Publications by authors named "Jean-Pierre J Issa"

181 Publications

Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas.

Nat Commun 2021 01 29;12(1):687. Epub 2021 Jan 29.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

The evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of methylation aberrations and significantly higher level of methylation ITH in later-stage lesions. The phylogenetic patterns inferred from methylation aberrations resemble those based on somatic mutations suggesting parallel methylation and genetic evolution. De-convolution reveal higher ratio of T regulatory cells (Tregs) versus CD8 + T cells in later-stage diseases, implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation is associated with higher mutation burden, copy number variation burden and AI burden as well as higher Treg/CD8 ratio, highlighting the potential impact of methylation on chromosomal instability, mutagenesis and tumor immune microenvironment during early carcinogenesis of lung adenocarcinomas.
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http://dx.doi.org/10.1038/s41467-021-20907-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846738PMC
January 2021

High folic acid intake increases methylation-dependent expression of Lsr and dysregulates hepatic cholesterol homeostasis.

J Nutr Biochem 2021 02 19;88:108554. Epub 2020 Nov 19.

Departments of Human Genetics and Pediatrics, McGill University, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada. Electronic address:

Food fortification with folic acid and increased use of vitamin supplements have raised concerns about high folic acid intake. We previously showed that high folic acid intake was associated with hepatic degeneration, decreased levels of methylenetetrahydrofolate reductase (MTHFR), lower methylation potential, and perturbations of lipid metabolism. MTHFR synthesizes the folate derivative for methylation reactions. In this study, we assessed the possibility that high folic acid diets, fed to wild-type and Mthfr mice, could alter DNA methylation and/or deregulate hepatic cholesterol homeostasis. Digital restriction enzyme analysis of methylation in liver revealed DNA hypomethylation of a CpG in the lipolysis-stimulated lipoprotein receptor (Lsr) gene, which is involved in hepatic uptake of cholesterol. Pyrosequencing confirmed this methylation change and identified hypomethylation of several neighboring CpG dinucleotides. Lsr expression was increased and correlated negatively with DNA methylation and plasma cholesterol. A putative binding site for E2F1 was identified. ChIP-qPCR confirmed reduced E2F1 binding when methylation at this site was altered, suggesting that it could be involved in increasing Lsr expression. Expression of genes in cholesterol synthesis, transport or turnover (Abcg5, Abcg8, Abcc2, Cyp46a1, and Hmgcs1) was perturbed by high folic acid intake. We also observed increased hepatic cholesterol and increased expression of genes such as Sirt1, which might be involved in a rescue response to restore cholesterol homeostasis. Our work suggests that high folic acid consumption disturbs cholesterol homeostasis in liver. This finding may have particular relevance for MTHFR-deficient individuals, who represent ~10% of many populations.
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http://dx.doi.org/10.1016/j.jnutbio.2020.108554DOI Listing
February 2021

Promoter methylation changes in ALOX12 and AIRE1: novel epigenetic markers for atherosclerosis.

Clin Epigenetics 2020 05 12;12(1):66. Epub 2020 May 12.

Department of Neurology and Neuroepigenetics Laboratory, School of Medicine and Hospital, Chungnam National University, Daejeon, South Korea.

Background: Atherosclerosis is the main cause of cardiovascular diseases such as ischemic stroke and coronary heart disease. Gene-specific promoter methylation changes have been suggested as one of the causes underlying the development of atherosclerosis. We aimed to identify and validate specific genes that are differentially expressed through promoter methylation in atherosclerotic plaques. We performed the present study in four steps: (1) profiling and identification of gene-specific promoter methylation changes in atherosclerotic tissues; (2) validation of the promoter methylation changes of genes in plaques by comparison with non-plaque intima; (3) evaluation of promoter methylation status of the genes in vascular cellular components composing atherosclerotic plaques; and (4) evaluation of promoter methylation differences in genes among monocytes, T cells, and B cells isolated from the blood of ischemic stroke patients.

Results: Upon profiling, AIRE1, ALOX12, FANK1, NETO1, and SERHL2 were found to have displayed changes in promoter methylation. Of these, AIRE1 and ALOX12 displayed higher methylation levels in plaques than in non-plaque intima, but lower than those in the buffy coat of blood. Between inflammatory cells, the three genes were significantly less methylated in monocytes than in T and B cells. In the vascular cells, AIRE1 methylation was lower in endothelial and smooth muscle cells. ALOX12 methylation was higher in endothelial, but lower in smooth muscle cells. Immunofluorescence staining showed that co-localization of ALOX12 and AIRE1 was more frequent in CD14(+)-monocytes than in CD4(+)-T cell in plaque than in non-plaque intima.

Conclusions: Promoter methylation changes in AIRE1 and ALOX12 occur in atherosclerosis and can be considered as novel epigenetic markers.
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http://dx.doi.org/10.1186/s13148-020-00846-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218560PMC
May 2020

DNA methylation aging clocks: challenges and recommendations.

Genome Biol 2019 11 25;20(1):249. Epub 2019 Nov 25.

The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual.
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http://dx.doi.org/10.1186/s13059-019-1824-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876109PMC
November 2019

Gestational high fat diet protects 3xTg offspring from memory impairments, synaptic dysfunction, and brain pathology.

Mol Psychiatry 2019 Aug 27. Epub 2019 Aug 27.

Alzheimer's Center at Temple, Lewis Katz School of Medicine Temple University, Philadelphia, PA, USA.

