Publications
129 results found
Lubecka K, Kurzava L, Flower K, et al., 2016, Differences in gene-specific DNA methylation in blood DNA as a biomarker for early detection of hepatocellular carcinoma in populations at risk, AACR 107th Annual Meeting on Bioinformatics and Systems Biology, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Lubecka K, Kurzava L, Flower K, et al., 2016, Stilbenoids remodel the DNA methylation patterns in breast cancer cells and inhibit oncogenic NOTCH signaling through epigenetic regulation of MAML2 transcriptional activity, Carcinogenesis, Vol: 37, Pages: 656-668, ISSN: 1460-2180
DNA hypomethylation was previously implicated in cancer progression and metastasis. The purpose of this study was to examine whether stilbenoids, resveratrol and pterostilbene thought to exert anticancer effects, target genes with oncogenic function for de novo methylation and silencing, leading to inactivation of related signaling pathways. Following Illumina 450K, genome-wide DNA methylation analysis reveals that stilbenoids alter DNA methylation patterns in breast cancer cells. On average, 75% of differentially methylated genes have increased methylation, and these genes are enriched for oncogenic functions, including NOTCH signaling pathway. MAML2, a coactivator of NOTCH targets, is methylated at the enhancer region and transcriptionally silenced in response to stilbenoids, possibly explaining the downregulation of NOTCH target genes. The increased DNA methylation at MAML2 enhancer coincides with increased occupancy of repressive histone marks and decrease in activating marks. This condensed chromatin structure is associated with binding of DNMT3B and decreased occupancy of OCT1 transcription factor at MAML2 enhancer, suggesting a role of DNMT3B in increasing methylation of MAML2 after stilbenoid treatment. Our results deliver a novel insight into epigenetic regulation of oncogenic signals in cancer and provide support for epigenetic-targeting strategies as an effective anticancer approach.
Flower KJ, Shenker NS, el-Bahrawy M, et al., 2016, DNA methylation profiling to assess pathogenicity of BRCA1 unclassified variants in breast cancer, Epigenetics, Vol: 10, Pages: 1121-1132, ISSN: 1559-2308
Germline pathogenic mutations in BRCA1 increase risk of developing breast cancer. Screening for mutations in BRCA1 frequently identifies sequence variants of unknown pathogenicity and recent work has aimed to develop methods for determining pathogenicity. We previously observed that tumor DNA methylation can differentiate BRCA1-mutated from BRCA1-wild type tumors. We hypothesized that we could predict pathogenicity of variants based on DNA methylation profiles of tumors that had arisen in carriers of unclassified variants. We selected 150 FFPE breast tumor DNA samples [47 BRCA1 pathogenic mutation carriers, 65 BRCAx (BRCA1-wild type), 38 BRCA1 test variants] and analyzed a subset (n=54) using the Illumina 450K methylation platform, using the remaining samples for bisulphite pyrosequencing validation. Three validated markers (BACH2, C8orf31, and LOC654342) were combined with sequence bioinformatics in a model to predict pathogenicity of 27 variants (independent test set). Predictions were compared with standard multifactorial likelihood analysis. Prediction was consistent for c.5194-12G>A (IVS 19-12 G>A) (P>0.99); 13 variants were considered not pathogenic or likely not pathogenic using both approaches. We conclude that tumor DNA methylation data alone has potential to be used in prediction of BRCA1 variant pathogenicity but is not independent of estrogen receptor status and grade, which are used in current multifactorial models to predict pathogenicity.
