Status Of Tumor Suppressor Gene Research Articles

Aronia melanocarpa L. fruit peels show anti-cancer effects in preclinical models of breast carcinoma: The perspectives in the chemoprevention and therapy modulation

IntroductionWithin oncology research, there is a high effort for new approaches to prevent and treat cancer as a life-threatening disease. Specific plant species that adapt to harsh conditions may possess unique properties that may be utilized in the management of cancer.HypothesisChokeberry fruit is rich in secondary metabolites with anti-cancer activities potentially useful in cancer prevention and treatment.Aims of the study and MethodsBased on mentioned hypothesis, the main goal of our study was to evaluate the antitumor effects of dietary administered Aronia melanocarpa L. fruit peels (in two concentrations of 0.3 and 3% [w/w]) in the therapeutic syngeneic 4T1 mouse adenocarcinoma model, the chemopreventive model of chemically induced mammary carcinogenesis in rats, a cell antioxidant assay, and robust in vitro analyses using MCF-7 and MDA-MB-231 cancer cells.ResultsThe dominant metabolites in the A. melanocarpa fruit peel extract tested were phenolic derivatives classified as anthocyanins and procyanidins. In a therapeutic model, aronia significantly reduced the volume of 4T1 tumors at both higher and lower doses. In the same tumors, we noted a significant dose-dependent decrease in the mitotic activity index compared to the control. In the chemopreventive model, the expression of Bax was significantly increased by aronia at both doses. Additionally, aronia decreased Bcl-2 and VEGF levels, increasing the Bax/Bcl-2 ratio compared to the control group. The cytoplasmic expression of caspase-3 was significantly enhanced when aronia was administered at a higher dosage, in contrast to both the control group and the aronia group treated with a lower dosage. Furthermore, the higher dosage of aronia exhibited a significant reduction in the expression of the tumor stem cell marker CD133 compared to the control group. In addition, the examination of aronia`s epigenetic impact on tumor tissue through in vivo analyses revealed significant alterations in histone chemical modifications, specifically H3K4m3 and H3K9m3, miRNAs expression (miR155, miR210, and miR34a) and methylation status of tumor suppressor genes (PTEN and TIMP3). In vitro studies utilizing a methanolic extract of A.melanocarpa demonstrated significant anti-cancer properties in the MCF-7 and MDA-MB-231 cell lines. Various analyses, including Resazurin, cell cycle, annexin V/PI, caspase-3/7, Bcl-2, PARP, and mitochondrial membrane potential, were conducted in this regard. Additionally, the aronia extract enhanced the responsiveness to epirubicin in both cancer cell lines.ConclusionThis study is the first to analyze the antitumor effect of A. melanocarpa in selected models of experimental breast carcinoma in vivo and in vitro. The utilization of the antitumor effects of aronia in clinical practice is still minimal and requires precise and long-term clinical evaluations. Individualized cancer-type profiling and patient stratification are crucial for effectively implementing plant nutraceuticals within targeted anti-cancer strategies in clinical oncology.

119 (PB-032) Poster - Epigenetic silencing of P16INK4a hasten disease stage in Carcinoma of Breast: A hospital-based study of North India

Background: Epigenetic alterations involved in the onset and progression of breast cancer may serve as biomarkers for early detection and prediction of disease prognosis. In the current study, it has been tried to determine the methylation status of tumor suppressor gene P16/INK4a in 50 breast cancer patients and their association with clinicopathological parameters.

Epigenetic Regulations of Perineural Invasion in Head and Neck Squamous Cell Carcinoma.

