therefore, identifying factors that influence the propensity for this epigenetic process throughout the respiratory epithelium is a high priority. The genes and the pathways they modulate underlying the inter-individual susceptibility to DNA methylation remain largely elusive. Accumulating evidence from our group and others implicate DNA damage as an important step in the acquisition of de novo methylation. We hypothesized that genetic variations in genes (n=66) involved in carcinogen metabolism and DNA damage response, including DNA damage repair, cell cycle control, apoptosis, and methylation related pathways will be associated with gene methylation in sputum from lung-cancer free smokers. Three databases including HapMap Stage I database, University of Southern California DNA repair and Children Pulmonary Function Development Oligo Pool Assay (OPA) database, and NIBC dbSNPs database were used to select a comprehensive set of SNPs (OPA1, n=1536) to capture the major genetic variations in these genes. A pilot study for testing the association between these SNPs and risk for methylation was conducted in a subset of people (n=261) selected from Lovelace Smokers Cohort (LSR) based on their methylation index (8-gene panel). Two gene-based analyses were conducted to rank the genes and 683 tagging SNPs from the top 42 genes were selected based on the OPA1 and the HapMap Stage II databases and genotyped in all people (n=1177) with methylation data (12-gene panel) in baseline sputum samples in LSR. The effect of SNPs was tested under an additive inheritance model. A reproducible association was identified in SNPs from the TP53, GSTP1, LIG1, CASP8, BOK, and PMAIP1 genes between the pilot study and the entire study. Ongoing functional studies reveled an association between genotype and expression of LIG1 in bronchial epithelial cells from smokers. This study identified six genes involved in carcinogen detoxification and DNA damage response that were associated with risk for gene methylation in sputum from smokers. (Supported from National Cancer Institute R01 CA097356 and the State of New Mexico as a direct appropriation from the Tobacco Settlement Fund)
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 2759. doi:10.1158/1538-7445.AM2011-2759
Abstract 276: Role of AP1 elements and TCL1 protein in regulation of the gene encoding PTPROt (protein tyrosine phosphatase receptor-type O) in chronic lymphocytic leukemia
Authors: Motiwala Tasneem , Datta Jharna , Kutay Huban , Roy Satavisha , Checovich Allyn , Zanesi Nicola , Kaou Mohamed , Johnson Amy , Hagan John , Byrd John C. , Croce Carlo M. , Jacob Samson T. 
Published: June 2012

Abstract
The gene for protein tyrosine phosphatase receptor-type O encodes two functional isoforms in a tissue-specific manner. The full-length form is expressed in epithelial cells, particularly in the brain and kidney, whereas the truncated form (PTPROt) is primarily expressed in hematopoietic cells. We have previously demonstrated that PTPROt is a bona fide tumor suppressor (J Biol Chem. 2009 Jan 2;284(1):455-64) and is down-regulated in primary CLL samples (Clin Cancer Res. 2007 Jun 1;13(11):3174-81). Further, studies from two laboratories including ours have shown that Syk and Lyn, two key protein tyrosine kinases involved in B-cell receptor signaling, are substrates of PTPROt, igniting interest in understanding deregulation of this tyrosine phosphatase in CLL. While the PTPRO promoter is methylated, the mechanism of its silencing in the pathogenesis of CLL is unexplored. Here, we utilized the Tcl1 transgenic (Tg) mouse model of CLL and a cell line with TPA-inducible expression of PTPROt to elucidate the mechanism of PTPROt silencing. This study demonstrates that PTPROt is transcriptionally silenced in CD19+ spleen B cells from Tcl1 transgenic (Tg) mouse when compared to wild type mice. As observed with primary human CLL, the methylation of PTPRO CGI (CpG island) is significantly higher in Tcl1 Tg CLL B-lymphocytes than in normal B lymphocytes. Significant suppression of PTPROt is also observed at very early time-point (∼7 wks) in CD19+ spleen B-cells from Tcl1 Tg mice compared to normal spleen B-lymphocytes from age-matched WT mice in the absence of detectable methylation at CGI. This data suggests that transcriptional silencing occurs prior to methylation. To understand further the potential transcriptional mechanism of PTPROt suppression in CLL, the role of AP1 in the expression of this gene was explored. We first demonstrate that AP-1 activation by TPA in U937 cells induces PTPROt expression with concurrent recruitment of c-fos and c-jun to its promoter. PTPROt promoter is also responsive to over- and under-expression of AP-1 confirming the role of AP-1 in PTPROt expression. Next, we demonstrate that Tcl1 can repress PTPROt promoter by altering c-fos expression and c-jun activation state. These findings further substantiate the importance of TCL1 in the pathogenesis of CLL.
[Supported, in part, by grants CA101956 and CA086978].
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 276. doi:10.1158/1538-7445.AM2011-276
Abstract 2764: High-resolution HLA typing by next-generation sequencing and risk of follicular lymphoma
Authors: Akers Nicholas K. , Conde Lucia , Smith Martyn T. , Bracci Paige M. , Skibola Christine F. 
Published: June 2012

