Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer to IDH1R132H, a structural alteration that leads to catalysis of α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate. In this study, we present evidence that small-molecule inhibitors of IDH1R132H that are being developed for cancer therapy may pose risks with coadministration of radiotherapy. Cancer cells heterozygous for the IDH1R132H mutation exhibited less IDH-mediated production of NADPH, such that after exposure to ionizing radiation (IR), there were higher levels of reactive oxygen species, DNA double-strand breaks, and cell death compared with IDH1 wild-type cells. These effects were reversed by the IDH1R132H inhibitor AGI-5198. Exposure of IDH1 wild-type cells to D-2-hydroxyglutarate was sufficient to reduce IDH-mediated NADPH production and increase IR sensitivity. Mechanistic investigations revealed that the radiosensitivity of heterozygous cells was independent of the well-described DNA hypermethylation phenotype in IDH1-mutated cancers. Thus, our results argue that altered oxidative stress responses are a plausible mechanism to understand the radiosensitivity of IDH1-mutated cancer cells. Further, they offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and they imply that administration of IDH1R132H inhibitors in these patients may limit irradiation efficacy in this setting. Cancer Res; 75(22); 4790–802. ©2015 AACR.

Epigenome-wide association studies (EWAS) have identified DNA methylation loci involved in adiposity. However, EWAS on adiposity in sub-Saharan Africans are lacking despite the high burden of adiposity among African populations. We undertook an EWAS for anthropometric indices of adiposity among Ghanaians aiming to identify DNA methylation loci that are significantly associated. The Illumina 450k DNA methylation array was used to profile DNA methylation in whole blood samples of 547 Ghanaians from the Research on Obesity and Diabetes among African Migrants (RODAM) study. Differentially methylated positions (DMPs) and differentially methylation regions (DMRs) were identified for BMI and obesity (BMI ≥ 30 kg/m2), as well as for waist circumference (WC) and abdominal obesity (WC ≥ 102 cm in men, ≥88 cm in women). All analyses were adjusted for age, sex, blood cell distribution estimates, technical covariates, recruitment site and population stratification. We also did a replication study of previously reported EWAS loci for anthropometric indices in other populations. We identified 18 DMPs for BMI and 23 for WC. For obesity and abdominal obesity, we identified three and one DMP, respectively. Fourteen DMPs overlapped between BMI and WC. DMP cg00574958 annotated to gene CPT1A was the only DMP associated with all outcomes analysed, attributing to 6.1 and 5.6% of variance in obesity and abdominal obesity, respectively. DMP cg07839457 (NLRC5) and cg20399616 (BCAT1) were significantly associated with BMI, obesity and with WC and had not been reported by previous EWAS on adiposity. This first EWAS for adiposity in Africans identified three epigenome-wide significant loci (CPT1A, NLRC5 and BCAT1) for both general adiposity and abdominal adiposity. The findings are a first step in understanding the role of DNA methylation in adiposity among sub-Saharan Africans. Studies on other sub-Saharan African populations as well as translational studies are needed to determine the role of these DNA methylation variants in the high burden of adiposity among sub-Saharan Africans.

The metabolic syndrome is a pathological state in which one of the key components is insulin resistance. A wide spectrum of body compartments is involved in its pathophysiology. Genetic and environmental factors such as diet and physical activity are both related to its etiology. Reversible modulation of gene expression without altering the DNA sequence, known as epigenetic modifications, has been shown to drive this complex metabolic cluster of conditions. Here, we aim to examine some of the recent research of specific epigenetically mediated mechanisms and microbiota-induced epigenetic modifications on the development of adipose tissue and obesity, β-cell dysfunction and diabetes, and hepatocytes and non-alcoholic fatty disease.

Crohn’s disease (CD) is a chronic inflammatory disorder belonging to the inflammatory bowel diseases (IBD). CD affects distinct parts of the gastrointestinal tract, leading to symptoms including diarrhea, fever, abdominal pain, weight loss, and anemia. The aim of this study was to assess whether the DNA methylome of peripheral blood cells can be associated with CD in women. Samples were obtained from 18 female patients with histologically confirmed ileal or ileocolic CD and 25 healthy age- and gender-matched controls (mean age and standard deviation: 30.5 ± 6.5 years for both groups). Genome-wide DNA methylation was determined using the Illumina HumanMethylation 450k BeadChip. Our analysis implicated 4287 differentially methylated positions (DMPs; corrected p < 0.05) that are associated to 2715 unique genes. Gene ontology enrichment analysis revealed significant enrichment of our DMPs in immune response processes and inflammatory pathways. Of the 4287 DMPs, 32 DMPs were located on chromosome X with several hits for MIR223 and PABPC5. Comparison with previously performed (epi)genome-wide studies revealed that we replicated 33 IBD-associated genes. In addition to DMPs, we found eight differentially methylated regions (DMRs). CD patients display a characteristic DNA methylation landscape, with the differentially methylated genes being implicated in immune response. Additionally, DMPs were found on chromosome X suggesting X-linked manifestations of CD that could be associated with female-specific symptoms.

Aim: Fetal alcohol spectrum disorder (FASD) involves prenatal growth delay, impaired facial and CNS development and causes severe clinical, social-economic burdens. Here, we aim to detect DNA-methylation aberrations associated with FASD and potential FASD diagnostic and prognostic biomarkers. Patients & methods: The FASD diagnosis was established according to golden-standard protocols in a discovery and independent replication cohort. Genome-wide differential methylation association and replication analyses were performed. Results: We identified several loci that were robustly associated with FASD or one of its sub phenotypes. Our findings were evaluated using previously reported genome-wide surveys. Conclusion: We have detected robust FASD associated differentially methylated positions and differentially methylated regions for FASD in general and for FASD subphenotypes, in other words on growth delay, impaired facial and CNS development.

Cow’s milk allergy (CMA) is a common disease in infancy. Early environmental factors are likely to contribute to CMA. It is known that epigenetic gene regulation can be altered by environmental factors. We have set up a proof of concept study, aiming to detect epigenetic associations specific with CMA. We studied children from the Dutch EuroPrevall birth cohort study (N = 20 CMA, N = 23 controls, N = 10 tolerant boys), age and gender matched. CMA was challenge proven. Bisulfite converted DNA (blood) was analyzed using the 450K infinium DNA-methylation array. Four groups (combined, girls, boys and tolerant boys) were analysed between CMA and controls. Statistical analysis and pathway-analysis were performed in “R” using IMA, Minfi and the global-test package. Differentially methylated regions in DHX58, ZNF281, EIF42A and HTRA2 genes were validated by quantitative amplicon sequencing (ROCHE 454®). General hypermethylation was found in the CMA group compared to control children, while this effect was absent in the tolerant group. Methylation differences were, among others, found in regions of DHX58, ZNF281, EIF42A and HTRA2 genes. Several of these genes are known to be involved in immunological pathways and associated with other allergies. We show that epigenetic associations are involved in CMA. Although, the statistical power of our study is limited and our sample was based on whole blood, we were still able to detect feasible loci and pathways. Therefore our findings might contribute to future diagnostic or therapeutic interventions for specific CMA. Further studies have to confirm the findings of our study.