Carcinomas of the oral cavity and oropharynx belong among the ten most common malignancies in the human population. The prognosis of head and neck squamous cell carcinoma (HNSCC) is determined by the degree of invasiveness of the primary tumor and by the extent of metastatic spread into regional and distant lymph nodes. Moreover, the level of the perineural invasion itself associates with tumor localization, invasion’s extent, and the presence of nodal metastases. Here, we summarize the current knowledge about different aspects of epigenetic changes, which can be associated with HNSCC while focusing on perineural invasion (PNI). We review epigenetic modifications of the genes involved in the PNI process in HNSCC from the omics perspective and specific epigenetic modifications in OSCC or other neurotropic cancers associated with perineural invasion. Moreover, we summarize DNA methylation status of tumor-suppressor genes, methylation and demethylation enzymes and histone post-translational modifications associated with PNI. The influence of other epigenetic factors on the HNSCC incidence and perineural invasion such as tobacco, alcohol and oral microbiome is overviewed and HPV infection is discussed as an epigenetic factor associated with OSCC and related perineural invasion. Understanding epigenetic regulations of axon growth that lead to tumorous spread or uncovering the molecular control of axon interaction with cancer tissue can help to discover new therapeutic targets for these tumors.

Liver-Targeting Class I Selective Histone Deacetylase Inhibitors Potently Suppress Hepatocellular Tumor Growth as Standalone Agents.

Simple SummaryLiver cancers are among the leading causes of global cancer deaths. The current therapy options for liver cancers, including hepatocellular carcinoma (HCC), which accounts for over 80% of all cases, have afforded limited benefit to patients with an advanced disease state. HCC results from genetic and epigenetic alterations, including gene-silencing chromatin histone hypoacetylation. The aim of this study was to investigate the potential utility of liver tissue-targeting HDAC inhibitors (HDACi) as a new class of anti-HCC agents. We showed that a class of macrolide-based HDACi, which are selective for sub-class I HDACs, preferentially accumulated in the liver tissue and robustly suppressed tumor growths in an orthotopic model of HCC. The liver tissue-selective accumulation property of these compounds gives them a unique advantage over most of the current HDACi, including those currently in clinical use.Dysfunctions in epigenetic regulation play critical roles in tumor development and progression. Histone deacetylases (HDACs) and histone acetyl transferase (HAT) are functionally opposing epigenetic regulators, which control the expression status of tumor suppressor genes. Upregulation of HDAC activities, which results in silencing of tumor suppressor genes and uncontrolled proliferation, predominates in malignant tumors. Inhibition of the deacetylase activity of HDACs is a clinically validated cancer therapy strategy. However, current HDAC inhibitors (HDACi) have elicited limited therapeutic benefit against solid tumors. Here, we disclosed a class of HDACi that are selective for sub-class I HDACs and preferentially accumulate within the normal liver tissue and orthotopically implanted liver tumors. We observed that these compounds possess exquisite on-target effects evidenced by their induction of dose-dependent histone H4 hyperacetylation without perturbation of tubulin acetylation status and G0/G1 cell cycle arrest. Representative compounds 2 and 3a are relatively non-toxic to mice and robustly suppressed tumor growths in an orthotopic model of HCC as standalone agents. Collectively, our results suggest that these compounds may have therapeutic advantage against HCC relative to the current systemic HDACi. This prospect merits further comprehensive preclinical investigations.

Methylation Status of Tumor Suppressor Genes in Circulating DNA of PDAC Patients: Facts and Hopes

Methylation Status of Tumor Suppressor Genes in Circulating DNA of PDAC Patients: Facts and Hopes