Maternal history for sporadic Alzheimer's disease (AD) predisposes the offspring to the disease later in life. However, the mechanisms behind this phenomenon are still unknown. Lifestyle and nutrition can directly modulate susceptibility to AD. Herein we investigated whether gestational high fat diet influences the offspring susceptibility to AD later in life. Triple transgenic dams were administered high fat diet or regular chow throughout 3 weeks gestation. Offspring were fed regular chow throughout their life and tested for spatial learning and memory, brain amyloidosis, tau pathology, and synaptic function. Gestational high fat diet attenuated memory decline, synaptic dysfunction, amyloid-β and tau neuropathology in the offspring by transcriptional regulation of BACE-1, CDK5, and tau gene expression via the upregulation of FOXP2 repressor. Gestational high fat diet protects offspring against the development of the AD phenotype. In utero dietary intervention could be implemented as preventative strategy against AD.
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http://dx.doi.org/10.1038/s41380-019-0489-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044032PMC
August 2019

Genomic and epigenomic predictors of response to guadecitabine in relapsed/refractory acute myelogenous leukemia.

Clin Epigenetics 2019 07 22;11(1):106. Epub 2019 Jul 22.

Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA.

Background: Guadecitabine is a novel DNA methyltransferase (DNMT) inhibitor with improved pharmacokinetics and clinical activity in a subset of patients with relapsed/refractory acute myeloid leukemia (r/r AML), but identification of this subset remains difficult.

Methods: To search for biomarkers of response, we measured genome-wide DNA methylation, mutations of 54 genes, and expression of a panel of 7 genes in pre-treatment samples from 128 patients treated at therapeutic doses in a phase I/II study.

Results: Response rate to guadecitabine was 17% (2 complete remission (CR), 3 CR with incomplete blood count recovery (CRi), or CR with incomplete platelets recovery (CRp)) in the phase I component and 23% (14 CR, 9 CRi/CRp) in phase II. There were no strong mutation or methylation predictors of response. Gene expression clustering defined a subset of patients (~ 20%) that had (i) high DNMT3B and low CDKN2B, CTCF, and CDA expression; (ii) enrichment for KRAS/NRAS mutations; (iii) frequent CpG island hypermethylation; (iv) low long interspersed nuclear element 1 (LINE-1) hypomethylation after treatment; and (v) resistance to guadecitabine in both phase I (response rate 0% vs. 33%, p = 0.07) and phase II components of the study (response rate 5% vs. 30%, p = 0.02). Multivariate analysis identified peripheral blood (PB) blasts and hemoglobin as predictors of response and cytogenetics, gene expression, RAS mutations, and hemoglobin as predictors of survival.

Conclusions: A subset of patients (~ 20%) with r/r AML is unlikely to benefit from guadecitabine as a single agent. In the remaining 80%, guadecitabine is a viable option with a median survival of 8 months and a 2-year survival rate of 21%.

Trial Registration: NCT01261312 .
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http://dx.doi.org/10.1186/s13148-019-0704-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647096PMC
July 2019

Guadecitabine (SGI-110) in patients with intermediate or high-risk myelodysplastic syndromes: phase 2 results from a multicentre, open-label, randomised, phase 1/2 trial.

Lancet Haematol 2019 Jun 3;6(6):e317-e327. Epub 2019 May 3.

Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.

Background: Guadecitabine is a next-generation hypomethylating agent whose active metabolite decitabine has a longer in-vivo exposure time than intravenous decitabine. More effective hypomethylating agents are needed for the treatment of myelodysplastic syndromes. In the present study, we aimed to compare the activity and safety of two doses of guadecitabine in hypomethylating agent treatment-naive or relapsed or refractory patients with intermediate-risk or high-risk myelodysplastic syndromes.

Methods: This phase 2 part of the phase 1/2, randomised, open-label study enrolled patients aged 18 years or older from 14 North American medical centres with International Prognostic Scoring System intermediate-1-risk, intermediate-2-risk, or high-risk myelodysplastic syndromes, or chronic myelomonocytic leukaemia. They were either hypomethylating agent treatment-naive or had relapsed or refractory disease after previous hypomethylating agent treatment as determined by the investigators' judgment. Eligible patients had Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1) using a computer algorithm for dynamic randomisation to subcutaneous guadecitabine 60 or 90 mg/m on days 1-5 of a 28-day treatment cycle. Treatment was stratified by previous treatment with hypomethylating agents and neither patients nor investigators were masked. The primary endpoint was overall response (a composite of complete response, partial response, marrow complete response, and haematological improvement) assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01261312.

Findings: Between July 9, 2012, and April 7, 2014, 105 patients were enrolled: 55 (52%) were allocated to guadecitabine 60 mg/m (28 patients were treatment-naive and 27 had relapsed or refractory disease after previous hypomethylating agent treatment) and 50 (48%) patients to 90 mg/m (23 patients were treatment-naive and 27 had relapsed or refractory disease). Three (3%) patients of 105 did not receive study treatment and were excluded from analyses. Median follow-up was 3·2 years (IQR 2·8-3·5). The proportion of patients achieving an overall response did not significantly differ between dose groups (21 of 53 [40%, 95% CI 27-54] with 60 mg/m and 27 of 49 [55%, 95% CI 40-69] with 90 mg/m; p=0·16). 25 of 49 (51%, 95% CI 36-66) patients who were treatment-naive and 23 of 53 (43%, 30-58) patients with relapsed or refractory disease achieved an overall response. The most common grade 3 or worse adverse events in both groups, regardless of relationship to treatment, were thrombocytopenia (22 [41%] of 53 patients in the 60 mg/m group and 28 [57%] of 49 in the 90 mg/m group), neutropaenia (21 [40%] and 25 [51%]), anaemia (25 [47%] and 24 [49%]), febrile neutropaenia (17 [32%] and 21 [43%]), and pneumonia (13 [25%] and 15 [31%]). Seven (7%) of 102 patients died due to adverse events (three with 90 mg/m and four with 60 mg/m), and all except one were in the relapsed or refractory cohort. Two deaths were deemed treatment related (septic shock with 60 mg/m; pneumonia with 90 mg/m).

