Journal articles on the topic 'Methylation frequencies'
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Cusack, Martin, and Paul Scotting. "DNA methylation in germ cell tumour aetiology: current understanding and outstanding questions." REPRODUCTION 146, no. 2 (August 2013): R49—R60. http://dx.doi.org/10.1530/rep-12-0382.
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Germ cell tumours (GCTs) are a diverse group of neoplasms that can be histologically subclassified as either seminomatous or non-seminomatous. These two subtypes have distinct levels of differentiation and clinical characteristics, the non-seminomatous tumours being associated with poorer prognosis. In this article, we review how different patterns of aberrant DNA methylation relate to these subtypes. Aberrant DNA methylation is a hallmark of all human cancers, but particular subsets of cancers show unusually high frequencies of promoter region hypermethylation. Such a ‘methylator phenotype’ has been described in non-seminomatous tumours. We discuss the possible cause of distinct methylation profiles in GCTs and the potential of DNA methylation to provide new targets for therapy. We also consider how recent developments in our understanding of this epigenetic modification and the development of genome-wide technologies are shedding new light on the role of DNA methylation in cancer aetiology.
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Jeong, D. H., M. Y. Youm, Y. N. Kim, K. B. Lee, M. S. Sung, H. K. Yoon, and K. T. Kim. "Promoter methylation of p16, DAPK, CDH1, and TIMP-3 genes in cervical cancer: correlation with clinicopathologic characteristics." International Journal of Gynecologic Cancer 16, no. 3 (2006): 1234–40. http://dx.doi.org/10.1136/ijgc-00009577-200605000-00043.
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This study was conducted to investigate the promoter methylation status of the p16, DAPK, CDH1, and TIMP-3 genes in primary cervical cancer and its correlation with clinicopathologic characteristics. Promoter methylation was evaluated using a methylation-specific polymerase chain reaction in 78 cervical cancer tissue specimens and 24 control, normal cervical tissue specimens. Clinicopathologic parameters were obtained from medical records, and the relationship between the discrete variables and the methylation status was evaluated. The frequencies of promoter methylation of p16, DAPK, CDH1, and TIMP-3 in cervical cancer were 57%, 44.9%, 52.6%, and 9%, respectively. Primary cervical cancer had significantly higher methylation frequencies for the p16 and DAPK promoters than did the control, normal cervix (P < 0.0001). The promoter methylation of TIMP-3 was significantly higher in adenocarcinoma than in squamous cell carcinoma (41.7% vs 3%, respectively, P = 0.0175). High-stage cancers exhibited an increased promoter methylation frequency for p16 (P = 0.0061). The promoter methylation of the p16 gene is a frequent event in cervical carcinogenesis and may have potential clinical application as a marker for the progression and prognosis of cancer.
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Jabbari, Kamel, and Giorgio Bernardi. "Cytosine methylation and CpG, TpG (CpA) and TpA frequencies." Gene 333 (May 2004): 143–49. http://dx.doi.org/10.1016/j.gene.2004.02.043.
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Yates, Phillip A., Robert Burman, James Simpson, Olga N. Ponomoreva, Mathew J. Thayer, and Mitchell S. Turker. "Silencing of Mouse Aprt Is a Gradual Process in Differentiated Cells." Molecular and Cellular Biology 23, no. 13 (July 1, 2003): 4461–70. http://dx.doi.org/10.1128/mcb.23.13.4461-4470.2003.
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ABSTRACT Mouse Aprt constructs that are highly susceptible to DNA methylation-associated inactivation in embryonal carcinoma cells were transfected into differentiated cells, where they were expressed. Construct silencing was induced by either whole-cell fusion of the expressing differentiated cells with embryonal carcinoma cells or by treatment of the differentiated cells with the DNA demethylating agent 5-aza-2′-deoxycytidine. Induction of silencing was enhanced significantly by the presence of a methylation center fragment positioned upstream of a truncated promoter comprised of two functional Sp1 binding sites. Initial silencing of the Aprt constructs was unstable, as evidenced by high spontaneous reversion frequencies (≈10−2). Stably silenced subclones with spontaneous reversion frequencies of <10−5 were isolated readily from the unstably silenced clones. These reversion frequencies were enhanced significantly by treatment of the cells with 5-aza-2′-deoxycytidine. A bisulfite sequence analysis demonstrated that CpG methylation initiated within the methylation center region on expressing alleles and that the induction of silencing allowed methylation to spread towards and eventually into the promoter region. Combined with the induction of revertants by 5-aza-2′-deoxycytidine, this result suggested that stabilization of silencing was due to an increased density of CpG methylation. All allelic methylation patterns were variegated, which is consistent with a gradual and evolving process. In total, our results demonstrate that silencing of mouse Aprt is a gradual process in the differentiated cells.
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Piras, Ignazio Stefano, Anna Costa, Maria Cristina Tirindelli, Andrea Stoccoro, Matthew J. Huentelman, Roberto Sacco, Fabio Coppedè, and Carla Lintas. "Genetic and epigenetic MTHFR gene variants in the mothers of attention-deficit/hyperactivity disorder affected children as possible risk factors for neurodevelopmental disorders." Epigenomics 12, no. 10 (May 2020): 813–23. http://dx.doi.org/10.2217/epi-2019-0356.
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Aim: To assess promoter methylation levels, gene expression levels and 677C>T/1298A>C genotype and allele frequencies of the MTHFR gene in 45 mothers of attention-deficit/hyperactivity disorder affected child/children (ADHDM) and compare it with age matched healthy control mothers (HCM). Materials & methods: High resolution melting analysis, quantitative real time PCR and PCR-RFLP were performed to assess methylation, gene expression and genotyping, respectively. Significance between ADHDM and HCM was assessed by linear (methylation and gene expression) and logistic regression (genotypes). Results: MTHFR gene expression levels were significantly higher in the ADHDM compared with the HCM group (adj-p < 7.7E-04). No differences in MTHFR promoter methylation level and 677C>T/1298A>C genotype frequencies were detected between ADHDM and HCM. Conclusion: We observed increased MTHFR expression levels not resulting from promoter methylation changes in ADHDM respect to HMC, potentially contributing to the ADHD condition in their children and deserving further investigation.
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Goyon, C., C. Barry, A. Grégoire, G. Faugeron, and J. L. Rossignol. "Methylation of DNA repeats of decreasing sizes in Ascobolus immersus." Molecular and Cellular Biology 16, no. 6 (June 1996): 3054–65. http://dx.doi.org/10.1128/mcb.16.6.3054.
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In Ascobolus immersus, DNA duplications are subject to the process of methylation induced premeiotically (MIP), which methylates the cytosine residues within the repeats and results in reversible gene silencing. The triggering of MIP requires pairing of the repeats, and its detection requires maintenance of the resulting methylation. MIP of kilobase-size duplications occurs frequently and leads to the methylation of all C residues in the repeats, including those belonging to non-CpG sequences. Using duplications of decreasing sizes, we observed that tandem repeats never escaped MIP when larger than 630 bp and showed a sudden and drastic drop in MIP frequencies when their sizes decreased from 630 to 317 bp. This contrasted with the progressive decrease of MIP frequencies observed with ectopic repeats, in which apparently the search for homology influences the MIP triggering efficiency. The minimal size actually required for a repeat to undergo detectable MIP was found to be close to 300 bp. Genomic sequencing and Southern hybridization analyses using restriction enzymes sensitive to C methylation showed a loss of methylation at non-CpG sites in short DNA segments, methylation being restricted to a limited number of CpG dinucleotides. Our data suggest the existence of two distinct mechanisms underlying methylation maintenance, one responsible for methylation at CpG sites and the other responsible for methylation at non-CpG sites.
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Derks, Sarah, Cindy Postma, Peter T. M. Moerkerk, Sandra M. van den Bosch, Beatriz Carvalho, Mario A. J. A. Hermsen, Walter Giaretti, et al. "Promoter Methylation Precedes Chromosomal Alterations in Colorectal Cancer Development." Analytical Cellular Pathology 28, no. 5-6 (January 1, 2006): 247–57. http://dx.doi.org/10.1155/2006/846251.
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Background: Colorectal cancers are characterized by genetic and epigenetic alterations. This study aimed to explore the timing of promoter methylation and relationship with mutations and chromosomal alterations in colorectal carcinogenesis. Methods: In a series of 47 nonprogressed adenomas, 41 progressed adenomas (malignant polyps), 38 colorectal carcinomas and 18 paired normal tissues, we evaluated promoter methylation status of hMLH1, O6MGMT, APC, p14ARF, p16INK4A, RASSF1A, GATA-4, GATA-5, and CHFR using methylation-specific PCR. Mutation status of TP53, APC and KRAS were studied by p53 immunohistochemistry and sequencing of the APC and KRAS mutation cluster regions. Chromosomal alterations were evaluated by comparative genomic hybridization. Results: Our data demonstrate that nonprogressed adenomas, progressed adenomas and carcinomas show similar frequencies of promoter methylation for the majority of the genes. Normal tissues showed significantly lower frequencies of promoter methylation of APC, p16INK4A, GATA-4, and GATA-5 (P-values: 0.02, 0.02, 1.1×10−5 and 0.008 respectively). P53 immunopositivity and chromosomal abnormalities occur predominantly in carcinomas (P values: 1.1×10−5 and 4.1×10−10). Conclusions: Since promoter methylation was already present in nonprogressed adenomas without chromosomal alterations, we conclude that promoter methylation can be regarded as an early event preceding TP53 mutation and chromosomal abnormalities in colorectal cancer development.
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Caban, Omar L., Aimee Pons, Nilka J. Barrios, and Adriana Baez. "Hypermethylation Status of Cancer-Associated Genes in Pediatric Acute Lymphoblastic Leukemia (ALL): Incidence and Potential Implications in Therapy." Blood 114, no. 22 (November 20, 2009): 4422. http://dx.doi.org/10.1182/blood.v114.22.4422.4422.