Clinical significance of promoter methylation status of tumor suppressor genes in circulating DNA of pancreatic cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive cancer. There are various sub-cellular events (both genetic and epigenetic) that get dysregulated leading to tumorigenesis. Methylation in promoters of tumor suppressor genes is one of these epigenetic phenomena contributing to the pathogenesis of cancer. Genes analyzed for promoter methylation status in this study namely SPARC (Secreted Protein Acidic and Rich in Cysteine, UCHL1 (ubiquitin carboxy-terminal hydrolase L1), NPTX2 (neuronal pentraxin 2), PENK (proenkephalin) had been studied in pancreatic cancer, but there is a need to check methylation in these genes as circulatory non-invasive markers. This study analyzed the absolute quantification of methylation levels of SPARC, UCHL1, PENK, and NPTX2 genes promoters in PDAC patients as well as in chronic pancreatitis (CP) patients and healthy subjects (HC) and evaluated its clinical significance in PDAC. The study included 65 PDAC patients, 25 CP patients, and 25 healthy controls. DNA was extracted from their plasma samples and subsequently given bisulfite treatment. Absolute quantization of methylated and unmethylated copies of gene promoters of all the four genes was performed using real-time PCR (SYBR green) by the standard curve method. Methylation levels were expressed as methylation index (MI) for each gene in each patient. MI was calculated from absolute copy numbers as follows: MI-methylated copy number/methylated copy number + unmethylated copy number). These indices were used to compare gene methylation levels within different groups and to correlate with clinicopathological features and survival of pancreatic cancer patients. An appropriate statistical analysis was applied. Methylation indices for all the four genes in PDAC cases were found to be significantly higher as compared to that in healthy individuals. SPARC MI values were found to differentiate early-stage PDAC patients from CP patients. PDAC patients with the metastasized disease and stage IV disease were found to have high MI for the SPARC gene as well as for the NPTX2 gene, while a higher UCHL1 methylation index was found to correlate with an advanced stage of the disease. Higher MI values for SPARC and NPTX2 genes were found to associate with poor survival in patients with PDAC. Methylation load in the form of MI for each of the four genes assessed in plasma may emerge as a non-invasive biomarker to differentiate pancreatic cancer from healthy individuals. But only SPARC and NPTX2 hypermethylation were able to distinguish pancreatic cancer from chronic pancreatitis. Association of aberrant methylation in SPARC and NPTX2 gene with metastasis and poor survival of patients suggest the role of methylation in these genes as prognostic markers.

Abstract 818: Changes in tumor suppressor methylation in SKBR3 cells during treatment with Olaparib or Doxorubicin

Abstract DNA methylation is an epigenetic mechanism that can alter gene expression without modifying the DNA sequence. Reactivation of tumor suppressor genes that have been epigenetically silenced in cancer could be a potential therapeutic approach. In this study, we performed long-term treatment of the breast cancer cell line SKBR3, with Olaparib or Doxorubicin in order to assess the methylation status of tumor suppressor genes, after the cell cultures had become resistant to these drugs. Using bisulphite conversion and massive parallel sequencing we examined CpG islands in promoter regions of 283 tumor suppressor genes at several time points under the two treatment regiments. Methylation analysis was carried out for each sample using our in-house bioinformatic pipeline established in collaboration with Roche and publicly available tools. We assessed differentially methylated CpG’s for each drug, compared to control samples treated with dimethyl sulfoxide (DMSO) using the R package methylKit. Gene ontology and pathway analysis revealed hypermethylation in genes belonging to homologous recombination pathway and hypomethylation in genes responding to cellular stress and protein kinase signaling in Olaparib-treated samples. In Doxorubicin-treated samples, we identified genes involved in inter-strand cross-link repair to be hypomethylated, while other genes associated with more general cellular response to DNA damage were hypermethylated. While in Olaparib-treated samples, differential methylation seemed to be reversible and dependent on the dosage of Olaparib, methylation patterns in Doxorubicin-treated samples appeared to change in an incremental manner, as a function of exposure time to the drug. Citation Format: Zuzana Sichmanova, Asta Ottesen, Per Eystein Lonning, Elisabet Ognedal Berge, Stian Knappskog. Changes in tumor suppressor methylation in SKBR3 cells during treatment with Olaparib or Doxorubicin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 818.

Effect of the Epigenetic Regulators (JAK2 and IDH-2) on the Methylation Status of Tumor Suppressor Genes (p15, FHIT, Calcitonin and SOCS-1) and Prognosis of MDS Patients: A Study from India

Effect of the Epigenetic Regulators (JAK2 and IDH-2) on the Methylation Status of Tumor Suppressor Genes (p15, FHIT, Calcitonin and SOCS-1) and Prognosis of MDS Patients: A Study from India

Abstract B46: Vorinostat modulates the expression of the progesterone receptor in subtypes of triple-negative breast cancer cell lines