Interpretation: Guadecitabine was clinically active with acceptable tolerability in patients with intermediate-risk and high-risk myelodysplastic syndromes. Responses and overall survival in the relapsed or refractory cohort offer the potential of a new therapeutic option for patients for whom currently available hypomethylating agents are not successful. We therefore recommend guadecitabine at a dose of 60 mg/m on a 5-day schedule for these patients.

Funding: Astex Pharmaceuticals and Stand Up To Cancer.
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http://dx.doi.org/10.1016/S2352-3026(19)30029-8DOI Listing
June 2019

Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer.

Cell 2018 11 25;175(5):1244-1258.e26. Epub 2018 Oct 25.

Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA. Electronic address:

Cyclin-dependent kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. We now report that CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell drug screen with genetic confirmation, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1, which contributes to gene reactivation. By optimization through gene expression, we developed a highly selective CDK9 inhibitor (MC180295, IC50 = 5 nM) that has broad anti-cancer activity in vitro and is effective in in vivo cancer models. Additionally, CDK9 inhibition sensitizes to the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.
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http://dx.doi.org/10.1016/j.cell.2018.09.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247954PMC
November 2018

TET1-Mediated Hypomethylation Activates Oncogenic Signaling in Triple-Negative Breast Cancer.

Cancer Res 2018 08 11;78(15):4126-4137. Epub 2018 Jun 11.

Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.

Both gains and losses of DNA methylation are common in cancer, but the factors controlling this balance of methylation remain unclear. Triple-negative breast cancer (TNBC), a subtype that does not overexpress hormone receptors or HER2/NEU, is one of the most hypomethylated cancers observed. Here, we discovered that the TET1 DNA demethylase is specifically overexpressed in about 40% of patients with TNBC, where it is associated with hypomethylation of up to 10% of queried CpG sites and a worse overall survival. Through bioinformatic analyses in both breast and ovarian cancer cell line panels, we uncovered an intricate network connecting TET1 to hypomethylation and activation of cancer-specific oncogenic pathways, including PI3K, EGFR, and PDGF. TET1 expression correlated with sensitivity to drugs targeting the PI3K-mTOR pathway, and CRISPR-mediated deletion of TET1 in two independent TNBC cell lines resulted in reduced expression of PI3K pathway genes, upregulation of immune response genes, and substantially reduced cellular proliferation, suggesting dependence of oncogenic pathways on TET1 overexpression. Our work establishes TET1 as a potential oncogene that contributes to aberrant hypomethylation in cancer and suggests that TET1 could serve as a druggable target for therapeutic intervention. This study addresses a critical gap in knowledge of how and why methylation is prognostic in breast cancer and shows how this information can be used to stratify patients with TNBC for targeted therapy. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072603PMC
August 2018

Nerve Injury-Induced Chronic Pain Is Associated with Persistent DNA Methylation Reprogramming in Dorsal Root Ganglion.

J Neurosci 2018 07 6;38(27):6090-6101. Epub 2018 Jun 6.

Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140 and

Nerve injury-induced hyperactivity of primary sensory neurons in the dorsal root ganglion (DRG) contributes to chronic pain development, but the underlying epigenetic mechanisms remain poorly understood. Here we determined genome-wide changes in DNA methylation in the nervous system in neuropathic pain. Spinal nerve ligation (SNL), but not paclitaxel treatment, in male Sprague Dawley rats induced a consistent low-level hypomethylation in the CpG sites in the DRG during the acute and chronic phases of neuropathic pain. DNA methylation remodeling in the DRG occurred early after SNL and persisted for at least 3 weeks. SNL caused DNA methylation changes at 8% of CpG sites with prevailing hypomethylation outside of CpG islands, in introns, intergenic regions, and repetitive sequences. In contrast, SNL caused more gains of methylation in the spinal cord and prefrontal cortex. The DNA methylation changes in the injured DRGs recapitulated developmental reprogramming at the neonatal stage. Methylation reprogramming was correlated with increased gene expression variability. A diet deficient in methyl donors induced hypomethylation and pain hypersensitivity. Intrathecal administration of the DNA methyltransferase inhibitor RG108 caused long-lasting pain hypersensitivity. DNA methylation reprogramming in the DRG thus contributes to nerve injury-induced chronic pain. Restoring DNA methylation may represent a new therapeutic approach to treat neuropathic pain. Epigenetic mechanisms are critically involved in the transition from acute to chronic pain after nerve injury. However, genome-wide changes in DNA methylation in the nervous system and their roles in neuropathic pain development remain unclear. Here we used digital restriction enzyme analysis of methylation to quantitatively determine genome-wide DNA methylation changes caused by nerve injury. We showed that nerve injury caused DNA methylation changes at 8% of CpG sites with prevailing hypomethylation outside of CpG islands in the dorsal root ganglion. Reducing DNA methylation induced pain hypersensitivity, whereas increasing DNA methylation attenuated neuropathic pain. These findings extend our understanding of the epigenetic mechanism of chronic neuropathic pain and suggest new strategies to treat nerve injury-induced chronic pain.
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http://dx.doi.org/10.1523/JNEUROSCI.2616-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031579PMC
July 2018

Demethylator phenotypes in acute myeloid leukemia.

Leukemia 2018 10 7;32(10):2178-2188. Epub 2018 Mar 7.

Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.