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Abstract Abstract 4422 Introduction Acute Lymphoblastic Leukemia (ALL) is the most common malignancy diagnosed in children, representing nearly one third of all pediatric cancers. Aberrant methylation of CpG island of the promoter region of genes causes gene silencing and could be critical in the initiation and progression ALL. Patients and Methods The study included a group of 10 de novo pediatric cases of ALL and 18 healthy control children. The cases were treated according to the University Children Hospital protocol and followed-up for 28 days. In the present study we assessed the methylation frequency of p14ARF, p15CDKN2B, p16CDKN2A, MLH1, CTNNB1, and APAF1 genes before cases started therapy (Day 0) and after completing the induction phase at Day 28. DNA was extracted from peripheral blood cells from cases and controls. Methylation status was performed using the MethyLight technique. The methylation index (MI; ratio between the number of genes methylated and the number of genes analyzed) was calculated and results were correlated to minimal residual disease (MRD) status of the cases. Results The gene most frequently methylated was p15CDKN2B (90% of cases on Day 0). Frequencies of p16CDKN2A, MLH1, CTNNB1 gene methylation were 80%, 70%, and 10% respectively. A coexistence of p15CDKN2B, p16CDKN2A and MLH1 gene methylation was observed. No patient showed methylation in p14ARF and APAF1 genes. The methylation index ranged from 0 to 0.67 with a median of 0.5. After induction therapy was completed (Day 28) the most frequently methylated gene was p15CDKN2B (80% of cases on Day 28). Frequencies of MLH1, p16CDKN2A, p14ARF and CTNNB1 gene methylation were 40%, 30%, 20% and 10% respectively. No patient showed methylation of the APAF1 genes on Day 28. The methylation index ranged from 0 to 0.67 with a median of 0.17 on Day 28. We found that after the induction treatment methylation of p15CDKN2B, p16CDKN2A, and MLH1 is a frequent event. Interestingly methylation of p14ARF was detected after induction. No significant differences in the frequencies of gene methylation and presence of minimal residual disease between patients with and without aberrant methylation, respectively, were found. We found that the methylation status was not associated with patient age at diagnosis, sex, FAB classification and cytogenetic changes. Conclusions Our findings suggest that aberrant methylation of p15CDKN2B gene is a frequent event in this pathology. The relationship between methylation of p15CDKN2B and leukemia has been reported previously. It appears that methylation of p15CDKN2B is an early event in ALL and continue to be present even after patients completed the induction treatment. Simultaneously, our data would confirm that, in our cohort, the methylation of p16CDKN2A and MLH1 gene promoters is a frequent event in pediatric ALL. However, to assess the impact of promoter methylation of these tumor suppressor genes on disease prognosis longer follow-up and a larger patient population is warranted. Disclosures: No relevant conflicts of interest to declare.
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Skeldal, Sune, Annelise Krogdahl, Jens Ahm Sørensen, Peter A. Andreasen, and Shan Gao. "CpG methylation of the PAI-1 gene 5’-flanking region is inversely correlated with PAI-1 mRNA levels in human cell lines." Thrombosis and Haemostasis 94, no. 09 (2005): 651–60. http://dx.doi.org/10.1160/th05-02-0114.
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SummaryThe physiological and pathophysiological functions of PAI-1 are related to its expression by specific cell types in normal and diseased tissues. We analysed the contribution of DNA methylation to the variation in PAI-1 mRNA levels in five cell lines. We found varying frequencies of methylation of 25 CpGs in the -805/+152 region of the PAI-1 gene in Bowes, MCF-7 and U937 cells, while little or no methylation was detected in Hep2 and HT-1080 cells. The methylation frequency was inversely correlated with PAI-1 mRNA level within its 20-fold range in Bowes, MCF-7,U937,and Hep2 cells, while the lack of methylation in both Hep2 and HT- 1080 cells suggested another mechanism behind the 150-fold higher level in HT-1080 cells than in Hep2 cells. However, all cell lines exhibited a high frequency of methylation of 10 CpGs in a CpG island at about -1800. Treatment with 5-aza-2‘-deoxycytidine led up to circa a 40-fold increase in the PAI-1 mRNA level and a strong decrease in the frequency of methylation in the -805/+152 region in Bowes, MCF-7 and U937. The histone deacetylase inhibitor trichostatin A induced a several fold increase of the PAI-1 mRNA level in cells with a high methylation frequency of the -805/+152 region. As compared with matched normal tissue, three samples of oral squamous cell carcinomas displayed decreased frequencies of methylation of the PAI-1 5' flanking region and increased levels of PAI-1 mRNA. These results for the first time implicate DNA methylation and histone acetylation in regulation of the PAI-1 gene, and indicate that without proper CpG islands in 5’-flanking region, trancription may be regulated by methylation of less dense CpGs in the 5’-flanking region rather than methylation of upstream CpG island.
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Zaletaev, Dmitry V., Vladimir V. Strelnikov, Tatiana V. Kekeeva, Valeria V. Zemliakova, Ekaterina B. Kuznetsova, and Dmitri S. Mikhaylenko. "Methylation anomalies in cancerogenesis: search for new genes, development of methods and DNA-markers for diagnosis." Ecological genetics 9, no. 3 (September 15, 2011): 27–32. http://dx.doi.org/10.17816/ecogen9327-32.
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The report considers the epigenetic defects and their diagnostics in tumors. Aberrant methylation of the promoter or regulatory region of a gene results in its functional inactivation, which is phenotypically similar to structural deletion. Cancerogenesis-associated genes are often methylated in tumors. Tumors differ in methylation frequencies, allowing differential diagnostics. Aberrant methylation of tumor suppressor genes occurs in early cancerogenesis, and its detection may be employed in presymptomatic and noninvasive diagnostics of tumors.
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Piras, Giovanna, Giuseppina Pala, Antonella Uras, Anna Calvisi, Maria Monne, Angelo D. Palmas, Annalisa Noli, et al. "Methylation of the PTEN Promoter Leads to PTEN Inactivation in Multiple Myeloma." Blood 112, no. 11 (November 16, 2008): 2717. http://dx.doi.org/10.1182/blood.v112.11.2717.2717.
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Abstract Aberrant methylation of CpG island of the promoter regions of genes is an important epigenetic mechanism, alternative to deletions or mutations, that cause the silencing of genes involved in carcinogenesis. We therefore investigated epigenetic events involved in multiple myeloma by screening 6 genes of interest for evidence of promoter hypermethylation. PATIENTS AND METHODS: The methylation patterns of the tumor suppressor genes p16INK4a (p16), E-cadherin (ECAD), FHIT and PTEN (negative regulator of AKT/PKB signalling pathway), Wnt signalling pathway antagonist genes WIF-1 and DKK-3 were determined in the bone marrow aspirates of 50 patients with Multiple Myeloma (MM) (37 at diagnosis; male 22; female 28; 68.8 median age. ISS stage: 47% stage I, 8% stage II and 45% stage III.), using the methylation-specific polymerase chain reaction after DNA bisulphite modification. Ten patients with monoclonal gammopathy of undetermined significance (MGUS) and 4 peripheral blood from controls were also evaluated. For statistical analysis Student t and Chi squared or Fisher exact tests were used. RESULTS: We found at least one hypermethylated gene in all MM patients. Gene methylation frequencies varied from 6% to 74%. ECAD, FHIT and p16 genes demonstrated a relatively high frequency of aberrant methylation with frequencies of 74%, 69% and 42%, respectively. WIF-1, PTEN, DKK-3 genes showed a low frequency of methylation with values of 28%, 14%, 6%, respectively. The methylation frequencies detected in MGUS were 91.6% for ECAD and FHIT, 41.6% for WIF-1, 16,6% for p16 and DKK3. The difference in methylation profile between MM and MGUS was statistically significant (X2= 37, df=5; p=0.0000). PTEN was found hypermethylated in 7/50 (14%) MM but none of MGUS or control samples were methylated. Of these 6 patients had IgG K isotype, 4 had abnormal cariotype with 13q deletion, one hyperdiploidia, one IgH rearrangements. Two patients were simultaneously hypermethylated in p16 gene promoter. No statistically significant correlation between methylation data and clinical parameters: gender, age, isotype of M component, type of light chain, haemoglobin, serum albumin level, calcium, β2 microglobulin, serum creatinine level, LDH, lytic bone lesions were found for any of examined genes. When correlation with Durie-Salmon Stage disease was tested hypermethylation of p16 and WIF-1 resulted more frequently associated with stage IIIA/B (p values 0.006 and 0.000, respectively). When gene methylation status and cytogenetics abnormalities were compared, we found that aberrant methylation of p16 and ECAD were significantly more frequent in MM patients with chromosome 13 abnormalities as sole entity or with 13q deletion associated to IgH translocations. By contrast, promoter hypermethylation of Wnt signalling antagonist genes was associated with 13q deletion co-occurring with a hyperdiploide cariotype. (X2=17; df=8 p value: 0.000). According to the number of methylated genes observed in each sample 48% MM had 3–4 hypermethylated genes. When differences between methylator phenotype and cytogenetics abnormalities were analyzed we found that 3–4 hypermethylated genes have the tendency to be associated with chromosome 13 abnormalities more often than with hyperdiploide cariotype (p value 0.05). CONCLUSION: Our results indicate that the accumulation of epigenetic events affecting genes regulating cell cycle control, cell adhesion and apoptosis is a common phenomenon in plasma cell disorders and may further contribute to the phenotype of MM cells. This is the first demonstration of PTEN inactivation as a result of promoter hypermethylation in MM patients. Since talidomide seems to have a role in the PTEN/PI3K/AKT pathway, the PTEN function is worthy to be further investigated in Multiple Myeloma.
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Shan, Ming, Lei Zhang, Yang Liu, Chunyang Gao, Wenli Kang, Weiwei Yang, Yan He, and Guoqiang Zhang. "DNA Methylation Profiles and Their Diagnostic Utility in BC." Disease Markers 2019 (May 6, 2019): 1–10. http://dx.doi.org/10.1155/2019/6328503.
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Biomarkers, including DNA methylation, have shown a great potential for use in personalized medicine for BC and especially for the diagnosis of BC in developing countries. According to the bisulfite sequencing PCR in twelve specimens (BC and matched normal tissues), nine genetic probes were designed to detect the frequency of methylation of the promoters in a total of 302 paired cases of BC and matched normal breast tissues. Finally, a total of 900 serum samples were used to validate the use of these methylation biomarkers for clinical diagnosis of BC. A high frequency of promoter methylation of SFN, HOXA11, P16, RARβ, PCDHGB7, hMLH1, WNT5a, HOXD13, and RASSF1a was observed in BC tissues. The methylation frequencies of HOXD13 and hMLH1 increased with the progression of BC. The methylation frequencies of HOXD13 and WNT5a were significantly higher in BC. We found that methylation modification-positive samples were most consistently associated with luminal BC. Finally, we confirmed that RASSF1a, P16, and PCDHGB7 displayed a significant sensitivity and specificity as diagnostic biomarkers for BC (P<0.001), and a panel that combined these three genes displayed increased significance (AUC, 0.781; P<0.001). These data suggest that epigenetic markers in serum can potentially be used to diagnose BC. The identification of additional BC-specific methylated genes would improve the sensitivity and specificity of this approach. This study could also indicate that different molecular subtypes of BC are caused by distinct genetic and epigenetic mechanisms.
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Moreira, Paula Rocha, Mariana Moreira Guimarães, Carolina Cavaliéri Gomes, Marina Gonçalves Diniz, João Artur Ricieri Brito, Wagner Henriques de Castro, and Ricardo Santiago Gomez. "Methylation frequencies of cell-cycle associated genes in epithelial odontogenic tumours." Archives of Oral Biology 54, no. 10 (October 2009): 893–97. http://dx.doi.org/10.1016/j.archoralbio.2009.07.006.
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Lita, Adrian, Joel Sjöberg, Stefan Filipescu, Orieta Celiku, Luigia Petre, Mark Gilbert, Houtan Noushmehr, Ion Petre, and Mioara Larion. "PATH-45. APOLLO: RAMAN-BASED PATHOLOGY OF MALIGNANT GLIOMA." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi125. http://dx.doi.org/10.1093/neuonc/noab196.497.