Abstract
The molecular basis of follicular lymphoma (FL) has been fairly well characterized, although its root causes remain less clear. Recently, in two genome-wide association studies of European-Americans, we identified novel genetic susceptibility loci for FL, narrowed down to two independent regions on chromosome 6p21.3 in the major histocompatibility complex (MHC) (Skibola et al., Nat Gen 41(8):873-5., 2009; Conde et al., Nat Gen 42(8):661-4, 2010). The first susceptibility locus, rs6457327 (combined allelic p-value=4.7 × 10-11 in 645 patients and 3,377 controls), is part of a 26-kb region of high linkage disequilibrium (LD) in the MHC Class 1 region at 6p21.33 in close proximity to the psoriasis susceptibility region 1 (PSORS1). A second locus at 6p21.32, in the MHC Class II region upstream of HLA-DQB1, two SNPs in high LD, rs10484561 and rs7755224, were associated with 2-fold increased risks for FL in 1,465 patients and 6,958 controls (combined p-values=1.12×10-29, 2.00×10-19). Using tag SNPs as surrogates for HLA allelotypes, the latter loci were found to be part of an extended haplotype that includes HLA-DRB1*0101-HLA-DQA1*0101-HLA-DQB1*0501 and that was associated with increased FL risk [odds ratio (OR) = 2.07, 95% confidence interval (CI) = 1.40-3.06]. These findings were further validated by direct typing of HLA-DQB1 alleles in a subset of 265 FL cases and 757 controls using multiplexed, ligation-dependent probe amplification. We verified the positive association between FL and the HLA-DQB1*05 allele group (OR=1.56, 95% CI 1.22-1.99; adjusted p-value=7.7×10-3), and found an inverse association between the HLA-DQB1*06 allele group and FL risk (OR=0.53, 95% CI 0.40-0.69; adjusted p-value=1.98×10-5).
To gain further insight into the role of HLA alleles in FL susceptibility, high-resolution HLA typing by next-generation sequencing of the HLA class I (A, B, C) and class II (DRB1/3/4/5, DQA1, DQB1, DPB1) genes was conducted in 222 FL patients and 220 sex- and age-matched controls. HLA typing was performed by sequencing exon 2 for the class II genes and exons 2-4 for the class I genes, as described previously (Bentley, G et al. Tissue Antigens. 74:393-403, 2009), and data analysis is underway. To our knowledge, this study will present the highest resolution (up to 8-digit) HLA typing reported in a sample of European-Americans, and is an important next step to determine the role of MHC genetic variation in the pathogenesis of FL.
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 2764. doi:10.1158/1538-7445.AM2011-2764
Abstract 2769: Evaluation of PPP2R2A as a prostate cancer susceptibility gene: Comprehensive germline and somatic study
Authors: Cheng Yu , Liu Wennuan , Sun Jishan , Kim Seong-Tae , Lu Lingyi , Sun Jielin , Zheng Siqun , Isaacs William B. , Xu Jianfeng 
Published: June 2012

Abstract
PPP2R2A, a gene mapped to 8p21.2, encodes α isoform of the regulatory B55 subfamily of the protein phosphatase 2 (PP2A). PP2A is one of the four major Ser/Thr phosphatases, and is implicated in the negative control of cell growth and division. Because of its known functions and its location within a chromosomal region where evidence for linkage and somatic loss of heterozygosity were found, we hypothesized that either germline sequence variants or somatic copy number changes in PPP2R2A may increase prostate cancer (PCa) risk. To address this, we first sequenced PPP2R2A in 96 probands of hereditary prostate cancer (HPC) families recruited at John Hopkins Hospital; each family had at least three first-degree relatives affected with prostate cancer. Twenty-five germ-line variants were identified in this analysis, including 15 known SNPs and 10 new sequence variants. Most new sequence variants were rare, except 2 new sequence variants with minor allele frequency (MAF) ≥ 0.05 (−482T/C MAF=0.072 and -78C/G MAF=0.058). Thereafter, it was less likely that these sequence variants of PPP2R2A would be co-segregated with PCa. Second, to see if there are any genetic variants in PPP2R2A associated with sporadic PCa, we analyzed 10 SNPs of 15 known SNPs that span the complete PPP2R2A gene in Cancer Genetic Markers of Susceptibility (CGEMS, 737 cases and 1,105 controls) and in Cancer of the Prostate in Sweden (CAPS, 498 cases and 494 controls) from a Sweden population, as genotypes of these 10 SNPs had already been available in both studies. No consistent significant differences in the allele and genotype frequencies were observed among these sporadic PCa cases and controls. Finally, we examined the deletion status in 141 clinical PCa samples from John Hopkins using Affymetrix 6.0 SNP arrays. With the allele-specific analysis of intensities from all paired tumor and normal tissue samples, it was found that PPP2R2A was commonly (67.1%) deleted in these tumor samples including a homozygous deletion in 3 tumors (2.1%). These results suggest that somatic deletion rather than germline sequence variants of PPP2R2A may play a more important role in prostate cancer susceptibility.
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 2769. doi:10.1158/1538-7445.AM2011-2769
Abstract 2775: Meat intake, genetic variation in carcinogen metabolic enzymes, and prostate cancer risk in a multiethnic case-control study of non-Hispanic Whites, African Americans and Hispanics
Authors: Joshi Amit D. , Corral Roman , Catsburg Chelsea , Koo Jocelyn , John Esther M. , Ingles Sue A. , Stern Mariana C. 
Published: June 2012