Acute myeloid leukemia (AML) often harbors mutations in epigenetic regulators, and also has frequent DNA hypermethylation, including the presence of CpG island methylator phenotypes (CIMPs). Although global hypomethylation is well known in cancer, the question of whether distinct demethylator phenotypes (DMPs) exist remains unanswered. Using Illumina 450k arrays for 194 patients from The Cancer Genome Atlas, we identified two distinct DMPs by hierarchical clustering: DMP.1 and DMP.2. DMP.1 cases harbored mutations in NPM1 (94%), FLT3 (71%) and DNMT3A (61%). Surprisingly, only 40% of patients with DNMT3A mutations were DMP.1, which has implications for mechanisms of transformation by this mutation. In contrast, DMP.2 AML was comprised of patients with t(8;21), inv(16) or t(15;17), suggesting common methylation defects connect these disparate rearrangements. RNA-seq revealed upregulated genes functioning in immune response (DMP.1) and development (DMP.2). We confirmed these findings by integrating independent 450k data sets (236 additional cases), and found prognostic effects by DMP status, independent of age and cytogenetics. The existence of DMPs has implications for AML pathogenesis and may augment existing tools in risk stratification.
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http://dx.doi.org/10.1038/s41375-018-0084-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128790PMC
October 2018

Digital Restriction Enzyme Analysis of Methylation (DREAM).

Methods Mol Biol 2018 ;1708:247-265

Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, 19140, USA.

Digital Restriction Enzyme Analysis of Methylation (DREAM) is a method for quantitative mapping of DNA methylation across genomes using next-generation sequencing (NGS) technology. The method is based on sequential cuts of genomic DNA with a pair of restriction enzymes (SmaI and XmaI) at CCCGGG target sites. Unmethylated sites are first digested with SmaI. This enzyme cuts the sites in the middle at CCC^GGG, leaving behind blunt ended fragments. CpG methylation completely blocks SmaI; therefore, only unmethylated sites are cleaved. The remaining methylated sites are digested with XmaI in the next step. This enzyme is not blocked by CpG methylation. It cuts the recognition site sideways at C^CCGGG forming 5'-CCGG overhangs. The sequential cuts thus create distinct methylation-specific signatures at the ends of restriction fragments: 5'-GGG for unmethylated CpG sites and 5'-CCGGG for methylated sites. The DNA fragments resulting from the digestions are ligated to NGS adapters. Sequencing libraries are prepared using hexanucleotide barcodes for sample identification. Individual libraries with distinct barcodes are pooled and sequenced using a paired ends protocol. The sequencing reads are aligned to the genome and mapped to unique CCCGGG target sites. Methylation at individual CpG sites is calculated as the ratio of sequencing reads with the methylated signature to the total number of reads mapping to the site. Sequencing of 25 million reads per sample typically yields 50,000 unique CpG sites covered with hundreds of reads enabling accurate determination of DNA methylation levels. DREAM does not require bisulfite conversion, has a very low background, and has high sensitivity to low levels of methylation. The method is simple, cost-effective, quantitative, highly reproducible, and can be applied to any species.
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http://dx.doi.org/10.1007/978-1-4939-7481-8_13DOI Listing
July 2018

Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia.

Cancer 2018 01 6;124(2):325-334. Epub 2017 Dec 6.

Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania.

Background: Outcomes for patients with relapsed or refractory acute myeloid leukemia (AML) are poor. Guadecitabine, a next-generation hypomethylating agent, could be useful in treating such patients.

Methods: In this multicenter, open-label, phase 2 dose-expansion study, AML patients from 10 North American medical centers were first randomized (1:1) to receive subcutaneous guadecitabine at 60 or 90 mg/m on 5 consecutive days in each 28-day cycle (5-day regimen). Subsequently, another cohort was treated for 10 days with 60 mg/m (10-day regimen).

Results: Between June 15, 2012, and August 19, 2013, 108 patients with previously treated AML consented to enroll in the study, and 103 of these patients were treated; 5 patients did not receive the study treatment. A total of 103 patients were included in the safety and efficacy analyses (24 and 26 patients who were randomly assigned to 60 and 90 mg/m /d, respectively [5-day regimen] and 53 patients who were assigned to 60 mg/m /d [10-day regimen]). The 90 mg/m dose showed no benefit in clinical outcomes in comparison with 60 mg/m in the randomized cohort. Composite complete response (CRc) and complete response (CR) rates were higher with the 10-day regimen versus the 5-day regimen (CRc, 30.2% vs 16.0%; P = .1061; CR, 18.9% vs 8%; P = .15). Adverse events (grade ≥ 3) were mainly hematologic, with a higher incidence on the 10-day regimen. Early all-cause mortality was low and similar between regimens. Twenty patients (8 on the 5-day regimen and 12 on the 10-day regimen) were bridged to hematopoietic cell transplantation.

Conclusions: Guadecitabine has promising clinical activity and an acceptable safety profile and thus warrants further development in this population. Cancer 2018;124:325-34. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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http://dx.doi.org/10.1002/cncr.31138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814873PMC
January 2018

Epigenetics and Precision Oncology.

Cancer J 2017 Sep/Oct;23(5):262-269

From the *Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA.