Abstract Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is characterized by a lack of clinically significant levels of hormone receptors for estrogen (ER) and progesterone (PR) and the human epidermal growth factor receptor-2 (HER2). TNBC has a high cell proliferation rate and has been described as an “interval cancer,” developing between yearly mammograms. TNBC accounts for 10-15% of all breast cancers diagnosed, and risk factors include age (> 40) and mutational status of tumor-suppressor genes (p53, BRCA1). Additionally, Hispanic American, African American, and women of African descent have been shown to be 3x more likely to develop this more aggressive subtype. The lack of cell surface receptors for ER, PR, and Her2 makes these tumors unresponsive to conventional hormone or targeted therapy, and currently there are no FDA-approved targeted therapies for this disease. This, combined with a higher rate of relapse and shorter overall survival period, leads to an overall poor prognosis for this breast cancer subtype. Vorinostat is a histone deacetylase inhibitor and has been shown to exert effects through epigenetic mechanisms. Previous studies have shown its ability to re-express ERα in triple-negative breast cancer cells. In this study we examined whether Vorinostat can re-express the PR in subtypes of TNBC cell lines HCC70, HCC1143, HCC1806, and BT549 and render these resistant cells sensitive to cancer agents. Using real-time PCR and immunostaining, the re-expression of the PR receptor was shown in BT549 (4-fold), HCC70 (13-fold), HCC 1143 (5-fold), and HCC1806 (20-fold). PR is known to modulate ERα in breast cancer. Indole-3-carbinol (I3C) alone or in combination with tamoxifen decreased PR expression in HCC1806 and HCC70 cells. Tamoxifen and I3C also inhibited cell growth of triple-negative breast cancer cells with vorinostat. These results show promise for the use of vorinostat in sensitizing subtypes of triple-negative breast cancer cells to tamoxifen and a dietary agent, I3C. Furthermore, this study revealed that vorinostat can re-express critical receptors in triple-negative breast cancer, suggesting its possible use in combinational therapy for this aggressive form of breast cancer. Citation Format: Beverly Lyn-Cook, Fatemeh NouriEmamzadeh, Beverly Word, Rhonda Moore, Gustav Miranda-Carboni. Vorinostat modulates the expression of the progesterone receptor in subtypes of triple-negative breast cancer cell lines [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B46.

Nicotine induces aberrant hypermethylation of tumor suppressor genes in pancreatic epithelial ductal cells

Tobacco smoking is an independent risk factor for the initiation of pancreatic cancer (PC). Hypermethylation of tumor suppressor genes has been demonstrated to be associated with smoking. This study aimed to find the relationship between nicotine exposure and hypermethylation of tumor suppressor genes in normal pancreatic epithelial cells. Human pancreatic epithelial cells ware cultured exposing to nicotine and the methylation status of tumor suppressor genes were detected. Proenkephalin (PENK) was chosen as the target gene and methylation level of PENK promoter region was measured. Expression of DNA methyltransferase (DNMT), nicotine acetylcholine receptor (α7nAChR) and signaling pathway downstream were analyzed. Nicotine induces overexpression of DNMT3A and 3B, and methylated-inactivation of PENK gene in normal pancreatic epithelial cells. An activation of α7nAChR and MAPK signaling pathway has been detected in the nicotine-treated group. Demethylated drug, antagonist of α7nAChR and inhibitor of p38 MAPK is verified to attenuate the overexpression of DNMTs stimulated by nicotine as well as inhibit aberrant hypermethylation-related silence of PENK gene. Nicotine stimulation can induce aberrant hypermethylation of tumor suppressor genes by α7nAChR and MAPK signaling pathway-mediated up-regulation of DNMTs in pancreatic epithelial cells, thus we can provide epigenetic evidence of the mechanisms by which smoking causes pancreatic cancer and find new therapeutic target.

Sleep quality and methylation status of selected tumor suppressor genes among nurses and midwives

ABSTRACTChronic sleep restriction may affect metabolism, hormone secretion patterns and inflammatory responses. Limited reports suggest also epigenetic effects, such as changes in DNA methylation profiles. The study aims to assess the potential association between poor sleep quality or sleep duration and the levels of 5-methylcytosine in the promoter regions of selected tumor suppressor genes. A cross-sectional study was conducted on 710 nurses and midwives aged 40–60 years. Data from interviews regarding sleep habits and potential confounders were used. The methylation status of tumor suppressor genes was determined via qMSP reactions using DNA samples derived from leucocytes. No significant findings were observed in the total study population or in the two subgroups of women stratified by the current system of work. A borderline significance association was observed between a shorter duration of sleep and an increased methylation level in CDKN2A among day working nurses and midwives. Further studies are warranted to explore this under-investigated topic.