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Abstract BACKGROUND DNA methylation is an essential component for integrative diagnosis in glioma. Methylation subtype prediction of gliomas is currently done via sample extraction of high-quality of reasonable amount of DNA (~1ug), methylome profiling, followed by probe identification, curation and subsequent analysis via different random forest classifiers. However, the DNA methylation classification is not always available for all the samples. METHODS Raman Spectroscopy performed of the regions of interest using 1mm2 FFPE tissue spots from 45 patient samples with LGm1 to LGm6 methylation subtypes. Spectral information was then used to train a convolutional neural network (CNN) and develop a prediction algorithm. 70 % of dataset - model training while the remaining 30% for validation. Supervised wrapper methods and random forests were used to identify the top 109 most discriminatory Raman frequencies out of 1738. RESULTS We identified the most discriminatory features from these analyses and demonstrated that these frequencies show differential spectral intensities for these frequencies depending upon the glioma subtypes across the larger areas of the tissue. We compared the results of the Ward linkage clustering with the separation induced by the “frequency criterion”, an empirical observation that Raman spectra of tumor spots are characterized by intensities higher than 5000 on some of the frequencies from 1463 to 1473. For each of the 45 samples we ran Ward linkage clustering with a variable number of clusters (from 2 to 7), with the majority cluster corresponding to tumor spots and the others corresponding to (various types of) non-tumor spots. We found that the majority cluster matches very well the tumor spots characterized by the frequency criterion, The average accuracy over all samples was 90:3%, the average precision was 99:6% and the average recall was 90:2%. For most samples, two clusters were sufficient to distinguish between tumor and non-tumor spots with accuracy.
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Euhus, D., D. Bu, S. Milchgrub, A. M. Leitch, and C. M. Lewis. "Cell-based breast cancer risk stratification based on DNA methylation in fine needle aspiration samples." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 1508. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.1508.
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1508 Background: Tumor suppressor gene (TSG) methylation is identified in nearly all breast cancers, but rarely in histologically normal breast tissue from wonen unaffected with breast cancer. Its occurrence in high risk preneoplasia and in benign breast tissue adjacent to breast cancer suggests that it may represent a high risk field change that could be exploited for cell-based breast cancer risk stratification. Methods: TSG methylation was measured by quantitative methylation-specific real time PCR in 53 breast tumor fine needle aspiration (FNA) biopsies, 84 cellular random periareolar FNAs (RP-FNA) ipsilateral or contralateral to these cancers, 36 cellular RP- FNAs from unaffected women at high risk for breast cancer by the Gail model, and 95 cellular RP-FNAs from unaffected women at lower risk by the Gail model. Results: The breast tumors showed a high frequency of TSG methylation: RASSF1A 80%, HIN-1 65%, Cyclin D2 60%, RAR-β2 53%, and APC 47%. In general, RP-FNA samples from cancer patients and Gail high risk patients showed a greater frequency of methylation than samples from Gail lower risk patients: RASSF1A 43% vs. 21%, P = 0.001, HIN-1 32% vs. 20%, P = 0.05; Cyclin D2 18% vs. 9%, P = 0.10; RAR-β2 21% vs. 18%, P = 0.68; and APC 25% vs. 16%, P = 0.17. Twelve of 215 RP-FNA samples (5%) showed very high levels of methylation (>10% methylation for two or more genes). Only two of these samples were from women classified as lower risk by the Gail model. Methylation frequencies were entirely independent of cell yields but the frequency of RASSF1A methylation increased with increasing Masood scores (P = 0.05). Methylation of RASSF1A in one breast was highly predictive of RASSF1A methylation in the opposite breast (P < 0.0001). Conclusions: TSG methylation appears to be a breast cancer risk-associated field change that can be quantified in RP-FNA samples. RASSF1A methylation occurs frequently in benign breast epithelium, provides reasonable discrimination between high and lower risk breasts (O.R. = 2.0), is related to cytological atypia, and may be an early marker of a methylator phenotype. Quantification of TSG methylation in RP-FNA samples may provide a valuable surrogate endpoint biomarker for Phase II prevention trials. No significant financial relationships to disclose.
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Shen, Lanlan, Hagop Kantarjian, Hussain Saba, E. Lin, Don Berry, Saira Ahmed, Jaroslav Jelinek, and Jean-Pierre J. Issa. "CpG Island Methylation Is a Poor Prognostic Factors in Myelodysplastic Syndrome Patients and Is Reversed by Decitabine Therapy-Results of a Phase III Randomized Study." Blood 106, no. 11 (November 16, 2005): 790. http://dx.doi.org/10.1182/blood.v106.11.790.790.
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Abstract Background. In human neoplasia, aberrant methylation of CpG islands leads to gene silencing, and has an essential role in tumorigenesis through down regulation of tumor suppressor genes. A phase III randomized study comparing a DNA methyltransferase inhibitor; decitabine (DAC) versus supportive care has been completed recently in myelodysplastic syndrome (MDS) patients. The purpose of our study was to determine the prognostic significance of CpG islands methylation in these patients, to test the significance of methylation events in predicting drug response, and to explore the correlation between modulation of DNA methylation and response to DAC. Methods. DNA was extracted from blood and bone marrow of 89 patients before treatment (baseline) and also from a subset of 34 patients at multiple time-points and modified by bisulfite. In this study, we selected 24 CpG islands based on previous studies and ongoing efforts to identify methylated genes by MCA/RDA. For 14 genes, very low levels of methylation were detected in an initial group of 20 MDS patients, and we excluded them from further study. We then analyzed the methylation status of a total of 10 genes in all the samples. Bisulfite-PCR followed by Pyrosequencing was used to analyze DNA methylation levels of each gene. For statistical analysis, methylation levels of each gene were normalized by a Z score method, and each patient was assigned a methylation “score” based on the sum of Z scores for all genes, or a selected group of genes. Samples before and after treatment were available for 20 patients on supportive care (SC) and 14 patients on DAC, and methylation levles at each time point were averaged across the 10 genes. Results. Methylation frequencies of RIL, PGRA, PGRB, Olig2, p15, CDH13, NPM2, ECAD, NOR1 and ER ranged from 7% to 70% in MDS patients at baseline. Methylation levels of all these genes were significantly linked, suggesting concurrent methylation affected by CpG Island Methylator Phenotype (CIMP). There was no association between methylation by Z scores with age, IPSS, or cytogenetics. There was no correlation between baseline methylation and response to DAC therapy. By univariate analysis, methylation was significantly associated with both shortened overall survival and progression-free survival. In multivariate analysis, IPSS score and methylation were independent predictors of progression free survival, and methylation was the only independent predictor of overall survival. Methylation changes were then analyzed for correlation with response in 34 patients (Decitabine arm: 2 CR, 3 PR, 4HI, 4 SD, 1 PD; supportive care arm: 2 HI, 6 SD, 12 PD) at multiple time-points. At the latest available time-point (>4 months at therapy), methylation decreased by 11.2% in patients in DAC but increased by 20.1% in patients in SC. A greater decrease was observed in patients with CR or PR (40.6+/− 15.7%) compared to HI (9.8+/− 13.2%). Methylation increased by 15.4% in patients with SD and 27.2% in patients with PD. Conclusions. Concordant methylation of multiple genes suggests the existence of a CpG island methylator phenotype in MDS. This methylation was associated with poor prognosis and risk of leukemia transformation. Decitabine therapy was associated with reduced methylation over time, which was associated with clinical responses.
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Ou, Xiufang, Likun Long, Ying Wu, Yingjie Yu, Xiuyun Lin, Xin Qi, and Bao Liu. "Spaceflight-induced genetic and epigenetic changes in the rice (Oryza sativa L.) genome are independent of each other." Genome 53, no. 7 (July 2010): 524–32. http://dx.doi.org/10.1139/g10-030.
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An array of studies have reported that the spaceflight environment is mutagenic and may induce phenotypic and genetic changes in diverse organisms. We reported recently that in at least some plant species (e.g., rice) the spaceflight environment can be particularly potent in generating heritable epigenetic changes in the form of altered cytosine methylation patterns and activation of transposable elements. To further study the issue of spaceflight-induced genomic instability, and in particular to test whether the incurred genetic and epigenetic changes are connected or independent of each other, we performed the present study. We subjected seeds of the standard laboratory rice ( Oryza sativa L.) cultivar Nipponbare to a spaceflight in the spaceship Long March 2 for 18 days. We then investigated the genetic and DNA methylation stabilities of 11 randomly selected plants germinated from the spaceflown seeds by using two kinds of DNA markers, amplified fragment length polymorphism (AFLP) and methylation sensitive amplified polymorphism (MSAP). For AFLP, by using 15 primer combinations, we assessed 460 genomic loci and found that the frequencies of genetic changes across the 11 plants ranged from 0.7% to 6.7% with an average frequency of 3.5%. For MSAP, by using 14 primer combinations, we assessed 467 loci and detected the occurrence of four major types of cytosine methylation alterations at the CCGG sites, namely CG or CNG hypomethylation and CG or CNG hypermethylation. Collectively, the frequencies of the two kinds of hypermethylation, CG (1.95%) and CNG (1.44%), are about two times higher than those of the two kinds of hypomethylation, CG (0.76%) and CNG (0.80%), though different plants showed variable frequencies for each type of alteration. Further analysis suggested that both the genetic and cytosine methylation changes manifested apparent mutational bias towards specific genomic regions, but the two kinds of instabilities are independent of each other based on correlation analysis.
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Yan, Haidan, Jun He, Qingzhou Guan, Hao Cai, Lin Zhang, Weicheng Zheng, Lishuang Qi, et al. "Identifying CpG sites with different differential methylation frequencies in colorectal cancer tissues based on individualized differential methylation analysis." Oncotarget 8, no. 29 (May 7, 2017): 47356–64. http://dx.doi.org/10.18632/oncotarget.17647.
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Voropaeva, Elena N., Tatjana I. Pospelova, Yuriy L. Orlov, Maria I. Churkina, Olga V. Berezina, Anna A. Gurazheva, Tatjana A. Ageeva, Olga B. Seregina, and Vladimir N. Maksimov. "The Methylation of the p53 Targets the Genes MIR-203, MIR-129-2, MIR-34A and MIR-34B/C in the Tumor Tissue of Diffuse Large B-Cell Lymphoma." Genes 13, no. 8 (August 7, 2022): 1401. http://dx.doi.org/10.3390/genes13081401.