Epigenetic alterations such as DNA methylation defects and aberrant covalent histone modifications occur within all cancers and are selected for throughout the natural history of tumor formation, with changes being detectable in early onset, progression, and ultimately recurrence and metastasis. The ascertainment and use of these marks to identify at-risk patient populations, refine diagnostic criteria, and provide prognostic and predictive factors to guide treatment decisions are of growing clinical relevance. Furthermore, the targetable nature of epigenetic modifications provides a unique opportunity to alter treatment paradigms and provide new therapeutic options for patients whose malignancies possess these aberrant epigenetic modifications, paving the way for new and personalized medicine. DNA methylation has proven to be of significant clinical utility for its stability and relative ease of testing. The intent of this review is to elaborate upon well-supported examples of epigenetic precision medicine and how the field is moving forward, primarily in the context of aberrant DNA methylation.
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http://dx.doi.org/10.1097/PPO.0000000000000281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708865PMC
May 2018

Introduction: Cancer as an Epigenetic Disease.

Cancer J 2017 Sep/Oct;23(5):255-256

From the Fels Institute, Temple University School of Medicine, Philadelphia, PA.

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http://dx.doi.org/10.1097/PPO.0000000000000285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708861PMC
March 2019

Caloric restriction delays age-related methylation drift.

Nat Commun 2017 09 14;8(1):539. Epub 2017 Sep 14.

Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, 19140, USA.

In mammals, caloric restriction consistently results in extended lifespan. Epigenetic information encoded by DNA methylation is tightly regulated, but shows a striking drift associated with age that includes both gains and losses of DNA methylation at various sites. Here, we report that epigenetic drift is conserved across species and the rate of drift correlates with lifespan when comparing mice, rhesus monkeys, and humans. Twenty-two to 30-year-old rhesus monkeys exposed to 30% caloric restriction since 7-14 years of age showed attenuation of age-related methylation drift compared to ad libitum-fed controls such that their blood methylation age appeared 7 years younger than their chronologic age. Even more pronounced effects were seen in 2.7-3.2-year-old mice exposed to 40% caloric restriction starting at 0.3 years of age. The effects of caloric restriction on DNA methylation were detectable across different tissues and correlated with gene expression. We propose that epigenetic drift is a determinant of lifespan in mammals.Caloric restriction has been shown to increase lifespan in mammals. Here, the authors provide evidence that age-related methylation drift correlates with lifespan and that caloric restriction in mice and rhesus monkeys results in attenuation of age-related methylation drift.
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http://dx.doi.org/10.1038/s41467-017-00607-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599616PMC
September 2017

Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial.

Lancet Oncol 2017 10 24;18(10):1317-1326. Epub 2017 Aug 24.

Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia PA, USA.

Background: The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy.

Methods: We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock, 15 patients were still in follow-up for overall survival. This study is registered with ClinicalTrials.gov, number NCT01261312.

Findings: Between Aug 24, 2012, and Sept 15, 2014, 107 patients were enrolled: 54 on the 5-day schedule (26 randomly assigned to 60 mg/m and 28 to 90 mg/m) and 53 were assigned to the 10-day schedule. Median age was 77 years (range 62-92), and median follow-up was 953 days (IQR 721-1040). All treated patients were assessable for a response. The number of patients who achieved a composite complete response did not differ between dose groups or schedules (13 [54%, 95% CI 32·8-74·4] with 60 mg/m on the 5-day schedule; 16 [59%; 38·8-77·6] with 90 mg/m on the 5-day schedule; and 26 [50%, 35·8-64·2] with 60 mg/m on the 10-day schedule). The most frequent grade 3 or worse adverse events, regardless of relationship to treatment, were febrile neutropenia (31 [61%] of 51 patients on the 5-day schedule vs 36 [69%] of 52 patients on the 10-day schedule), thrombocytopenia (25 [49%] vs 22 [42%]), neutropenia (20 [39%] vs 18 [35%]), pneumonia (15 [29%] vs 19 [37%]), anaemia (15 [29%] vs 12 [23%]), and sepsis (eight [16%] vs 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5-day and 10-day schedules, respectively, were febrile neutropenia (27 [53%] vs 25 [48%]), pneumonia (14 [27%] vs 16 [31%]), and sepsis (eight [16%] vs 14 [27%]). 23 (22%) patients died because of adverse events (mainly from sepsis, eight [8%]; and pneumonia, five [5%]); four deaths were from adverse events deemed treatment-related (pneumonia, two [2%]; multiorgan failure, one [1%]; and sepsis, one [1%], all in the 10-day cohort).

Interpretation: More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m in a 5-day schedule. A phase 3 study in this patient population is ongoing (NCT02348489) to assess guadecitabine 60 mg/m in a 5-day schedule versus standard of care.

Funding: Astex Pharmaceuticals and Stand Up To Cancer.
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http://dx.doi.org/10.1016/S1470-2045(17)30576-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925750PMC
October 2017

A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer.

Nucleic Acids Res 2017 Aug;45(14):8269-8281

Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.

TET1 oxidizes methylated cytosine into 5-hydroxymethylcytosine (5hmC), resulting in regulation of DNA methylation and gene expression. Full length TET1 (TET1FL) has a CXXC domain that binds to unmethylated CpG islands (CGIs). This CXXC domain allows TET1 to protect CGIs from aberrant methylation, but it also limits its ability to regulate genes outside of CGIs. Here, we report a novel isoform of TET1 (TET1ALT) that has a unique transcription start site from an alternate promoter in intron 2, yielding a protein with a unique translation start site. Importantly, TET1ALT lacks the CXXC domain but retains the catalytic domain. TET1ALT is repressed in embryonic stem cells (ESCs) but becomes activated in embryonic and adult tissues while TET1FL is expressed in ESCs, but repressed in adult tissues. Overexpression of TET1ALT shows production of 5hmC with distinct (and weaker) effects on DNA methylation or gene expression when compared to TET1FL. TET1ALT is aberrantly activated in multiple cancer types including breast, uterine and glioblastoma, and TET1 activation is associated with a worse overall survival in breast, uterine and ovarian cancers. Our data suggest that the predominantly activated isoform of TET1 in cancer cells does not protect from CGI methylation and likely mediates dynamic site-specific demethylation outside of CGIs.
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http://dx.doi.org/10.1093/nar/gkx435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737541PMC
August 2017

The promise of epigenetic therapy: reprogramming the cancer epigenome.