Abstract 1332: NOTCH - HEY1 pathway induces EMT in head and neck squamous cell carcinoma

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is noted to have a NOTCH mutation rate of 20% within the Cancer Genome Atlas (TCGA) dataset consistent with tumor suppressor gene status. However, NOTCH genes are also upregulated in wild type HNSCC and show signs of downstream activation in a substantial proportion of HNSCC. In this study, we aimed to further explore the potential for NOTCH pathways to be activated in HNSCC. Material and Methods mRNA sequence of TCGA data includes 520 HNSCC tumors and 46 normal tissues. We used 447 HNSCC excluding 73 tumors with NOTCH mutations. The activated groups of NOTCH downstream genes were defined as tumors with expression 1 standard deviation above the mean of normal tissue. We used four HNSCC cell lines (SKN3, Cal27, SCC61, SCC090) to ascertain the results of the TCGA analysis in vitro. Result In TCGA analysis, HEY1 activated HNSCC had significant more expression of NOTCH pathway genes. In particular NOTCH4 had the most significant correlation with HEY1 activation among NOTCH receptors. To confirm this result in vitro, HEY1 expression was compared between si-control and si-NOTCH4 of SKN3, Cal27, SCC61 and SCC090. As expected, HEY1 expression in all si-NOTCH4 treated cell lines were significant decreased. Next, we examined the relationship about NOTCH4 and an epithelial mesenchymal transition phenotype (EMT). Using TCGA data, we found that mesenchymal marker genes were significantly increased in high NOTCH4 group. In vitro experiments, si-NOTCH4 cells decreased mesenchymal marker gene expression such as Fibronectin and TWIST1. We also examined HEY1 function. Similar to NOTCH4, it was found that HEY1 is significantly related to EMT in silico and in vitro. Conclusion The NOTCH4-HEY1 pathway is significantly upregulated in HNSCC and induces EMT. Citation Format: Takahito Fukusumi, Theresa W. Guo, Shuling Ren, Akihiro Sakai, Mizuo Ando, Sunny Haft, Chao Liu, Joseph A. Califano. NOTCH - HEY1 pathway induces EMT in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1332. doi:10.1158/1538-7445.AM2017-1332

Integration of DNA methylation and gene transcription across nineteen cell types reveals cell type-specific and genomic region-dependent regulatory patterns

Despite numerous studies done on understanding the role of DNA methylation, limited work has focused on systems integration of cell type-specific interplay between DNA methylation and gene transcription. Through a genome-wide analysis of DNA methylation across 19 cell types with T-47D as reference, we identified 106,252 cell type-specific differentially-methylated CpGs categorized into 7,537 differentially (46.6% hyper- and 53.4% hypo-) methylated regions. We found 44% promoter regions and 75% CpG islands were T-47D cell type-specific methylated. Pyrosequencing experiments validated the cell type-specific methylation across three benchmark cell lines. Interestingly, these DMRs overlapped with 1,145 known tumor suppressor genes. We then developed a Bayesian Gaussian Regression model to measure the relationship among DNA methylation, genomic segment distribution, differential gene expression and tumor suppressor gene status. The model uncovered that 3′UTR methylation has much less impact on transcriptional activity than other regions. Integration of DNA methylation and 82 transcription factor binding information across the 19 cell types suggested diverse interplay patterns between the two regulators. Our integrative analysis reveals cell type-specific and genomic region-dependent regulatory patterns and provides a perspective for integrating hundreds of various omics-seq data together.