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The regulation of oncogenes by microRNA is a focus of medical research. hsa-miR-203, hsa-mir-129, hsa-miR-34a, hsa-miR-34b and hsa-miR-34c are oncosuppressive microRNAs that mediate the antitumor activity of p53. We seek to evaluate the frequencies, co-occurrence and clinical significance of the methylation of the MIR-203, MIR-129-2, MIR-34A and MIR-34B/C genes in the tumor tissue of diffuse large B-cell lymphoma (DLBCL). The methylation was assessed in 73 samples of DLBCL and in 11 samples of lymph nodes of reactive follicular hyperplasia by Methyl-Specific Polymerase Chain Reaction (MS-PCR) and Methylation-Sensitive High-Resolution-Melting (MS-HRM) methods. All four studied genes were not methylated in the tissue of reactive lymphatic nodes. The methylation frequencies of the MIR-129-2, MIR-203, MIR-34A and MIR-34B/C genes in lymphoma tissue were 67%, 66%, 27% and 62%, respectively. Co-occurrence of MIR-203, MIR-129-2 and MIR-34B/C genes methylation, as well as the methylation of MIR-34B/C and MIR-34A pair genes were detected. The MIR-34A gene methylation was associated with increased International Prognostic Index (IPI) (p = 0.002), whereas the MIR-34B/C (p = 0.026) and MIR-203 (p = 0.011) genes’ methylation was connected with Ki-67 expression level in tumor tissue at more than 45%. We found an increasing frequency of detection of MIR-34A gene methylation in the group of patients with the Germinal-Center B-cell like (GCB-like) subtype of DLBCL (p = 0.046). There was a trend towards a decrease in the remission frequency after the first line of therapy (p = 0.060) and deterioration in overall survival (OS) (p = 0.162) in patients with DLBCL with methylation of the MIR-34A promoter. The methylation of the MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 genes in DLBCL is tumor-specific and occurs in combination. The methylation of the studied genes may be a potential differential diagnostic biomarker to distinguish between lymphoma and reactive lymph nodes, while its independent predictive value has not been confirmed yet.
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Thuan, Lao Duc, Thieu Hong Hue, Hoang Van Nam, Nguyen Hoang Danh, Le Huyen Ai Thuy, Ngo Dong Kha, and Nguyen Hoang Anh Tuan. "In silico analysis of hypermethylation in CpGislands of UCHL1 gene’s promoter in nasopharyngeal carcinoma." ENGINEERING AND TECHNOLOGY 8, no. 1 (August 17, 2020): 28–34. http://dx.doi.org/10.46223/hcmcoujs.tech.en.8.1.333.2018.
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Background and Objective: The methylation of Ubiquitin C-Terminal Hydrolase L1 (UCHL1) gene has been reported in many human cancers including nasopharyngeal carcinoma (NPC). In Vietnam, the methylation of
UCHL1 gene’s promoter in NPC has not been demonstrated yet. In this study, a systematic literature revision was carried out to summarize the current evidences about the frequencies of UCHL-1 gene’s promoter methylation in
NPC for further application in Vietnamese population.
Methods: A systematic literature analysis was conducted based on the comprehensive studies. Moreover, many bioinformatic tools such as Methprimer, TFsearch, IDT OligoAnalyzer 3.1 were used to predict the CpG
islands, transcriptional factors, and to pick up the MSP (Methylation-Specific PCR) primers.
Results: Total of three previous studies were summarized and accessed for eligibility from literature research. As the results, the average weight methylated frequencies were 72.4% and 13.0% for NPC and non-cancerous
samples, respectively. The significant association between UCHL-1 promoter methylation and NPC with the OR of 10.459 (95% CI = 4.915 – 22.254, p < 0.001) and RR of 4.117 (95% CI = 1.958 – 6.645, p < 0.0001) based on the
random effects model, was observed. Moreover, we were successful in predicting the CpG islands as well as identifying transcriptional factor binding sites which served as “hot spot” for ideal primer pick up and located in gene promoter.
Conclusion: The methylation of UCHL-1 gene promoter was significantly associated and contributed to NPC developmentin which it could be further applied in evaluation of UCHL-1 gene promoter status in Vietnamese population.
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Pimson, Charinya, Tipaya Ekalaksananan, Chamsai Pientong, Supannee Promthet, Nuntiput Putthanachote, Krittika Suwanrungruang, and Surapon Wiangnon. "Aberrant methylation ofPCDH10andRASSF1Agenes in blood samples for non-invasive diagnosis and prognostic assessment of gastric cancer." PeerJ 4 (June 9, 2016): e2112. http://dx.doi.org/10.7717/peerj.2112.
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Background.Assessment of DNA methylation of specific genes is one approach to the diagnosis of cancer worldwide. Early stage detection is necessary to reduce the mortality rate of cancers, including those occurring in the stomach. For this purpose, tumor cells in circulating blood offer promising candidates for non-invasive diagnosis. Transcriptional inactivation of tumor suppressor genes, likePCDH10andRASSF1A, by methylation is associated with progression of gastric cancer, and such methylation can therefore be utilized as a biomarker.Methods.The present research was conducted to evaluate DNA methylation in these two genes using blood samples of gastric cancer cases. Clinicopathological data were also analyzed and cumulative survival rates generated for comparison.Results.High frequencies ofPCDH10andRASSF1Amethylations in the gastric cancer group were noted (94.1% and 83.2%, respectively, as compared to 2.97% and 5.45% in 202 matched controls). Most patients (53.4%) were in severe stage of the disease, with a median survival time of 8.4 months after diagnosis. Likewise, the patients with metastases, orRASSF1AandPCDH10methylations, had median survival times of 7.3, 7.8, and 8.4 months, respectively. A Kaplan–Meier analysis showed that cumulative survival was significantly lower in those cases positive for methylation ofRASSF1Athan in their negative counterparts. Similarly, whereas almost 100% of patients positive forPCDH10methylation had died after five years, none of the negative cases died over this period. Notably, the methylations ofRASSF1AandPCDH10were found to be higher in the late-stage patients and were also significantly correlated with metastasis and histology.Conclusions.PCDH10andRASSF1Amethylations in blood samples can serve as potential non-invasive diagnostic indicators in blood for gastric cancer. In addition toRASSF1Amethylation, tumor stage proved to be a major prognostic factor in terms of survival rates.
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Lita, Adrian, Joel Sjöberg, Stefan Filipescu, Orieta Celiku, Luigia Petre, Mark Gilbert, Houtan Noushmehr, Ion Petre, and Mioara Larion. "TBMT-02. APOLLO: RAMAN-BASED PATHOLOGY OF MALIGNANT GLIOMA." Neuro-Oncology Advances 3, Supplement_1 (March 1, 2021): i20. http://dx.doi.org/10.1093/noajnl/vdab024.084.
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Abstract BACKGROUND DNA methylation is an essential component for integrative diagnosis of gliomas. Methylation subtype prediction of gliomas is currently done via sample extraction of high-quality DNA (~1ug), methylome profiling, followed by probe identification, curation and subsequent analysis via different random forest classifiers. However, the DNA methylation classification is not always available for all the samples. Examples include when the existing material is not suitable for methylation profiling or the sample is very limiting. Therefore, we hypothesized that Raman spectroscopy might be suitable to predict the glioma methylome, based upon its ability to create a molecular fingerprint of the tumor and would provide biological insights unknown before. METHODS Coherent Raman Spectroscopy was used for molecular fingerprinting of the regions of interest using 1mm2 FFPE tissue spots from 39 patient samples with LGm1 to LGm6 methylation subtypes. Spectral information was then used to train a convolutional neural network (CNN) and develop a prediction algorithm, capable of detecting the glioma methylation subtypes. 70 % of the dataset was used for model training while the remaining 30% for validation. Oversampling was used to obtain a subtype-balanced data distribution. In addition, supervised wrapper methods and random forests were used to identify the top 50 most discriminatory Raman frequencies out of 1738. RESULTS We demonstrate that Raman spectroscopy can accurately and rapidly classify gliomas according to their methylation subtype from achieved FFPE samples, which are routinely present in pathological laboratories as a complementary mean to obtain this important classification when other analyses are not available. The most discriminatory frequencies show differential spectral intensities depending upon the glioma subtypes across the larger areas of the tissue. CONCLUSIONS The non-destructive nature of this method and the ability to be applied on FFPE samples directly, allows the histopathologist to reuse of the same slide for subsequent staining and downstream analyses.
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Kupčinskaitė-Noreikienė, Rita, Dainius Jančiauskas, and Elona Juozaitytė. "Frequency of gene hMLH1 promoter methylation in the stomach antral and body area tissue of chronic atrophic pangastritis patients." Acta medica Lituanica 20, no. 2 (September 19, 2013): 67–71. http://dx.doi.org/10.6001/actamedica.v20i2.2694.
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Aim. To compare hMLH1 methylation frequency in stomach antral and body area tissue in chronic atrophic pangastritis patients, and to evaluate possible correlation severity of chronic atrophic gastritis markers. Methods. The study population consisted of 24 participants (with histologically confirmed chronic atrophic pangastritis), who underwent upper endoscopy. Biopsy specimens were taken from the gastric antral and body area. The methylation status of the gene hMlH1 was investigated. Results. Methylation of the CpG island of gene hMLH1 was found in the antral stomach area group 9/24, compared with the body area 2/24. There was a significant difference in gene methylation frequencies in the observed stomach parts (Fisher’s exact test, p = 0.04). There was a significant association between gene hMLH1 methylation and the occurrence of severe atrophic gastritis, intestinal metaplasia and the presence of hyperplastic mucosal changes (Fisher’s exact test, p
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Karray-Chouayekh, Sondes, Fatma Trifa, Abdelmajid Khabir, Nouredine Boujelbane, Tahia Sellami-Boudawara, Jamel Daoud, Mounir Frikha, Ali Gargouri, and Raja Mokdad-Gargouri. "Clinical Significance of Epigenetic Inactivation of hMLH1 and BRCA1 in Tunisian Patients with Invasive Breast Carcinoma." Journal of Biomedicine and Biotechnology 2009 (2009): 1–7. http://dx.doi.org/10.1155/2009/369129.
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Aberrant hypermethylation of gene promoter regions is one of the mechanisms for inactivation of tumour suppressor genes in many human cancers including breast carcinoma. In the current study, we aimed to assess by MSP, the methylation pattern of two cancer-related genes involved in DNA repair: hMLH1 (mutL homolog 1,colon cancer,nonpolyposis type 2(E. coli) and BRCA1 (breast cancer 1,early onset) in 78 primary breast cancers from Tunisian patients. The methylation frequencies were 24.36% for hMLH1 and 46% for BRCA1. BRCA1 methylation correlated with age at diagnosis (P=.015) and 5-years disease free survival (P=.016) while hMLH1 methylation was more frequent in larger tumors (P=.002) and in presence of distant metastasis (P=.004). Furthermore, methylation of hMLH1 significantly correlated with high level of P53 expression (P=.006) and with overall survival (P=.015) suggesting that silencing of hMLH1 through aberrant promoter methylation could be used as a poor prognosis indicator in breast cancer.
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Guillerm, Gaëlle, Emmanuel Gyan, Darius Wolowiec, Thierry Facon, Hervé Avet-Loiseau, Kazimierz Kuliczkowski, Francis Bauters, Pierre Fenaux, and Bruno Quesnel. "p16 INK4a andp15INK4b gene methylations in plasma cells from monoclonal gammopathy of undetermined significance." Blood 98, no. 1 (July 1, 2001): 244–46. http://dx.doi.org/10.1182/blood.v98.1.244.