French JD, Johnatty SE, Lu Y, et al., 2016, Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer, Oncotarget, Vol: 7, Pages: 6353-6368, ISSN: 1949-2553
Bolton KL, Tyrer J, Song H, et al., 2016, Common variants at 19p13 are associated with susceptibility to ovarian cancer (vol 42, pg 880, 2010), NATURE GENETICS, Vol: 48, Pages: 101-101, ISSN: 1061-4036
Bolton KL, Tyrer J, Song H, et al., 2015, Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer., Nature Genetics, Vol: 48, ISSN: 1546-1718
van veldhoven K, Polidoro S, Baglietto L, et al., 2015, Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis, Clinical Epigenetics, Vol: 7, ISSN: 1868-7083
Background. Interest in the potential of DNA methylation in peripheral blood as a biomarker of cancer risk is increasing. We aimed to assess whether epigenome-wide DNA methylation measured in peripheral blood samples obtained before onset of the disease is associated with increased risk of breast cancer.Methods. We report on three independent prospective nested case-control studies from the European Prospective Investigation into Cancer and Nutrition (EPIC-Italy, n=162 matched case-control pairs); the Norwegian Women and Cancer study (NOWAC, n=168 matched pairs); and the Breakthrough Generations Study (BGS, n=548 matched pairs). We used the Illumina 450k array to measure methylation in the EPIC and NOWAC cohorts. Whole genome bisulphite sequencing (WGBS) was performed on the BGS cohort using pooled DNA samples, combined to reach 50x-coverage across ~16 million CpG sites in the genome including 450k array CpG sites. Mean β values over all probes were calculated as a measurement for epigenome-wide methylation.Results. In EPIC we found that high epigenome-wide methylation was associated with lower risk of breast cancer (OR per 1SD=0.61, 95%CI 0.47–0.80; -0.2% average difference in epigenome-wide methylation for cases and controls). Specifically, this was observed in gene bodies (OR=0.51, 95%CI 0.38–0.69) but not in gene promoters (OR=0.92, 95%CI 0.64–1.32). The association was not replicated in NOWAC (OR=1.03 95%CI 0.81–1.30). The reasons for heterogeneity across studies are unclear. However, data from the BGS cohort was consistent with epigenome-wide hypomethylation in breast cancer cases across the overlapping 450k probe sites (difference in average epigenome-wide methylation in case and control DNA pools=-0.2%).Conclusions. We conclude that epigenome-wide hypomethylation of DNA from pre-diagnostic blood samples may be predictive of breast cancer risk and may thus be useful as a clinical biomarker.
Shenker NS, Flower KJ, Wilhelm-Benartzi C, et al., 2015, Transcriptional implications of intragenic DNA methylation in the estrogen receptor alpha gene in breast cancer cells and tissues, 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: American Association for Cancer Research, ISSN: 1538-7445
Lubecka-Pietruszewska K, Kurzava L, Buvala H, et al., 2015, Differential DNA methylation in peripheral blood DNA as a biomarker of hepatocellular carcinoma risk, 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Sobral-Leite M, Wesseling J, Smit VTHBM, et al., 2015, Annexin A1 expression in a pooled breast cancer series: association with tumor subtypes and prognosis, BMC MEDICINE, Vol: 13, ISSN: 1741-7015
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- Citations: 43
Shenker NS, Flower KJ, Wilhelm-Benartzi CS, et al., 2015, Transcriptional implications of intragenic DNA methylation in the oestrogen receptor alpha gene in breast cancer cells and tissues., BMC Cancer, Vol: 15, Pages: 337-337, ISSN: 1471-2407
BACKGROUND: DNA methylation variability regions (MVRs) across the oestrogen receptor alpha (ESR1) gene have been identified in peripheral blood cells from breast cancer patients and healthy individuals. In contrast to promoter methylation, gene body methylation may be important in maintaining active transcription. This study aimed to assess MVRs in ESR1 in breast cancer cell lines, tumour biopsies and exfoliated epithelial cells from expressed breast milk (EBM), to determine their significance for ESR1 transcription. METHODS: DNA methylation levels in eight MVRs across ESR1 were assessed by pyrosequencing bisulphite-converted DNA from three oestrogen receptor (ER)-positive and three ER-negative breast cancer cell lines. DNA methylation and expression were assessed following treatment with DAC (1 μM), or DMSO (controls). ESR1 methylation levels were also assayed in DNA from 155 invasive ductal carcinoma biopsies provided by the Breast Cancer Campaign Tissue Bank, and validated with DNA methylation profiles from the TCGA breast tumours (n = 356 ER-pos, n = 109 ER-neg). DNA methylation was profiled in exfoliated breast epithelial cells from EBM using the Illumina 450 K (n = 36) and pyrosequencing in a further 53 donor samples. ESR1 mRNA levels were measured by qRT-PCR. RESULTS: We show that ER-positive cell lines had unmethylated ESR1 promoter regions and highly methylated intragenic regions (median, 80.45%) while ER-negative cells had methylated promoters and lower intragenic methylation levels (median, 38.62%). DAC treatment increased ESR1 expression in ER-negative cells, but significantly reduced methylation and expression of ESR1 in ER-positive cells. The ESR1 promoter was unmethylated in breast tumour biopsies with high levels of intragenic methylation, independent of ER status. However, ESR1 methylation in the strongly ER-positive EBM DNA samples were very similar to ER-positive tumour cell lines. CONCLUSION:
Flanagan JM, Brook MN, Orr N, et al., 2015, Temporal Stability and Determinants of White Blood Cell DNA Methylation in the Breakthrough Generations Study, CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, Vol: 24, Pages: 221-229, ISSN: 1055-9965
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- Citations: 49
Flanagan JM, 2015, Epigenome-Wide Association Studies (EWAS): Past, Present, and Future, CANCER EPIGENETICS: RISK ASSESSMENT, DIAGNOSIS, TREATMENT, AND PROGNOSIS, Vol: 1238, Pages: 51-63, ISSN: 1064-3745
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- Citations: 76
Hedditch EL, Gao B, Russell AJ, et al., 2014, ABCA transporter gene expression and poor outcome in epithelial ovarian cancer, JNCI: Journal of the National Cancer Institute, Vol: 106, ISSN: 0027-8874
BackgroundATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown.MethodsThe relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA–mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan–Meier analysis and log-rank tests. All statistical tests were two-sided.ResultsAssociations with outcome were observed with ABC transporters of the “A” subfamily, but not with multidrug transporters. High-level expression of ABCA1 , ABCA6 , ABCA8 , and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e−6). The combined expression pattern of ABCA1 , ABCA5 , and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration.ConclusionsExpression of ABCA transporters was associate
Block MS, Charbonneau B, Vierkant RA, et al., 2014, Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer, CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, Vol: 23, Pages: 1421-1427, ISSN: 1055-9965
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- Citations: 10
Earp MA, Kelemen LE, Magliocco AM, et al., 2014, Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA, HUMAN GENETICS, Vol: 133, Pages: 481-497, ISSN: 0340-6717
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- Citations: 18
Charbonneau B, Moysich KB, Kalli KR, et al., 2014, Large-Scale Evaluation of Common Variation in Regulatory T Cell-Related Genes and Ovarian Cancer Outcome, CANCER IMMUNOLOGY RESEARCH, Vol: 2, Pages: 332-340, ISSN: 2326-6066
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- Citations: 22
Funes JM, Henderson S, Kaufman R, et al., 2014, Oncogenic transformation of mesenchymal stem cells decreases Nrf2 expression favoring in vivo tumor growth and poorer survival, Molecular Cancer, Vol: 13, ISSN: 1476-4598
BACKGROUND: The transcription factor Nrf2 is a key regulator of the cellular antioxidant response, and its activation by chemoprotective agents has been proposed as a potential strategy to prevent cancer. However, activating mutations in the Nrf2 pathway have been found to promote tumorigenesis in certain models. Therefore, the role of Nrf2 in cancer remains contentious. METHODS: We employed a well-characterized model of stepwise human mesenchymal stem cell (MSC) transformation and breast cancer cell lines to investigate oxidative stress and the role of Nrf2 during tumorigenesis. The Nrf2 pathway was studied by microarray analyses, qRT-PCR, and western-blotting. To assess the contribution of Nrf2 to transformation, we established tumor xenografts with transformed MSC expressing Nrf2 (n = 6 mice per group). Expression and survival data for Nrf2 in different cancers were obtained from GEO and TCGA databases. All statistical tests were two-sided. RESULTS: We found an accumulation of reactive oxygen species during MSC transformation that correlated with the transcriptional down-regulation of antioxidants and Nrf2-downstream genes. Nrf2 was repressed in transformed MSC and in breast cancer cells via oncogene-induced activation of the RAS/RAF/ERK pathway. Furthermore, restoration of Nrf2 function in transformed cells decreased reactive oxygen species and impaired in vivo tumor growth (P = 0.001) by mechanisms that included sensitization to apoptosis, and a decreased hypoxic/angiogenic response through HIF-1α destabilization and VEGFA repression. Microarray analyses showed down-regulation of Nrf2 in a panel of human tumors and, strikingly, low Nrf2 expression correlated with poorer survival in patients with melanoma (P = 0.0341), kidney (P = 0.0203) and prostate (P = 0.00279) cancers. CONCLUSIONS: Our data indicate that oncogene-induced Nrf2 repression is an adaptive response for certain cancers to acquire a pro-oxidant state that favors cell survival and in vivo tum
Charbonneau B, Block MS, Bamlet WR, et al., 2014, Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with <i>IL1A</i> and <i>TNFSF10</i>, CANCER RESEARCH, Vol: 74, Pages: 852-861, ISSN: 0008-5472
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- Citations: 36
Demetriou CA, Chen J, Polidoro S, et al., 2013, Methylome Analysis and Epigenetic Changes Associated with Menarcheal Age, PLOS One, Vol: 8, ISSN: 1932-6203