Cell-Free DNA Quantification and Methylation Status of DCC Gene as Predictive Diagnostic Biomarkers of Lung Cancer in Patients Reported at Gulab Devi Chest Hospital, Lahore

The worldwide high mortality rate of lung cancer could be reduced significantly by its noninvasive early detection. The quantitative analysis of cell-free circulating DNA in plasma presents a potential noninvasive approach for liquid biopsy of tumor. In this study, real-time polymerase chain reaction–based approach was used to quantify free circulating DNA in plasma. The concentration of free circulating DNA was checked using human telomerase reverse transcriptase gene as marker, and amplification status of oncogene RAC-β serine/threonine protein kinase along with the DNA methylation status of tumor suppressor gene (deleted in colorectal cancer) was assessed. The concentration of free circulating DNA in patients with lung cancer (22.8 ng/mL) was found approximately 6 times above than the value detected in controls (2.8 ng/mL). Considerable variation in the AKT2 copy number was observed in patients with lung cancer and controls (P < .000). Aberrant methylation of the deleted in colorectal cancer promoter was found to be highly specific (100%), as none of the control plasma samples showed aberrant methylation. The quantification of free circulating DNA along with determination of AKT2 amplification and deleted in colorectal cancer promoter methylation status appeared promising to differentiate patients with lung cancer from healthy individuals.

Erratum to: “A comparative analysis of methylation status of tumor suppressor genes in paired biopsy and serum samples from cervical cancer patients among North Indian population”

Erratum to: “A comparative analysis of methylation status of tumor suppressor genes in paired biopsy and serum samples from cervical cancer patients among North Indian population”

Promoter methylation status of tumor suppressor genes and inhibition of expression of DNA methyltransferase 1 in non-small cell lung cancer.

DNA methylation is an epigenetic DNA modification catalyzed by DNA methyltransferase 1 (DNMT1). The purpose of this study was to investigate DNMT1 gene and protein expression and the effects of methylation status on tumor suppressor genes in human non-small cell lung cancer (NSCLC) cell lines grown invitro and invivo Human lung adenocarcinoma cell lines, A549 and H838, were grown invitro and inoculated subcutaneously into nude mice to form tumors and were then treated with the DNA methylation inhibitor, 5-aza-2'-deoxycytidine, with and without treatment with the benzamide histone deacetylase inhibitor, entinostat (MS-275). DNMT1 protein expression was quantified by Western blot. Promoter methylation status of tumor suppressor genes (RASSF1A, ASC, APC, MGMT, CDH13, DAPK, ECAD, P16, and GATA4) was evaluated by methylation-specific polymerase chain reaction. Methylation status of the tumor suppressor genes was regulated by the DNMT1 gene, with the decrease of DNMT1 expression following DNA methylation treatment. Demethylation of tumor suppressor genes (APC, ASC, and RASSF1A) restored tumor growth in nude mice. The results of this study support a role for methylation of DNA as a potential epigenetic clinical biomarker of prognosis or response to therapy and for DNMT1 as a potential therapeutic target in NSCLC.

Quantitative proteomic analysis of histone modifications in decitabine sensitive and resistant leukemia cell lines

BackgroundThe refractory nature of many cancers remains the main health challenge over the past century. The epigenetic drug, decitabine (DAC), represents one of the most promising therapeutic agents in cancers particularly in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, its ambiguous anti-tumor mechanism and the unpredictable drug-resistant nature in some population compromise its application in cancer therapy. In crosstalk with DNA methylation, histone post-translational modifications (PTMs) are the key players in modulating the downstream epigenetic status of tumor suppressor genes. This study targets the role of decitabine in epigenetic regulation in leukemia therapy and searches responsive predictors and therapeutic targets for pretreatment evaluation and drug development.ResultsA simple, fast, and robust proteomic strategy identified 15 novel PTMs and 60 PTM combinations in two leukemia cell lines (MDS-L and TF-1). Histone modification profiles have been generated and compared between DAC sensitive and resistant groups (n = 3) in response to DAC treatment. Among these histone PTMs, five of which were found differentially upon DAC treatment in drug sensitive and resistant cells: H3.3K36me3, H4K8acK12acK16ac in MDS-L cells; and H3.1K27me1, H3.1K36me1, H3.1K27me1K36me1 in TF-1 cells. They may serve as biomarkers in predicting leukemia and drug responsiveness. In addition, we also explored PTM differences in two cell lines which were developed from early and advanced stages of AML. Three PTMs (H3.1K27me3, H3.1K27me2K36me2 and H3.3K27me2K36me2) are highly abundant in TF-1 cells (advanced AML cell line), suggesting their relevance to leukemogenesis. Our method allowed deep analysis of histone proteins and elucidation of a large number of histone PTMs with high precision and sensitivity.ConclusionDAC-induced DNA hypomethylation has wide impact on chromatin modifications. This study represents first effort to investigate the undefined epigenetic mechanism of decitabine in leukemia therapy. The identification of 15 novel PTMs and the discovery of several marks have relevance to epigenetic directed therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12014-016-9115-z) contains supplementary material, which is available to authorized users.