Abstract
Background: The role of meat and meat-induced carcinogens in prostate cancer (PCa) is still inconclusive. The process of cooking meat increases the content of chemical carcinogens such as heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs), which are metabolized to active carcinogens, or detoxified by metabolic enzymes in the liver and the prostate.
Study objectives: We tested whether diets high in red or white meats are associated with PCa risk, taking into account cooking practices, and whether polymorphisms in carcinogen metabolism genes modify these associations.
Methods: We used data and DNA samples from the California Collaborative Prostate Cancer Study, a multiethnic, population-based study of non-Hispanic White, African American and Hispanic men (717 localized PCa cases, 1,140 advanced PCa cases, and 1,096 controls). We considered nutrient density (g/ 1000 kcal / day) adjusted variables that captured intake of red meat, poultry, and processed meat, taking into account cooking methods, levels of doneness, and estimated meat mutagens, obtained using the CHARRED database. We considered the following polymorphisms: CYP1A2 -154 A&gt;C, CYP1B1 L432V, CYP2E1 -1054 C&gt;T, COX2 -765 G&gt;C, EPHX1 Y113H, GSTP1 I105V, UGT1A6 T181A and the NAT2 predicted phenotype. Conditional logistic regression was used to estimate odds ratios for PCa risk adjusting for age, body mass index, total calorie intake, family history of PCa, saturated fat intake, pack-years of cigarette smoking, total fruit consumption and total vegetable consumption.
Results: Diets high in baked poultry, were inversely associated (Ptrend = 0.028), whereas diets high in pan-fried red meat (Ptrend = 0.040) and well done red meat (Ptrend = 0.016) were positively associated with advanced PCa risk. Estimated meat mutagens (PhIP, MeIQX) were positively associated with advanced PCa risk only among Hispanic men (Ptrend = 0.022 and 0.04, respectively). The UGT1A6 T181A polymorphism modified the associations of localized PCa risk with consumption of high temperature cooked, well done, or oven broiled poultry and with estimated PhIP, suggesting positive associations between these exposures and localized PCa risk only among carriers of 1 or 2 copies of the Alanine allele.
Conclusions: Diets high in red or white meat cooked with high temperature methods may be modifiable risk factors for advanced PCa, and risk factors for localized disease among carriers of selected metabolic enzyme variants.
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 2775. doi:10.1158/1538-7445.AM2011-2775
Abstract 278: Role of AF4 and Dot1 in MLL-AF9 mediated leukemogenesis
Authors: Lumba Bhavna , Hemenway Charles S. 
Published: June 2012

Abstract
Mixed lineage leukemia (MLL) is characterized by rearrangement of the MLL gene at chromosome band 11q23. MLL gene rearrangements give rise to chimeric proteins that contain the N-terminal portion of MLL fused to the C-terminal portion of over 50 different fusion partners. MLL chimeras do not retain the histone methyltransferase activity of wild type MLL and it is unclear how they deregulate the expression of MLL target genes. Our laboratory studies the two most common MLL fusion partners encountered in patients with leukemia, AF4 and AF9. We have previously shown that AF4 and AF9 heterodimerize and peptides that block this interaction are toxic to MLL leukemia cell lines. This supports the hypothesis that the interaction of MLL-AF9 with AF4 is required for leukemogenesis. However, we have also shown that AF4 and H3K79 methyltransferase, Dot1 have similar binding sites on AF9. Furthermore, we have found that Dot1 is required for immortalization of hematopoietic progenitor cells by MLL fusion genes. The work of Yokoyama and others demonstrated that AF4, ENL (a close homologue of AF9) and Dot1L do not exist in the same multimeric complex. To understand the role of AF4 and Dot1 in MLL-AF9 mediated leukemogenesis, we made point mutants of AF9 with differential binding for AF4 and Dot1. Based on our preliminary data and recent studies, we hypothesize that the binding of AF4 and not Dot1 to MLL-AF9 is required for MLL-AF9 mediated leukemogenesis. Nevertheless, Dot1 remains a critical factor in MLL-AF9 leukemia. We hypothesize that Dot1 recruitment is mediated by wild type AF9 rather than MLL-AF9.
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 278. doi:10.1158/1538-7445.AM2011-278
Abstract 2791: SINE retrotransposons cause epigenetic reprogramming of adjacent gene promoters
Authors: Estecio Marcos R.H , Dekmezian Mhair , Gallegos Juan , Liang Shoudan , Issa Jean-Pierre 
Published: June 2012