Reproductive factors have been linked to both breast cancer and DNA methylation, suggesting methylation as an importantmechanism by which reproductive factors impact on disease risk. However, few studies have investigated the link betweenreproductive factors and DNA methylation in humans. Genome-wide methylation in peripheral blood lymphocytes of 376healthy women from the prospective EPIC study was investigated using LUminometric Methylation Assay (LUMA). Also,methylation of 458877 CpG sites was additionally investigated in an independent group of 332 participants of the EPIC-Italysub-cohort, using the Infinium HumanMethylation 450 BeadChip. Multivariate logistic regression and linear models wereused to investigate the association between reproductive risk factors and genome wide and CpG-specific DNA methylation,respectively. Menarcheal age was inversely associated with global DNA methylation as measured with LUMA. For eachyearly increase in age at menarche, the risk of having genome wide methylation below median level was increased by 32%(OR:1.32, 95%CI:1.14–1.53). When age at menarche was treated as a categorical variable, there was an inverse dose-responserelationship with LUMA methylation levels (OR12–14vs.#11 yrs:1.78, 95%CI:1.01–3.17 and OR$15vs.#11 yrs:4.59, 95%CI:2.04–10.33; P for trend,0.0001). However, average levels of global methylation as measured by the Illumina technology were notsignificantly associated with menarcheal age. In locus by locus comparative analyses, only one CpG site had significantlydifferent methylation depending on the menarcheal age category examined, but this finding was not replicated bypyrosequencing in an independent data set. This study suggests a link between age at menarche and genome wide DNAmethylation, and the difference in results between the two arrays suggests that repetitive element methylation has a role inthe association. Epigenetic changes may be modulated by menarcheal age, or the associatio
Flanagan JM, Wilhelm-Benartzi CS, Metcalf M, et al., 2013, Association of somatic DNA methylation variability with progression-free survival and toxicity in ovarian cancer patients., Annals of Oncology, Vol: 24, Pages: 2813-2818, ISSN: 1569-8041
Eccles SA, Aboagye EO, Ali S, et al., 2013, Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer, Breast Cancer Research, Vol: 15, Pages: R-R, ISSN: 1465-542X
IntroductionBreast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.MethodsMore than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.ResultsThe 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease
Shenker NS, Ueland PM, Polidoro S, et al., 2013, DNA Methylation as a Long-term Biomarker of Exposure to Tobacco Smoke, EPIDEMIOLOGY, Vol: 24, Pages: 712-716, ISSN: 1044-3983
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- Citations: 130
Wilhelm-Benartzi CS, Koestler DC, Karagas MR, et al., 2013, Review of processing and analysis methods for DNA methylation array data, British Journal of Cancer, Vol: 109, Pages: 1394-1402, ISSN: 1532-1827
The promise of epigenome-wide association studies and cancer-specific somatic DNA methylation changes in improving our understanding of cancer, coupled with the decreasing cost and increasing coverage of DNA methylation microarrays, has brought about a surge in the use of these technologies. Here, we aim to provide both a review of issues encountered in the processing and analysis of array-based DNA methylation data and a summary of the advantages of recent approaches proposed for handling those issues, focusing on approaches publicly available in open-source environments such as R and Bioconductor. We hope that the processing tools and analysis flowchart described herein will facilitate researchers to effectively use these powerful DNA methylation array-based platforms, thereby advancing our understanding of human health and disease.
Brennan K, Flanagan JM, 2013, Genome-Wide Hypomethylation and Cancer Risk-Response, CANCER PREVENTION RESEARCH, Vol: 6, Pages: 754-754, ISSN: 1940-6207
White KL, Vierkant RA, Fogarty ZC, et al., 2013, Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome, CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, Vol: 22, Pages: 987-992, ISSN: 1055-9965
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- Citations: 18
Bojesen SE, Pooley KA, Johnatty SE, et al., 2013, Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer, NATURE GENETICS, Vol: 45, Pages: 371-384, ISSN: 1061-4036
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- Citations: 426
Stemke-Hale K, Shipman K, Kitsou-Mylona I, et al., 2013, Frequency of mutations and polymorphisms in borderline ovarian tumors of known cancer genes, MODERN PATHOLOGY, Vol: 26, Pages: 544-552, ISSN: 0893-3952
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- Citations: 14
Pharoah PDP, Tsai Y-Y, Ramus SJ, et al., 2013, GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer, Nature Genetics, Vol: 45, Pages: 362-370, ISSN: 1546-1718
Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10−9) and 10p12 (rs1243180, P = 1.8 × 10−8) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10−10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
Permuth-Wey J, Lawrenson K, Shen HC, et al., 2013, Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31, Nature Communications, Vol: 4, ISSN: 2041-1723
Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3′ untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene–environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10−8) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10−10). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
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