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Abstract p15INK4b and p16INK4a proteins are cell cycle regulators involved in the inhibition of G1 phase progression. High frequency of methylation of both genes has been reported in multiple myeloma (MM), but it remains to be determined how and when these alterations contribute to tumorigenesis. Monoclonal gammopathy of undetermined significance (MGUS) represents an early disease stage in a fraction of MMs. Plasma cells from 33 patients with MGUS and 33 patients with MM were isolated and analyzed forp15INK4b and p16INK4amethylation by methylation-specific polymerase chain reaction. Selective methylation was found in 19% forp16INK4a, 36% forp15INK4b, and 6.5% for both genes in MGUS, and frequencies were similar in MM suggesting that methylation of these genes is an early event, not associated with transition from MGUS to MM. p15INK4b andp16INK4a gene methylation might contribute to immortalization of plasma cells rather than malignant transformation in the natural history of MM.
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Tong, Hongyan, Chen Mei, Kongfei Li, and Jie Jin. "Methylation Analysis of the Wnt Antagonist in Myelodysplastic Syndrome." Blood 118, no. 21 (November 18, 2011): 5048. http://dx.doi.org/10.1182/blood.v118.21.5048.5048.
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Abstract Abstract 5048 Background and Objectives: Myelodysplastic syndrome (MDS) is one of the most threatening hematological malignancies. Recently, the epigenetic changes have been recognized in the MDS, and some research found that the aberrant DNA methylation had close relationship with the MDS. Meanwhile, some studies showed that the activation of the Wnt signaling pathway and abnormal methylation of the Wnt antagonists had close relationship with hematological malignancies, such as AML AALL Aand CLL, but less is known in MDS. In our research, we studied the methylation status of Wnt antagonists (DKK1, DKK3, HDPR1, WIF-1, SFRP1 and SFRP4) in the patients with MDS and evaluated the role of them in the pathogenesis and progression of MDS, with providing a new theory support for clarifying the complicated pathogenesis and progression of MDS. Methods: The methylation status of Wnt antagonists (DKK1, DKK3, HDPR1, WIF-1, SFRP1 and SFRP4) in pretreatment bone marrow samples from 53 patients with MDS was measured by methylation-specific polymerase chain reaction (MSP). On the other hand, we collected the clinical materials of the patients with MDS and follow up the patients. Then the correlation between methylation and clinical features as well as prognosis of MDS patients was analyzed byχ2 test and Kaplan-Meier method. Results: In 53 bone marrow samples, the methylation frequencies of the Wnt antagonists were as follows: SFRP4 for 62.3 % (33/53), DKK1 for 45.3 % (24/53), HDPR1 for 34.0 % (18/53), SFRP1 for 15.1 % (8/53), DKK3 for 9.4 % (5/53), and WIF-1 for 5.7 % (3/53). After analyzing individual tumor suppressor gene, clinical parameters and prognostic information, it was found that the patients with the percentage of BM blast above 5% had higher methylation frequency of HDPR1 than the patients with the percentage of BM blast bellow 5% (44.4%∼a13.3%, P=0.034); besides, the methylation frequency of HDPR1 exhibited significant differences in the MDS subtypes (P=0.019), and was significantly correlated with the WPSS (P=0.037); In addition, Kaplan-Meier survival curve indicated that the mean overall survival of patients with methylation was significantly shorter than that of patients without HDPR1 methylation (457.3 days vs. 919.6 days, P=0.037) (Fig.1). Conclusion: The methylation of the Wnt antagonists (DKK1, DKK3, HDPR1, WIF-1, SFRP1 and SFRP4) were observed in patients with MDS and their methylation frequencies were different. The aberrant methylation of HDPR1 may play an important role in the progression and prognosis of MDS. Disclosures: No relevant conflicts of interest to declare.
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Upadhyay, M., J. Samal, M. Kandpal, S. Vasaikar, B. Biswas, J. Gomes, and P. Vivekanandan. "CpG Dinucleotide Frequencies Reveal the Role of Host Methylation Capabilities in Parvovirus Evolution." Journal of Virology 87, no. 24 (October 9, 2013): 13816–24. http://dx.doi.org/10.1128/jvi.02515-13.
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Chen, L., Y. Wang, and Z. Yu. "Identification of epigenetic aberrant promoter methylation of RASSF1A in serum DNA and its clinicopathological significance in lung cancer." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 21014. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.21014.
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21014 Objective: To detect the hypermethylation status of RASSF1A promoter in serum DNA of lung cancer patients and to analyze its correlation with clinicopathological features. Methods: Serum DNA was extracted from peripheral blood from 80 primary lung cancer patients, 35 benign pulmonary disease patients and 15 healthy donors. The methylation status of RASSF1A promoter was determined using methylation-specific PCR technique, and the correlation between methylation profiles and clinicopathological parameters was statistically analyzed. Results: Aberrant methylation of RASSF1A was detected in 27 of the 80 (33.8%) patients with lung cancer but no benign pulmonary disease patients or healthy donors (p<0.001). RASSF1A was preferentially observed in small cell lung cancer (p=0.042), while no statistical difference was found among methylation frequencies of different subtypes of non-small cell lung cancer. The methylation status was also found to be associated with relative poor differentiation (p=0.009) and late stage (p=0.013), but not with gender, age or treatment. Conclusion: RASSF1A promoter is frequently hypermethylated in serum DNA of primary lung cancer patients, and RASSF1A is a promising novel biomarker for lung cancer diagnosis. No significant financial relationships to disclose.
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Chena, Christian, Carmen Stanganelli, Guillermo Arrossagaray, Julio Cesar Sanchez Avalos, and Irma Slavutsky. "Aberrant Methylation of Tumor Suppressor Genes in Chronic Lymphocytic Leukemia." Blood 112, no. 11 (November 16, 2008): 4156. http://dx.doi.org/10.1182/blood.v112.11.4156.4156.
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Abstract Aberrant methylation of CpG islands of the promoter regions of tumor suppressor genes (TSG) is now considered an important epigenetic mechanism for gene inactivation. Chronic lymphocytic leukemia (CLL) is the most frequent type of adult leukemia in the Western world, accounting for about 30% of all leukemic cases. It is characterized by a highly variable clinical course with survival times ranging from months to decades. Some patients have a more stable, indolent disease whereas others exhibit a progressive disease requiring early therapy. During this prolonged period of clinical history, different genetic alterations may be sequentially acquired, including aberrant promoter hypermethylation. In this study, we have evaluated methylation status of p15INK4b, p16INK4a, p14ARF, SOCS-1, p27KIP1, RASSF1A and TP73 (TAp73 isoform) genes in patients with CLL. Results were correlated with clinicopathologic characteristics of these patients. Thirty-three CLL patients (16 males; median age 65 years; Rai stage: 0: 9, I–II: 14 and III–IV: 10) were evaluated. All patients gave informed consent and the study was approved by the Ethics Committee of our Institution. Peripheral blood samples from 10 normal individuals and CpGenome Universal Methylated DNA (Chemicon International) were used as negative and positive controls, respectively. DNA was extracted from peripheral blood cells from patients and controls using phenol/chloroform method. Methylation status was performed using Methylation Specific PCR technique and DNA sequencing. For statistical analysis, Student’s t and Fisher’s exact tests were used. The methylation index (MI; ratio between the number of genes methylated and the number of genes analyzed) was also calculated. Cytogenetic and FISH (fluorescence in situ hybridization) analysis using specific DNA probes for CLL (LSI p53/ATM/13q14/13q34/CEP12, Vysis-Abbott) were also performed. The gene most frequently methylated was TP73 (70% of cases). Frequencies of p15INK4band p16INK4a gene methylation were 9% and 3%, respectively. A coexistence of p15INK4b and TP73 gene methylation was observed. No patient showed methylation in p14ARF, SOCS-1, p27KIP1 and RASSF1A genes. The methylation index ranged from 0 to 0.29 with a median of 0.14, corresponding to one gene/sample. No significant differences in the frequencies of cytogenetic (31,3% and 50%) and FISH genomic alterations (62% and 87,5%) between patients with and without aberrant methylation, respectively, were found. Similarly, the correlation with clinical characteristics: sex, age, Rai stage, lymphocytosis, β2 microglobulin, LDH, and treatment free survival in both groups of patients did not reach statistical significance. Our findings suggest that aberrant methylation of TP73 gene is a frequent event in this pathology. TAp73 isoform is involved in cell cycle arrest and apoptosis. Thus, its silencing could be important for CLL cells survival. Simultaneously, our data would confirm that, in Caucasian population, the methylation of p15INK4band p16INK4a gene promoters can be detected in a small subset of CLL patients.
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Kalantari, Mina, Itzel E. Calleja-Macias, Devansu Tewari, Bjørn Hagmar, Kathrine Lie, Hugo A. Barrera-Saldana, Dorothy J. Wiley, and Hans-Ulrich Bernard. "Conserved Methylation Patterns of Human Papillomavirus Type 16 DNA in Asymptomatic Infection and Cervical Neoplasia." Journal of Virology 78, no. 23 (December 1, 2004): 12762–72. http://dx.doi.org/10.1128/jvi.78.23.12762-12772.2004.
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ABSTRACT DNA methylation contributes to the chromatin conformation that represses transcription of human papillomavirus type16 (HPV-16), which is prevalent in the etiology of cervical carcinoma. In an effort to clarify the role of this phenomenon in the regulation and carcinogenicity of HPV-16, 115 clinical samples were studied to establish the methylation patterns of the 19 CpG dinucleotides within the long control region and part of the L1 gene by bisulfite modification, PCR amplification, DNA cloning, and sequencing. We observed major heterogeneities between clones from different samples as well as between clones from individual samples. The methylation frequency of CpGs was measured at 14.5%. In addition, 0.21 and 0.23%, respectively, of the CpA and CpT sites, indicators of de novo methylation, were methylated. Methylation frequencies exceeded 30% in the CpGs overlapping with the L1 gene and were about 10% for most other positions. A CpG site located in the linker between two nucleosomes positioned over the enhancer and promoter of HPV-16 had minimal methylation. This region forms part of the HPV replication origin and is close to binding sites of master-regulators of transcription during epithelial differentiation. Methylation of most sites was highest in carcinomas, possibly due to tandem repetition and chromosomal integration of HPV-16 DNA. Methylation was lowest in dysplasia, likely reflecting the transcriptional activity in these infections. Our data document the efficient targeting of HPV genomes by the epithelial methylation machinery, possibly as a cellular defense mechanism, and suggest involvement of methylation in HPV oncogene expression and the early-late switch.