A comparative analysis of methylation status of tumor suppressor genes in paired biopsy and serum samples from cervical cancer patients among north indian population

Tumor-specific genetic or epigenetic alterations have been detected in serum DNA in case of various types of cancers. In breast cancer, the detection of tumor suppressor gene hypermethylation has been reported in several body fluids. Promoter hypermethylation of some genes like MYOD1, CALCA, hTERT etc. has also been detected in serum samples from cervical cancer. The present study is the first report on the comparison of promoter hypermethylation of tumor suppressor genes likep14, p15, p16, p21, p27, p57, p53, p73, RARβ2, FHIT, DAPK, STAT1 and-RB1 genes in paired biopsy and serum samples from cervical cancer patients among north Indian population. This is also the first report on the hypermethylation of these genes in serum samples from cervical cancer patients among north Indian population. According to the results of the present study, promoter hypermethylation of these genes can also be detected in serum samples of cervical cancer patients. The sensitivity of detection of promoter hypermethylation in serum samples of cervical cancer patients as compared to paired biopsy samples was found to be around 83.3%. It was observed that promoter hypermethylation was mainly observed in the serum samples in the higher stages and very rarely in the lower stages. The present study clearly showed that serum of patients with cervical cancer can also be used to study methylated genes as biomarkers.

A COMPARATIVE ANALYSIS OF METHYLATION STATUS OF TUMOR SUPPRESSOR GENES IN PAIRED BIOPSY AND SERUM SAMPLES FROM CERVICAL CANCER PATIENTS AMONG NORTH INDIAN POPULATION.

Tumor-specific genetic or epigenetic alterations have been detected in serum DNA in case of various types of cancers. In breast cancer, the detection of tumor suppressor gene hypermethylation has been reported in several body fluids. Promoter hypermethylation of some genes like MYOD1, CALCA, hTERT etc. has also been detected in serum samples from cervical cancer. The present study is the first report on the comparison of promoter hypermethylation of tumor suppressor genes likep14, p15, p16, p21, p27, p57, p53, p73, RARβ2, FHIT, DAPK, STAT1 and-RB1 genes in paired biopsy and serum samples from cervical cancer patients among north Indian population. This is also the first report on the hypermethylation of these genes in serum samples from cervical cancer patients among north Indian population. According to the results of the present study, promoter hypermethylation of these genes can also be detected in serum samples of cervical cancer patients. The sensitivity of detection of promoter hypermethylation in serum samples of cervical cancer patients as compared to paired biopsy samples was found to be around 83.3%. It was observed that promoter hypermethylation was mainly observed in the serum samples in the higher stages and very rarely in the lower stages. The present study clearly showed that serum of patients with cervical cancer can also be used to study methylated genes as biomarkers.

Update in management of optic nerve glioma (part 2)

SummarySignificant controversy exists in the treatment of optic nerve glioma because of the absence of evidenced‐based trials demonstrating efficacy for various treatments administered over the years, from radiation therapy to various chemotherapeutic regimens and combinations thereof. Elements of tumor biology will be discussed along with fundamental properties of anti‐mitotic regimens administered to date, as well as newer agents proposed targeting protein synthesis rather than DNA replication. Discussion of how tumor suppressor gene status (NF1) should be taken into consideration when deciding upon a treatment modality will also be discussed. Novel vision sparing surgical modalities applicable to NF1‐associated orbital gliomas in particular will be reviewed.