Abstract
Retrotransposons of SINE and LINE classes have been extremely successful in colonizing mammalian genomes. Almost half of the human genome and as much as 40% of the mouse genome is composed of repetitive DNA sequences. The comparison of human and mouse genomes revealed a spatial concordance in positioning of SINE but not LINE repeats, indicating evolutionary pressure to maintain and/or exclude these repeats from orthologous regions. We hypothesized that this phenomenon is due to a negative influence of SINE repeats on gene expression and counter selection over evolution, resulting in exclusion of these repeats from vulnerable genomic environments. To test the capacity of SINE B1 elements in promoting gene silencing, we generated a system where the luciferase gene is under the control of three different mouse gene promoters (cdkn2a, p14arf and mlh1), and we inserted two and four copies of SINE B1 elements upstream to these promoters. Using this in vitro system, we found that SINE B1 elements can influence the activity of downstream gene promoters, with acquisition of DNA methylation and loss of activating histone marks, thus resulting in a repressed state. Interestingly, SINE sequences themselves do not immediately acquired DNA methylation, but became marked by H3K9me2 and H3K27me3. Moreover, gain of DNA methylation depended on cryptic genomic methylation centers rather than spreading from SINE B1 repeats. Since mouse SINE B1 elements caused transcriptional repression, we sought to investigate whether human SINE Alu repeats could have the same effect. The human E-cadherin gene has three SINE Alus adjacent to the 3’ region of its CpG island, and in reporter assays the removal of these repeats resulted in higher, stable promoter activity. Genome-wide analysis of SINE repeats distribution in the human and mouse genomes showed that they are excluded from proximal promoters and their enrichment is directly correlated with the presence of USF1, USF2 and CTCF binding, proteins with insulator function. In conclusion, our work supports the concept that SINE repeats interfere negatively with gene expression and that their presence near gene promoters is dependent on, and co-evolved with the presence of insulator elements.
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 2791. doi:10.1158/1538-7445.AM2011-2791
Abstract 2800: BAY 94-9392 – A new derivative of L-glutamate for tumor specific PET imaging
Authors: Koglin Norman , Mueller Andre , Friebe Matthias , Berndt Mathias , Schmitt-Willich Heribert , Gekeler Volker , Dinkelborg Ludger M. 
Published: June 2012

Abstract
There is a high demand for a tumor specific imaging, staging and therapy monitoring by PET. Currently, FDG (2-[F-18]fluoro-2-deoxyglucose) is the commonly used agent for tumor detection and staging. However, this method cannot differentiate between tumor and inflammatory lesions. In addition, FDG does not accumulate in tumors with low glycolytic activities, such as prostate cancer. It is not optimal for specific detection of brain tumors and metastases due to a high background signal resulting from healthy brain metabolism. The amino acids L-glutamine and L-glutamate as well as their corresponding transporters play a key role in the adapted intermediary metabolism of tumors. We synthesized and evaluated a new PET imaging agent BAY 94-9392, a derivative of L-glutamate. This agent was successfully used for tumor detection with high sensitivity and specificity as demonstrated in various preclinical models.
Methods: The radiosynthesis of (4S)-4-(3-[F-18]fluoropropyl)-L-glutamate (BAY 94-9392) was established on a commercial synthesis module. BAY 94-9392 was investigated in a variety of tumor cell lines as well as tumor models for uptake, biodistribution, mode of action, and its potential to differentiate between tumor versus inflammation.
Results: BAY 94-9392 is specifically transported by the cystine/glutamate exchanger (xCT, SLC7A11) and it is not metabolized. Compared to FDG, the agent displayed a high accumulation rate in a panel of tumor cells. PET imaging with excellent tumor visualization and high tumor to background ratios was achieved in a variety of preclinical tumor models. BAY 94-9392 did not accumulate in inflammatory lesions, whereas FDG shows a strong uptake in this turpentine oil induced and histopathologically confirmed rat model.
Conclusions: BAY 94-9392 is a new, promising tumor specific PET tracer. Both preclinical and clinical studies are in progress for further characterization.
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 2800. doi:10.1158/1538-7445.AM2011-2800