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Onuchic, Vitor, Eugene Lurie, Ivenise Carrero, Piotr Pawliczek, Ronak Y. Patel, Joel Rozowsky, Timur Galeev, et al. "Allele-specific epigenome maps reveal sequence-dependent stochastic switching at regulatory loci." Science 361, no. 6409 (August 23, 2018): eaar3146. http://dx.doi.org/10.1126/science.aar3146.
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To assess the impact of genetic variation in regulatory loci on human health, we constructed a high-resolution map of allelic imbalances in DNA methylation, histone marks, and gene transcription in 71 epigenomes from 36 distinct cell and tissue types from 13 donors. Deep whole-genome bisulfite sequencing of 49 methylomes revealed sequence-dependent CpG methylation imbalances at thousands of heterozygous regulatory loci. Such loci are enriched for stochastic switching, which is defined as random transitions between fully methylated and unmethylated states of DNA. The methylation imbalances at thousands of loci are explainable by different relative frequencies of the methylated and unmethylated states for the two alleles. Further analyses provided a unifying model that links sequence-dependent allelic imbalances of the epigenome, stochastic switching at gene regulatory loci, and disease-associated genetic variation.
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Shen, Lanlan, Hagop Kantarjian, Yi Guo, E. Lin, Jianqin Shan, Xuelin Huang, Donald Berry, et al. "DNA Methylation Predicts Survival and Response to Therapy in Patients With Myelodysplastic Syndromes." Journal of Clinical Oncology 28, no. 4 (February 1, 2010): 605–13. http://dx.doi.org/10.1200/jco.2009.23.4781.
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Purpose The current classification systems of myelodysplastic syndromes (MDS), including the International Prognostic Scoring System (IPSS), do not fully reflect the molecular heterogeneity of the disease. Molecular characterization may predict clinical outcome and help stratify patients for targeted therapies. Epigenetic therapy using decitabine, a DNA hypomethylating agent, is clinically effective for the treatment of MDS. Therefore, we investigated the association between DNA methylation and clinical outcome in MDS. Patients and Methods We screened 24 patients with MDS for promoter CpG island methylation of 24 genes and identified aberrant hypermethylation at 10 genes. We then performed quantitative methylation analyses by bisulfite pyrosequencing of the identified genes in 317 patient samples from three independent studies and assessed relations between methylation and clinical outcome. Results In an initial training cohort of 89 patients with MDS, methylation frequencies of individual genes ranged from 7% to 70% and were highly concordant. Therefore, we defined a methylation z score based on all genes for each patient. We found that patients with higher levels of methylation, compared with patients with lower levels, had a shorter median overall survival (12.3 v 17.5 months, respectively; P = .04) and shorter median progression-free survival (6.4 v 14.9 months, respectively; P = .009). This methylation prognostic model was independent of age, sex, and IPSS group. Applied to two validation cohorts (228 patients), this model was confirmed as an independent prognostic predictor for survival. Although methylation at baseline did not correlate with clinical response to decitabine, we observed a significant correlation between reduced methylation over time and clinical responses. Conclusion DNA methylation predicts overall and progression-free survival in MDS.
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De Strooper, Lise M. A., Marjolein van Zummeren, Renske D. M. Steenbergen, Maaike C. G. Bleeker, Albertus T. Hesselink, G. Bea A. Wisman, Peter J. F. Snijders, Daniëlle A. M. Heideman, and Chris J. L. M. Meijer. "CADM1, MAL and miR124-2 methylation analysis in cervical scrapes to detect cervical and endometrial cancer." Journal of Clinical Pathology 67, no. 12 (October 3, 2014): 1067–71. http://dx.doi.org/10.1136/jclinpath-2014-202616.
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AimsGene promoter hypermethylation is recognised as an essential early step in carcinogenesis, indicating important application areas for DNA methylation analysis in early cancer detection. The current study was set out to assess the performance of CADM1, MAL and miR124-2 methylation analysis in cervical scrapes for detection of cervical and endometrial cancer.MethodsA series of cervical scrapes of women with cervical (n=79) or endometrial (n=21) cancer, cervical intraepithelial neoplasia grade 3 (CIN3) (n=16) or CIN2 (n=32), and women without evidence of CIN2 or worse (n=120) were assessed for methylation of CADM1, MAL and miR124-2. Methylation analysis was done by the PreCursor-M assay, a multiplex quantitative methylation-specific PCR.ResultsAll samples of women with cervical cancer (79/79, 100%), independent of the histotype, and 76% (16/21; 95% CI 58.0% to 94.4%) of women with endometrial cancer scored positive for DNA methylation for at least one of the three genes. In women without cancer, methylation frequencies increased significantly with severity of disease from 19.2% (23/120; 95% CI 12.1% to 26.2%) in women without CIN2 or worse to 37.5% (12/32; 95% CI 20.7% to 54.3%) and 68.8% (11/16; 95% CI 46.0% to 91.5%) in women with CIN2 and CIN3, respectively. Overall methylation positivity and the number of methylated genes increased proportionally to the lesion severity.ConclusionsDNA methylation analysis of CADM1, MAL and miR124-2 in cervical scrapes consistently detects cervical cancer and the majority of CIN3 lesions, and has the capacity to broaden its use on cervical scrapes through the detection of a substantial subset of endometrial carcinomas.
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Irelan, Jeffrey T., and Eric U. Selker. "Cytosine Methylation Associated With Repeat-Induced Point Mutation Causes Epigenetic Gene Silencing in Neurospora crassa." Genetics 146, no. 2 (June 1, 1997): 509–23. http://dx.doi.org/10.1093/genetics/146.2.509.
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Repeated DNA sequences are frequently mutated during the sexual cycle in Neurospora crassa by a process named repeat-induced point mutation (RIP). RIP is often associated with methylation of cytosine residues in and around the mutated sequences. Here we demonstrate that this methylation can silence a gene located in nearby, unique sequences. A large proportion of strains that had undergone RIP of a linked duplication flanking a single-copy transgene, hph (hygromycin B phosphotransferase), showed partial silencing of hph. These strains were all heavily methylated throughout the single-copy hph sequences and the flanking sequences. Silencing was alleviated by preventing methylation, either by 5-azacytidine (5AC) treatment or by introduction of a mutation (eth-I) known to reduce intracellular levels of S-adenosylmethionine. Silenced strains exhibited spontaneous reactivation of hph at frequencies of 10–4 to 0.5. Reactivated strains, as well as cells that were treated with 5AC, gave rise to cultures that were hypomethylated and partially hygromycin resistant, indicating that some of the original methylation was propagated by a maintenance mechanism. Gene expression levels were found to be variable within a population of clonally related cells, and this variation was correlated with epigenetically propagated differences in methylation patterns.
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Griffiths, Elizabeth A., Craig M. Hooker, Michael A. McDevitt, Judith E. Karp, James G. Herman, and Hetty E. Carraway. "Differences in Promoter Methylation of Tumor Suppressor Genes in Cytogenetically Normal and Abnormal Acute Myeloid Leukemias." Blood 112, no. 11 (November 16, 2008): 2249. http://dx.doi.org/10.1182/blood.v112.11.2249.2249.
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Abstract Methylation of CpG islands within the promoter regions of a number of tumor suppressor genes (TSG), including CTNNA1, CEBP-α, CEBP-δ, DAPK1, CDH1, ER1, FHIT, MLH1, MGMT, p15INK4b, p73, and SOCS1 have been reported in patients with myeloid malignancy. Promoter methylation of these genes has been associated with clinical prognosis. In myelodysplastic syndrome (MDS), methylation of CDH1, ER1, FHIT and p15INK4b have been reported to correlate with higher international prognostic system score (IPSS) and advanced disease. Despite these reports, there has been limited investigation of TSG methylation within the recognized paradigm of risk stratification for acute myeloid leukemias (AML). To elucidate whether distinct patterns of TSG methylation occur within prognostically important cytogenetic risk groups in patients with AML, we obtained 189 bone marrow samples from the Johns Hopkins Hospital leukemia tumor bank. Samples were annotated for age, karyotype, history of antecedent cytopenia(s) or MDS, and treatment. Patients had a median age of 61 years (interquartile range 48–70) and were treated with high dose induction therapy including timed sequential therapy at the Johns Hopkins Hospital. Samples were also analyzed for FLT3-ITD and NPM1 mutation status. For the purpose of analysis, samples were divided into those with normal cytogenetics (n=114) and those with cytogenetic abnormalities [favorable (n=14), intermediate (n=16), single adverse (n=14) and complex (n=30)]. Patients with normal cytogenetics (n=73) who were treated with high dose induction therapy at diagnosis were annotated for overall and event free survival and further subdivided into those with (n=33) and without (n=40) an antecedent hematologic diagnosis, in order to determine if TSG methylation was associated with survival. In addition, we studied patients with normal cytogenetics for whom only relapse samples were available (n=41) to confirm previous reports suggesting that promoter methylation may be enhanced at the time of relapse. RESULTS: Overall methylation frequencies were similar to those in the reported literature for CDH1 (28%;53/189), ER1 (27%;51/189), FHIT (10%;18/189), p15INK4b (42%;80/189), p73 (24%;45/189), and SOCS1 (71%;134/189). Methylation of DAPK was infrequent (2%;2/109). Methylation of CTNNA1, CEBP-α, CEBP-δ, MLH1 and MGMT have rarely been reported in patients with AML and were present in 10% (19/189), 15% (28/189), 2% (4/189), 22% (42/189) and 10% (18/189) of samples, respectively. No distinct patterns of methylation were observed amongst the cytogenetic groups. Significant differences in promoter methylation were seen between samples with a normal karyotype and those with any cytogenetic abnormality. CTNNA1 (14 vs. 4%), CEBP-α (24 vs. 9%), ER1 (43 vs. 14%) and FHIT (13 vs. 4%) were more frequently methylated in samples with a normal karyotype, while p73 methylation (12 vs. 35%) was more common in samples with a genetic abnormality (p<0.04 for all comparisons). In patients with normal cytogenetics, methylation of the above genes was not associated with event free or overall survival, even when adjusted for FLT3-ITD and NPM1 mutational status. Furthermore, no differences in methylation frequency were observed for those with and without a history of MDS. In those with a normal karyotype, methylation frequencies for the above genes were similar at diagnosis and relapse. In conclusion, in patients with AML (a) methylation of a number of genes is more frequent in patients with a normal karyotype; (b) in patients with normal cytogenetics, an antecedent hematological diagnosis does not affect methylation frequency; (c) the association of p73 methylation with cytogenetic abnormalities may reflect the known role of p73 in maintaining genetic stability; and (d) no significant acquisition of methylation is observed at the time of relapse in patients with normal cytogenetics.
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Wang, Chuan-Ming, Rasmus Y. Brogaard, Bert M. Weckhuysen, Jens K. Nørskov, and Felix Studt. "Reactivity Descriptor in Solid Acid Catalysis: Predicting Turnover Frequencies for Propene Methylation in Zeotypes." Journal of Physical Chemistry Letters 5, no. 9 (April 14, 2014): 1516–21. http://dx.doi.org/10.1021/jz500482z.