Curr Opin Genet Dev 2017 Feb 14;42:68-77. Epub 2017 Apr 14.

Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA. Electronic address:

Epigenetics refers to heritable molecular determinants of phenotype independent of DNA sequence. Epigenetic features include DNA methylation, histone modifications, non-coding RNAs, and chromatin structure. The epigenetic status of cells plays a crucial role in determining their differentiation state and proper function within multicellular organisms. Disruption of these processes is now understood to be a major contributor to cancer development and progression, and recent efforts have attempted to pharmacologically reverse such altered epigenetics. In this mini-review we introduce the concept of epigenetic drivers of cancer and discuss how aberrant DNA methylation, histone modifications, and chromatin states are being targeted using drugs either in preclinical, or clinical development, and how they fit in the context of existing therapies.
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http://dx.doi.org/10.1016/j.gde.2017.03.015DOI Listing
February 2017

DNA Hypomethylating Drugs in Cancer Therapy.

Cold Spring Harb Perspect Med 2017 May 1;7(5). Epub 2017 May 1.

Fox Chase Cancer Center, Temple Health, Philadelphia, Pennsylvania 19111.

Aberrant DNA methylation is a critically important modification in cancer cells, which, through promoter and enhancer DNA methylation changes, use this mechanism to activate oncogenes and silence of tumor-suppressor genes. Targeting DNA methylation in cancer using DNA hypomethylating drugs reprograms tumor cells to a more normal-like state by affecting multiple pathways, and also sensitizes these cells to chemotherapy and immunotherapy. The first generation hypomethylating drugs azacitidine and decitabine are routinely used for the treatment of myeloid leukemias and a next-generation drug (guadecitabine) is currently in clinical trials. This review will summarize preclinical and clinical data on DNA hypomethylating drugs as a cancer therapy.
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http://dx.doi.org/10.1101/cshperspect.a026948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411681PMC
May 2017

Genetic Variants in Epigenetic Pathways and Risks of Multiple Cancers in the GAME-ON Consortium.

Cancer Epidemiol Biomarkers Prev 2017 06 23;26(6):816-825. Epub 2017 Jan 23.

National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background. In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate-corrected values (q values < 0.05) were considered statistically significant. Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants in were confirmed as a susceptibility locus for squamous cell lung, overall breast, estrogen receptor (ER)-negative breast, and overall prostate, and overall serous ovarian cancer; the most significant variant was rs4808076 [OR = 1.14; 95% confidence interval (CI) = 1.10-1.19; q = 6.87 × 10]. rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, and overall and aggressive prostate cancer risk (OR = 0.93; 95% CI = 0.91-0.96; q = 0.005). Variants in were associated with colorectal, overall breast, ER-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g., rs9388766: OR = 1.06; 95% CI = 1.03-1.08; q = 0.02). Variants in were significantly associated with overall breast, overall prostate, overall ovarian, and endometrioid ovarian cancer risk, with rs62331150 showing bidirectional effects. Analyses of subpathways did not reveal gene subsets that contributed disproportionately to susceptibility. Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology. This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes. .
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http://dx.doi.org/10.1158/1055-9965.EPI-16-0728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054308PMC
June 2017

Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome.

Mol Cancer Ther 2017 02 15;16(2):397-407. Epub 2016 Dec 15.

Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.

Epigenetic drugs, such as DNA methylation inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi), are approved in monotherapy for cancer treatment. These drugs reprogram gene expression profiles, reactivate tumor suppressor genes (TSG) producing cancer cell differentiation and apoptosis. Epigenetic drugs have been shown to synergize with other epigenetic drugs or various anticancer drugs. To discover new molecular entities that enhance epigenetic therapy, we performed a high-throughput screening using FDA-approved libraries in combination with DNMTi or HDACi. As a screening model, we used YB5 system, a human colon cancer cell line, which contains an epigenetically silenced CMV-GFP locus, mimicking TSG silencing in cancer. CMV-GFP reactivation is triggered by DNMTi or HDACi and responds synergistically to DNMTi/HDACi combination, which phenocopies TSG reactivation upon epigenetic therapy. GFP fluorescence was used as a quantitative readout for epigenetic activity. We discovered that 45 FDA-approved drugs (4% of all drugs tested) in our FDA-approved libraries enhanced DNMTi and HDACi activity, mainly belonging to anticancer and antiarrhythmic drug classes. Transcriptome analysis revealed that combination of decitabine (DNMTi) with the antiarrhythmic proscillaridin A produced profound gene expression reprogramming, which was associated with downregulation of 153 epigenetic regulators, including two known oncogenes in colon cancer (SYMD3 and KDM8). Also, we identified about 85 FDA-approved drugs that antagonized DNMTi and HDACi activity through cytotoxic mechanisms, suggesting detrimental drug interactions for patients undergoing epigenetic therapy. Overall, our drug screening identified new combinations of epigenetic and FDA-approved drugs, which can be rapidly implemented into clinical trials. Mol Cancer Ther; 16(2); 397-407. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292054PMC
February 2017

Transcriptional Selectivity of Epigenetic Therapy in Cancer.

Cancer Res 2017 01 22;77(2):470-481. Epub 2016 Nov 22.

Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania.

A central challenge in the development of epigenetic cancer therapy is the ability to direct selectivity in modulating gene expression for disease-selective efficacy. To address this issue, we characterized by RNA-seq, DNA methylation, and ChIP-seq analyses the epigenetic response of a set of colon, breast, and leukemia cancer cell lines to small-molecule inhibitors against DNA methyltransferases (DAC), histone deacetylases (Depsi), histone demethylases (KDM1A inhibitor S2101), and histone methylases (EHMT2 inhibitor UNC0638 and EZH2 inhibitor GSK343). We also characterized the effects of DAC as combined with the other compounds. Averaged over the cancer cell models used, we found that DAC affected 8.6% of the transcriptome and that 95.4% of the genes affected were upregulated. DAC preferentially regulated genes that were silenced in cancer and that were methylated at their promoters. In contrast, Depsi affected the expression of 30.4% of the transcriptome but showed little selectivity for gene upregulation or silenced genes. S2101, UNC0638, and GSK343 affected only 2% of the transcriptome, with UNC0638 and GSK343 preferentially targeting genes marked with H3K9me2 or H3K27me3, respectively. When combined with histone methylase inhibitors, the extent of gene upregulation by DAC was extended while still maintaining selectivity for DNA-methylated genes and silenced genes. However, the genes upregulated by combination treatment exhibited limited overlap, indicating the possibility of targeting distinct sets of genes based on different epigenetic therapy combinations. Overall, our results demonstrated that DNA methyltransferase inhibitors preferentially target cancer-relevant genes and can be combined with inhibitors targeting histone methylation for synergistic effects while still maintaining selectivity. Cancer Res; 77(2); 470-81. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5243171PMC
January 2017

Targeting the cancer epigenome for therapy.

Nat Rev Genet 2016 09;17(10):630-41

Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.

Next-generation sequencing has revealed that more than 50% of human cancers harbour mutations in enzymes that are involved in chromatin organization. Tumour cells not only are activated by genetic and epigenetic alterations, but also routinely use epigenetic processes to ensure their escape from chemotherapy and host immune surveillance. Hence, a growing emphasis of recent drug discovery efforts has been on targeting the epigenome, including DNA methylation and histone modifications, with several new drugs being tested and some already approved by the US Food and Drug Administration (FDA). The future will see the increasing success of combining epigenetic drugs with other therapies. As epigenetic drugs target the epigenome as a whole, these true 'genomic medicines' lessen the need for precision approaches to individualized therapies.
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http://dx.doi.org/10.1038/nrg.2016.93DOI Listing
September 2016

Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer.

Cancer Res 2016 Mar 30;76(6):1494-505. Epub 2015 Dec 30.

Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.

Targeting epigenetic pathways is a promising approach for cancer therapy. Here, we report on the unexpected finding that targeting calcium signaling can reverse epigenetic silencing of tumor suppressor genes (TSG). In a screen for drugs that reactivate silenced gene expression in colon cancer cells, we found three classical epigenetic targeted drugs (DNA methylation and histone deacetylase inhibitors) and 11 other drugs that induced methylated and silenced CpG island promoters driving a reporter gene (GFP) as well as endogenous TSGs in multiple cancer cell lines. These newly identified drugs, most prominently cardiac glycosides, did not change DNA methylation locally or histone modifications globally. Instead, all 11 drugs altered calcium signaling and triggered calcium-calmodulin kinase (CamK) activity, leading to MeCP2 nuclear exclusion. Blocking CamK activity abolished gene reactivation and cancer cell killing by these drugs, showing that triggering calcium fluxes is an essential component of their epigenetic mechanism of action. Our data identify calcium signaling as a new pathway that can be targeted to reactivate TSGs in cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-2391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794357PMC
March 2016

Zebrafish embryos as a screen for DNA methylation modifications after compound exposure.

Toxicol Appl Pharmacol 2016 Jan 19;291:84-96. Epub 2015 Dec 19.

Center for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands. Electronic address:

Modified epigenetic programming early in life is proposed to underlie the development of an adverse adult phenotype, known as the Developmental Origins of Health and Disease (DOHaD) concept. Several environmental contaminants have been implicated as modifying factors of the developing epigenome. This underlines the need to investigate this newly recognized toxicological risk and systematically screen for the epigenome modifying potential of compounds. In this study, we examined the applicability of the zebrafish embryo as a screening model for DNA methylation modifications. Embryos were exposed from 0 to 72 h post fertilization (hpf) to bisphenol-A (BPA), diethylstilbestrol, 17α-ethynylestradiol, nickel, cadmium, tributyltin, arsenite, perfluoroctanoic acid, valproic acid, flusilazole, 5-azacytidine (5AC) in subtoxic concentrations. Both global and site-specific methylation was examined. Global methylation was only affected by 5AC. Genome wide locus-specific analysis was performed for BPA exposed embryos using Digital Restriction Enzyme Analysis of Methylation (DREAM), which showed minimal wide scale effects on the genome, whereas potential informative markers were not confirmed by pyrosequencing. Site-specific methylation was examined in the promoter regions of three selected genes vasa, vtg1 and cyp19a2, of which vasa (ddx4) was the most responsive. This analysis distinguished estrogenic compounds from metals by direction and sensitivity of the effect compared to embryotoxicity. In conclusion, the zebrafish embryo is a potential screening tool to examine DNA methylation modifications after xenobiotic exposure. The next step is to examine the adult phenotype of exposed embryos and to analyze molecular mechanisms that potentially link epigenetic effects and altered phenotypes, to support the DOHaD hypothesis.
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http://dx.doi.org/10.1016/j.taap.2015.12.012DOI Listing
January 2016

Hypomethylation of TET2 Target Genes Identifies a Curable Subset of Acute Myeloid Leukemia.