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Ahuja, Nita, Ruby Kwak, Brian Keeley, Alejandro Stark, Angela Anna Guzzetta, Christopher Lee Wolfgang, James Gordon Herman, Christine A. Iacobuzio-Donahue, and Tza Huei Wang. "Blood-based screening for methylation changes in colorectal cancer patients using novel nanotechnologies." Journal of Clinical Oncology 31, no. 4_suppl (February 1, 2013): 384. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.384.
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384 Background: Identification of blood-based biomarkers for cancer screening is essential in order to develop novel and minimally invasive methods for colorectal cancer screening. Our lab has successfully applied a novel nanotechnology that allows us to detect and amplify a single tumor DNA fragment in a plasma sample. This DNA is tested for methylation of several genes including TFPI2 which has shown to be highly sensitive and specific for the detection colorectal cancer in stool. Methods: Whole blood was obtained from 18 colorectal cancer patients and plasma was isolated. Plasma was processed using Methylation On Beads nanotechnology (MOB) and bisulfate treated. Methylation status was determined via quantitative PCR method. Results: Two genes, TFPI2 and IGFBP3, were detected with a high sensitivity. TFPI2, demonstrated a methylation frequency of 94.4%, which is concordant with the TFPI2 methylation frequency of 99% in primary colorectal cancer tissues. IGFBP3 showed the methylation frequency of 61.1%, which corresponds with the methylation frequency of 52% in retrospective colorectal cancer tissues in previous studies. Quantification using standard curves indicated a single copy level of DNA found in plasma. Conclusions: Blood-based screening is challenging due to extremely low quantities of circulating DNA in blood. Utilizing a novel nanotechnology that detects DNA at a single copy level, the methylation changes in colorectal cancer were successfully detected in plasmas at similar frequencies as in tissue samples. This study has demonstrated the feasablility and applicability to blood-based screening. Future studies will focus on improving the sensitivity and determining the specificity of this method.
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Fu, Rong, Xiaoshuang Chen, and Zonghong Shao. "Plasma DNA Methylation of p16 and shp1 in Patients with B-Cell Non-Hodgkin Lymphoma." Blood 124, no. 21 (December 6, 2014): 5369. http://dx.doi.org/10.1182/blood.v124.21.5369.5369.
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Abstract To discuss the clinical implications of cell free DNA, methylation status of the p16 and shp1 genes in plasma DNA from patients with B-NHL were analyzed. Methylation specific polymerase chain reaction (MSP) was used to detect the methylation status of these genes in plasma, peripheral blood leukocytes (PBLs), and formaldehyde-fixed, paraffin-embedded (FFPE) tumor tissues of 73 B-NHL patients. Results showed methylation frequencies of p16 in plasma, PBLs, and FFPE tumor tissues of B-NHL patients were 37%(27/73), 16% (12/73), 39% (16/41); Whereas those of shp1 were 47% (34/73), 25% (18/73), 63% (26/41). High methylation consistencies of p16/shp1 were observed between plasma and FFPE tumor tissues. In plasma and FFPE tumor tissues, there was a higher frequency of methylated p16 in B-NHL patients who had later disease stage, while no similar association was observed in PBLs samples; Higher frequency of methylated p16 was observed in B-NHL patients who had B symptoms and lower platelet count (<100×109/L) in all three samples. Methylated shp1 was frequently detected in patients with high serum LDH level. In summary, DNA methylation in plasma may be promising biomarkers for B-NHL diagnosis, prognosis evaluation, and targeted therapy. Disclosures No relevant conflicts of interest to declare.
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Broday, Limor, Yong-Woo Lee, and Max Costa. "5-Azacytidine Induces Transgene Silencing by DNA Methylation in Chinese Hamster Cells." Molecular and Cellular Biology 19, no. 4 (April 1, 1999): 3198–204. http://dx.doi.org/10.1128/mcb.19.4.3198.
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ABSTRACT The cytosine analog 5-azacytidine (5-AzaC) is a demethylating agent that is also known to induce mutagenesis in mammalian cells. In this study, the mutagenic potential of this drug was tested in the G10 and G12 transgenic Chinese hamster cell lines, which have a single bacterial gpt gene integrated into the genome at different sites, with its expression driven by a simian virus 40 (SV40) promoter. We show that the mutation frequencies following a 48-h exposure to different concentrations of 5-AzaC were 10 to 20 times higher than those of any of the other numerous mutagens that have been tested in the G10-G12 system. Moreover, the mutation frequencies were much higher in the G10 cell line than in the G12 cells. Detailed molecular analysis of the 6-thioguanine (6-TG)-resistant variants demonstrated that transgene silencing by de novo DNA methylation and increased chromatin condensation in the SV40 promoter was the major factor responsible for this high level of 6-TG resistance. As would be expected, exposure to 5-AzaC lowered the overall genomic DNA methylation levels, but it unexpectedly caused hypermethylation and increased chromatin condensation of the transgene in both the G10 and G12 cell lines. These results provide the first evidence that 5-AzaC may also induce transgene-specific DNA methylation, a phenomenon that can further be used for the elucidation of the mechanism that controls silencing of foreign DNA.
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Chen, Shi, Mengqi Li, Wenqiang Xin, Shengze Liu, Linfei Zheng, Yan Li, Mengyao Li, Mengxiong Zhan, and Xinyu Yang. "Intracranial aneurysm’s association with genetic variants, transcription abnormality, and methylation changes in ADAMTS genes." PeerJ 8 (February 14, 2020): e8596. http://dx.doi.org/10.7717/peerj.8596.
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Purpose The development of intracranial aneurysm (IA) has been linked to genetic factors. The current study examines the potential role of genes encoding disintegrin and metalloproteinase using thrombospondin motifs (ADAMTS) in IA development. Material and Methods High-throughput whole-genome and whole-exome sequencing were used when screening for deleterious single-nucleotide variants (SNVs) in ADAMTS genes using samples from 20 Han Chinese patients: 19 with familial IA and one patient with sporadic IA. The variant frequencies in these subjects were compared to those in control individuals found in the Genome Aggregation Database. Transcriptome sequencing and methylation sequencing data were retrieved from the Gene Expression Omnibus (GEO) database to identify differentially expressed ADAMTS genes and their methylation sites. We predicted the network of interactions among proteins encoded by the overlapping set of ADAMTS genes showing deleterious variants and both differential expression and abnormal methylation in IA. Possible candidate proteins linked to IA were validated using Western blot analysis. The associations between IA and SNVs rs11750568 in ADAMTS2, as well as rs2301612 and rs2285489 in ADAMTS13, were verified using the Sequenom MassArray system on a separate sample set of 595 Han Chinese patients with sporadic IA and 600 control individuals. Results A total of 16 deleterious variants in 13 ADAMTS genes were identified in our patients, and seven of these genes overlapped with the genes found to be differentially expressed and differentially methylated in the GEO database. Protein–protein interaction analysis predicted that ADAMTSL1 was at the center of the seven genes. ADAMTSL1 protein was lower expressed in IA tissue than in the control cerebral artery. Frequencies of the IA-related SNVs rs11750568 in ADAMTS2 and rs2301612 and rs2285489 in ADAMTS13 were not significantly different between sporadic IA patients and controls. Conclusion IA is associated with genetic variants, differential expression, and abnormal methylation in ADAMTS genes, ADAMTSL1 in particular.
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Chen, Y., H. Feng, D. Chen, K. Abuduwaili, X. Li, and H. Zhang. "Protective effects of folic acid on DNA damage and DNA methylation levels induced by N-methyl-N′-nitro-N-nitrosoguanidine in Kazakh esophageal epithelial cells." Human & Experimental Toxicology 37, no. 12 (April 12, 2018): 1258–67. http://dx.doi.org/10.1177/0960327118769709.
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The protective effects of folic acid on DNA damage and DNA methylation induced by N-methyl- N′-nitro- N-nitrosoguanidine (MNNG) in Kazakh esophageal epithelial cells were investigated using a 3 × 3 factorial design trial. The cells were cultured in vitro and exposed to media containing different concentrations of folic acid and MNNG, after which growth indices were detected. DNA damage levels were measured using comet assays, and genome-wide DNA methylation levels (MLs) were measured using high-performance liquid chromatography. The DNA methylation of methylenetetrahydrofolate reductase (MTHFR) and folate receptor- α (FR α) genes was detected by bisulfite sequencing polymerase chain reaction (PCR). The results showed significant increases in tail DNA concentration, tail length, and Olive tail moment ( p < 0.01); a significant reduction of genome-wide DNA MLs ( p < 0.01); and an increase in the methylation frequencies of MTHFR and FR α genes. In particular, significant differences were observed in the promoter regions of both genes ( p < 0.01). Our study indicated that a reduction in folic acid concentration promotes DNA damage and DNA methylation in Kazakh esophageal epithelial cells upon MNNG exposure. Thus, sufficient folic acid levels could play a protective role against the damage induced by this compound.
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Parrella, Paola, Antonella la Torre, Massimiliano Copetti, Vanna M. Valori, Raffaela Barbano, Angelo Notarangelo, Michele Bisceglia, et al. "High Specificity of Quantitative Methylation-Specific PCR Analysis forMGMTPromoter Hypermethylation Detection in Gliomas." Journal of Biomedicine and Biotechnology 2009 (2009): 1–8. http://dx.doi.org/10.1155/2009/531692.
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Normal brain tissue from 28 individuals and 50 glioma samples were analyzed by real-time Quantitative Methylation-Specific PCR (QMSP). Data from this analysis were compared with results obtained on the same samples by MSP. QMSP analysis demonstrated a statistically significant difference in both methylation level (P=.000009Mann Whitney Test) and frequencies (P=.0000007, Z-test) in tumour samples as compared with normal brain tissues. Although QMSP and MSP showed similar sensitivity, the specificity of QMSP analysis was significantly higher (93%; CI95%: 84%–100%) as compared with MSP (64%; 95%CI: 46%–82%). Our results suggest that QMSP analysis may represent a powerful tool to identify glioma patients that will benefit from alkylating agents chemotherapy.
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Lao, Thuan Duc, Hue Hong Thieu, Dung Huu Nguyen, and Thuy Ai Huyen Le. "Hypermethylation of the RASSF1A gene promoter as the tumor DNA marker for nasopharyngeal carcinoma." International Journal of Biological Markers 37, no. 1 (December 22, 2021): 31–39. http://dx.doi.org/10.1177/17246008211065472.