J Natl Cancer Inst 2015 Nov 13;108(2). Epub 2015 Nov 13.

Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA (JY, JJ, NJMR, MC, JPJI); Department of Leukemia (JY, RT, JJ, NJMR, SAP, SMK, FR, HMK, JPJI) and Department of Hematopathology (CEBR), The University of Texas MD Anderson Cancer Center, Houston, TX.

Background: Acute myeloid leukemia (AML) is curable in a subset of cases. The DNA methylation regulator TET2 is frequently mutated in AML, and we hypothesized that studying TET2-specific differentially methylated CpGs (tet2-DMCs) improves AML classification.

Methods: We used bisulfite pyrosequencing to analyze the methylation status of four tet2-DMCs (SP140, MCCC1, EHMT1, and MTSS1) in a test group of 94 consecutive patients and a validation group of 92 consecutive patients treated with cytarabine-based chemotherapy. Data were analyzed with hierarchical clustering, Cox proportional hazards regression, and Kaplan-Meier analyses. All statistical tests were two-sided.

Results: In the test cohort, hierarchical clustering analysis identified low levels of tet2-DMC methylation in 31 of 94 (33%) cases, and these had markedly longer overall survival (median survival 72+ vs 14 months, P = .002). Similar results were seen in the validation cohort. tet2-DMC-low status was shown to be an independent predictor of overall survival (hazard ratio = 0.29, P = .0002). In The Cancer Genome Atlas (TCGA) dataset where DNA methylation was analyzed by a different platform, tet2-DMC-low methylation was also associated with improved outcome (median survival = 55 vs 15 months, P = .0003) and was a better predictor of survival than mutations in TET2, IDH1, or IDH2, individually or combined.

Conclusions: Low levels of tet2-DMC methylation define a subgroup of AML that is highly curable and cannot be identified solely by genetic and cytogenetic analyses.
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http://dx.doi.org/10.1093/jnci/djv323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862435PMC
November 2015

Will next-generation agents deliver on the promise of epigenetic hypomethylation therapy?

Epigenomics 2015 Oct 6;7(7):1083-8. Epub 2015 Nov 6.

Fels Institute, Temple University School of Medicine & Cancer Epigenetics Program, Fox Chase Cancer Center, Temple Health, 3307 North Broad Street, Room 154, Philadelphia, PA 19140, USA.

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http://dx.doi.org/10.2217/epi.15.66DOI Listing
October 2015

Healthcare utilization and costs associated with tyrosine kinase inhibitor switching in patients with chronic myeloid leukemia.

Leuk Lymphoma 2016 20;57(4):935-41. Epub 2015 Nov 20.

c Fels Institute for Cancer Research , Temple University School of Medicine , Philadelphia , PA , USA.

Differences in healthcare utilization and costs were examined in chronic myeloid leukemia (CML) patients experiencing first-, second- and third-line tyrosine kinase inhibitor (TKI) therapy. Three CML cohorts were identified from the Truven Health MarketScan® database: No-Switch Cohort (NSc) = did not switch from first-line; One-Switch Cohort (OSc) = switched from first- to second-line only; Two-Switch Cohort (TSc) = switched to second- and then third-line. A total of 3510 patients were identified (mean = 54%; age = 55.8 years). NSc comprised 81% of the sample, OSc comprised 15% and 4% were in the TSc. First-line utilization/costs were significantly higher in the OSc/TSc compared to the NSc. Second-line hospital/outpatient visits and costs were higher in TSc compared to OSc. TSc experienced a significant cost increase from first- to second-line ($4226.46), twice that of OSc ($2488.03). TKI switching is associated with a substantial increase in healthcare utilization and costs, particularly for patients who switch twice.
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http://dx.doi.org/10.3109/10428194.2015.1088654DOI Listing
December 2016

Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer.

J Clin Oncol 2015 Dec 12;33(34):4032-8. Epub 2015 Oct 12.

Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.

Purpose: BRAF V600E mutation is seen in 5% to 8% of patients with metastatic colorectal cancer (CRC) and is associated with poor prognosis. Vemurafenib, an oral BRAF V600 inhibitor, has pronounced activity in patients with metastatic melanoma, but its activity in patients with BRAF V600E-positive metastatic CRC was unknown.

Patients And Methods: In this multi-institutional, open-label study, patients with metastatic CRC with BRAF V600 mutations were recruited to an expansion cohort at the previously determined maximum-tolerated dose of 960 mg orally twice a day.

Results: Twenty-one patients were enrolled, of whom 20 had received at least one prior metastatic chemotherapy regimen. Grade 3 toxicities included keratoacanthomas, rash, fatigue, and arthralgia. Of the 21 patients treated, one patient had a confirmed partial response (5%; 95% CI, 1% to 24%) and seven other patients had stable disease by RECIST criteria. Median progression-free survival was 2.1 months. Patterns of concurrent mutations, microsatellite instability status, CpG island methylation status, PTEN loss, EGFR expression, and copy number alterations were not associated with clinical benefit. In contrast to prior expectations, concurrent KRAS and NRAS mutations were detected at low allele frequency in a subset of the patients' tumors (median, 0.21% allele frequency) and were apparent mechanisms of acquired resistance in vemurafenib-sensitive patient-derived xenograft models.

Conclusion: In marked contrast to the results seen in patients with BRAF V600E-mutant melanoma, single-agent vemurafenib did not show meaningful clinical activity in patients with BRAF V600E mutant CRC. Combination strategies are now under development and may be informed by the presence of intratumor heterogeneity of KRAS and NRAS mutations.
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http://dx.doi.org/10.1200/JCO.2015.63.2497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669589PMC
December 2015