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Background RASSF1A is a tumor suppressor gene. The methylation of RASSF1A has been reported to be associated with nasopharyngeal tumorigenesis. However, the heterogeneity was high among different studies. A meta-analysis was performed to evaluate the value of RASSF1A methylation for the diagnosis and early screening of nasopharyngeal carcinoma. Methods Relevant articles were identified by searching the MEDLINE database. Frequency and odds ratio (OR) were applied to estimate the effect of CDH-1 methylation based on random-/fixed-effect models. The meta-analysis was performed by using MedCalc® software. Subgroup analyses were performed by test method, ethnicity, and source of nasopharyngeal carcinoma samples to determine likely sources of heterogeneity. Results A total of 17 studies, including 1688 samples (1165 nasopharyngeal carcinoma samples, and 523 from non-cancerous samples) were used for the meta-analysis. The overall frequencies of RASSF1A methylation were 59.68% and 2.65% in case-group and control-group, respectively. By removing the poor relative studies, the heterogeneity was not observed among the studies included. The association between RASSF1A gene methylation and the risk of nasopharyngeal carcinoma was also confirmed by calculating the OR value of 30.32 (95%CI = 18.22–50.47) in the fixed-effect model (Q = 16.41, p = 0.36,I 2 = 8.62, 95% CI = 0.00–45.27). Additionally, the significant association was also found between the methylation of the RASSF1A gene and the subgroups. Conclusions This is the first meta-analysis that has provided scientific evidence that the methylation of RASSF1A is the potential diagnosis, prognosis, and early screening biomarker for nasopharyngeal carcinoma.
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Zhang, Zhiming, Jian Gao, Cheng Qin, Li Liu, Haijian Lin, Yaou Shen, Shibin Gao, Maojun Zhao, Haiping Ding, and Guangtang Pan. "A High-Through Technique to Measure DNA Methylation." Genetics & Epigenetics 3 (January 2010): GEG.S5035. http://dx.doi.org/10.4137/geg.s5035.
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MethyLight is a sodium-bisulfite-dependent, quantitative, fluorescence-based, real-time PCR strategy that is used to detect and quantify DNA methylation in genomic DNA. High-throughput MethyLight allows the rapid and sensitive detection of very low frequencies of hypermethylated alleles in populations of alternated individuals. The high sensitivity and specificity of MethyLight can be applied not only to make it uniquely suited disease clinical but also quantitatively assessed of these low-frequency methylation events. Owing to its full of advantages of simple procedure, high efficiency and high sensitivity, MethyLight provides a powerful approach for clinical examination, Gene expression analysis, SNP analysis and allele analysis. Coupled with other techniques, MethyLight can be used immediately in identifying allelic alterations in genes exhibiting expressions correlating with phenotypes, Locating an allelic series of induced point mutations in genes of interest. The development of this technique should considerably enhance our ability to rapidly and accurately generate epigenetic profiles of samples.
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Daniunaite, Kristina, Arnas Bakavicius, Kristina Zukauskaite, Ieva Rauluseviciute, Juozas Rimantas Lazutka, Albertas Ulys, Feliksas Jankevicius, and Sonata Jarmalaite. "Promoter Methylation of PRKCB, ADAMTS12, and NAALAD2 Is Specific to Prostate Cancer and Predicts Biochemical Disease Recurrence." International Journal of Molecular Sciences 22, no. 11 (June 5, 2021): 6091. http://dx.doi.org/10.3390/ijms22116091.
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The molecular diversity of prostate cancer (PCa) has been demonstrated by recent genome-wide studies, proposing a significant number of different molecular markers. However, only a few of them have been transferred into clinical practice so far. The present study aimed to identify and validate novel DNA methylation biomarkers for PCa diagnosis and prognosis. Microarray-based methylome data of well-characterized cancerous and noncancerous prostate tissue (NPT) pairs was used for the initial screening. Ten protein-coding genes were selected for validation in a set of 151 PCa, 51 NPT, as well as 17 benign prostatic hyperplasia samples. The Prostate Cancer Dataset (PRAD) of The Cancer Genome Atlas (TCGA) was utilized for independent validation of our findings. Methylation frequencies of ADAMTS12, CCDC181, FILIP1L, NAALAD2, PRKCB, and ZMIZ1 were up to 91% in our study. PCa specific methylation of ADAMTS12, CCDC181, NAALAD2, and PRKCB was demonstrated by qualitative and quantitative means (all p < 0.05). In agreement with PRAD, promoter methylation of these four genes was associated with the transcript down-regulation in the Lithuanian cohort (all p < 0.05). Methylation of ADAMTS12, NAALAD2, and PRKCB was independently predictive for biochemical disease recurrence, while NAALAD2 and PRKCB increased the prognostic power of multivariate models (all p < 0.01). The present study identified methylation of ADAMTS12, NAALAD2, and PRKCB as novel diagnostic and prognostic PCa biomarkers that might guide treatment decisions in clinical practice.
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Tantray, Javeed Ahmad, Karnati Pratap Reddy, Kaiser Jamil, Waseem Gul Lone, and Shiva Kumar Yerra. "Genetic and Epigenetic Factors of E3/E3 Genotypes of APO-E Gene as a Strong Predictor for the Diagnosis of Coronary Artery Disease Patients of South India." Current Proteomics 17, no. 2 (January 30, 2020): 147–53. http://dx.doi.org/10.2174/1570164616666190724095158.
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Background: The role of Apolipoprotein-E (APO-E) in lipid metabolism and cholesterol transport is a key component of lipid metabolism which plays a role in diseases like hypercholesterolemia, diabetes, and cardiovascular disease. The aim of this study was to determine the genotypes, allelic frequencies, gene expression and methylation related to apolipoprotein E polymorphism in Coronary Artery Disease (CAD) patients and compare with non-CAD healthy subjects of South Indian population. Methods: The APO-E alleles and genotypes were determined by PCR-RFLP. Gene expression profiles for E3/E3 genotypes were determined using RT-PCR and methylation status was determined using Methyl Specific PCR assay in one hundred patients and an equal number of controls. Results: Four APO-E genotypes (E4/E4, E3/E3, E3/E4, and E2/E3) were identified with different allele frequency. Among these, E3/E3 genotype and E3 allele were found to be significantly higher in cases than controls. The present study showed that the mRNA expression of APO-E was up-regulated in CAD patients with E3/E3 genotype in comparison with controls. Methylation status indicated a significant association of E3/E3 genotypes with the disease. Conclusion: Different populations studied worldwide showed inherent variable frequencies of the APO-E alleles and genotypes, with the most frequent allele being E3. In this study, the APO-E genotypes E2/E3/E4 showed variable response to CAD, further, there was a significant association of E3/E3 genotypes to CAD risk; this genotype can be suggested for the diagnosis of CAD.
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Chan, Annie O., Amr S. Soliman, Qing Zhang, Asif Rashid, Ahmed Bedeir, P. Scott Houlihan, Nadia Mokhtar, et al. "Differing DNA Methylation Patterns and Gene Mutation Frequencies in Colorectal Carcinomas from Middle Eastern Countries." Clinical Cancer Research 11, no. 23 (December 1, 2005): 8281–87. http://dx.doi.org/10.1158/1078-0432.ccr-05-1000.
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Rodriguez, M. P., G. D. L. Cervigni, C. L. Quarin, and J. P. A. Ortiz. "Frequencies and variation in cytosine methylation patterns in diploid and tetraploid cytotypes of Paspalum notatum." Biologia plantarum 56, no. 2 (June 1, 2012): 276–82. http://dx.doi.org/10.1007/s10535-012-0087-1.
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Mir, Ab Rashid, Imtiyaz Ahmad Najar, Prasant Yadav, Jamsheed Javed, Mariyam Zubari, Shazia Farooq, Gauri Gandhi, Prakash C. Ray, Sagar Dholariya, and Alpana Saxnena. "Prognostic and diagnostic significance of epigenetic alterations of p16 and DAPK1 promoter sequences in patients with epithelial ovarian carcinoma (EOC)." Journal of Clinical Oncology 30, no. 30_suppl (October 20, 2012): 62. http://dx.doi.org/10.1200/jco.2012.30.30_suppl.62.
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62 Background: Novel strategies for early detection of EOC, the most common and second most lethal cancer in Indian women, are urgently needed. Silencing tumor suppressor genes via DNA methylation has established hypermethylation as one of the most frequent molecular alterations that may initiate and drive many types of human neoplasia including EOC. To determine the alterations of tumor suppressor gene DAPK1 and p16INK4A in EOC patients to explore the possibilities of identifying potential minimally invasive markers in blood of the patients, which could help in the clinical practice as a diagnostic and prognostic marker. Methods: Fifty EOC patients with primary epithelial ovarian cancer were selected for the study; these patients were followed for a median of 20 months. Genomic DNA extracted from fresh peripheral blood and serum followed by sodium bisulfate modification. The DAPK1 and p16 methylation was detected using methylation-specific PCR (MSP). The DAPK1 and p16 methylation status was correlated with age, stage,menopause, Ca125.5 and clinic pathological features. Results: The frequencies of DAPK1 and p16 methylation in EOC patients was found to be 68% and 84% respectively . Aberrant methylation of DAPK1 and p16 was associated with age at diagnosis (p = 0.043) .The significant association was seen with age,menopause. Patients with high methylation indices had poor prognosis (p<0.001, Hazards ratio=14.58) with age (p = 0.043), and tumor stage (p = 0.033). Aberrant methylation of DAPK1 and p16 was strongly associated with EOC patients (p = 0.037 respectively). Conclusions: our results that the methylated loci of TSGs (DAPK1 and p16) may be employed as clinically useful biomarkers for prognosis and diagnosis of EOC noninvasively using readily available body fluid by MS-PCR and proved to be efficient and cost-effective method.
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Lee, Dohoon, Sangseon Lee, and Sun Kim. "PRISM: methylation pattern-based, reference-free inference of subclonal makeup." Bioinformatics 35, no. 14 (July 2019): i520—i529. http://dx.doi.org/10.1093/bioinformatics/btz327.
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Abstract Motivation Characterizing cancer subclones is crucial for the ultimate conquest of cancer. Thus, a number of bioinformatic tools have been developed to infer heterogeneous tumor populations based on genomic signatures such as mutations and copy number variations. Despite accumulating evidence for the significance of global DNA methylation reprogramming in certain cancer types including myeloid malignancies, none of the bioinformatic tools are designed to exploit subclonally reprogrammed methylation patterns to reveal constituent populations of a tumor. In accordance with the notion of global methylation reprogramming, our preliminary observations on acute myeloid leukemia (AML) samples implied the existence of subclonally occurring focal methylation aberrance throughout the genome. Results We present PRISM, a tool for inferring the composition of epigenetically distinct subclones of a tumor solely from methylation patterns obtained by reduced representation bisulfite sequencing. PRISM adopts DNA methyltransferase 1-like hidden Markov model-based in silico proofreading for the correction of erroneous methylation patterns. With error-corrected methylation patterns, PRISM focuses on a short individual genomic region harboring dichotomous patterns that can be split into fully methylated and unmethylated patterns. Frequencies of such two patterns form a sufficient statistic for subclonal abundance. A set of statistics collected from each genomic region is modeled with a beta-binomial mixture. Fitting the mixture with expectation-maximization algorithm finally provides inferred composition of subclones. Applying PRISM for two AML samples, we demonstrate that PRISM could infer the evolutionary history of malignant samples from an epigenetic point of view. Availability and implementation PRISM is freely available on GitHub (https://github.com/dohlee/prism). Supplementary information Supplementary data are available at Bioinformatics online.