Genetic Variation Throughout the Folate Metabolic Pathway Influences Negative Symptom Severity in Schizophrenia

Low serum folate levels previously have been associated with negative symptom risk in schizophrenia, as has the hypofunctional 677C>T variant of the MTHFR gene. This study examined whether other missense polymorphisms in folate-regulating enzymes, in concert with MTHFR, influence negative symptoms in schizophrenia, and whether total risk allele load interacts with serum folate status to further stratify negative symptom risk. Medicated outpatients with schizophrenia (n = 219), all of European origin and some included in a previous report, were rated with the Positive and Negative Syndrome Scale. A subset of 82 patients also underwent nonfasting serum folate testing. Patients were genotyped for the MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), MTR 2756A>G (rs1805087), MTRR 203A>G (rs1801394), FOLH1 484T>C (rs202676), RFC 80A>G (rs1051266), and COMT 675G>A (rs4680) polymorphisms. All genotypes were entered into a linear regression model to determine significant predictors of negative symptoms, and risk scores were calculated based on total risk allele dose. Four variants, MTHFR 677T, MTR 2756A, FOLH1 484C, and COMT 675A, emerged as significant independent predictors of negative symptom severity, accounting for significantly greater variance in negative symptoms than MTHFR 677C>T alone. Total allele dose across the 4 variants predicted negative symptom severity only among patients with low folate levels. These findings indicate that multiple genetic variants within the folate metabolic pathway contribute to negative symptoms of schizophrenia. A relationship between folate level and negative symptom severity among patients with greater genetic vulnerability is biologically plausible and suggests the utility of folate supplementation in these patients.     

Genome‐wide DNA‐methylation profiles in human bone marrow mesenchymal stem cells on titanium surfaces

The characteristics of titanium (Ti) have been shown to influence dental implant fixation. Treatment of surfaces using the sandblasted, large‐grit, acid‐etched (SLA) method is widely used to provide effective osseointegration. However, the DNA methylation‐associated mechanism by which SLA surface treatment affects osseointegration of human bone marrow mesenchymal stem cells (hBMSCs) remains elusive. Genome‐wide methylation profiling of hBMSCs on SLA‐treated and machined smooth Ti was performed using Illumina Infinium Methylation EPIC BeadChip at day 7 of osteogenic induction. In total, 2,846 CpG sites were differentially methylated in the SLA group compared with the machined group. Of these sites, 1,651 (covering 1,066 genes) were significantly hypermethylated and 1,195 (covering 775 genes) were significantly hypomethylated. Thirty significant enrichment pathways were observed, with Wnt signaling being the most significant. mRNA expression was identified by microarray and combined with DNA‐methylation profiles. Thirty‐seven genes displayed negative association between mRNA expression and DNA‐methylation level, with the osteogenesis‐related genes insulin‐like growth factor 2 (IGF2) and carboxypeptidase X, M14 Family Member 2 (CPXM2) showing significant up‐regulation and down‐regulation, respectively. In summary, our results demonstrate differences between SLA‐treated and machined surfaces in their effects on genome‐wide DNA methylation and enrichment of osteogenic pathways in hBMSCs. We provide novel insights into genes and pathways affected by SLA treatment in hBMSCs at the molecular level.     

Cancer–germline antigen vaccines and epigenetic enhancers: future strategies for cancer treatment

Importance of the field: Immunotherapy holds great potential for disseminated cancer, and cancer–germline (CG) antigens are among the most promising tumor targets. They are widely expressed in different cancer types and are essentially tumor-specific, since their expression in normal tissues is largely restricted to immune-privileged sites. Although the therapeutic potential of these antigens may be compromised by their highly heterogeneous expression in many tumors and low frequency in some cancers, recent developments suggest that tumor-cell-selective enhancement of CG antigen gene expression can be achieved using epigenetic modifiers.

Areas covered in this review: We provide an overview of the potential of CG antigens as targets for cancer immunotherapy, including advantages and disadvantages. We also discuss the current state of development of CG antigen vaccines, and the potential synergistic effect of combining CG antigen immunotherapeutic strategies with epigenetic modifiers.

What the reader will gain: The reader will gain an overview of the past, present and future role of CG antigens in cancer immunotherapy.

Take home message: Chemoimmunotherapy using epigenetic drugs and CG antigen vaccines may be a useful approach for treating cancer.     

DNA methyltransferase inhibitors in cancer: a chemical and therapeutic patent overview and selected clinical studies

Introduction: DNA methylation is an epigenetic modification that modulates gene expression without altering the DNA base sequence. It plays a crucial role in cancer by silencing tumor suppressor genes (TSG). The DNA methyltransferases (DNMT) are the enzymes that catalyze DNA methylation and they are interesting therapeutical targets since DNA methylation is reversible such that an aberrant hypermethylation of DNA can be reverted by inhibition of DNMTs. Today, two drugs are on the market for the treatment of myelodysplastic syndrome, azacitidine and decitabine.

Areas covered: Here, we present a review of the patents describing the chemistry and biological activities of novel DNMT inhibitors and discuss select clinical studies.

Expert opinion: DNMT inhibitors have shown efficacy in clinics. However, highly efficient and specific DNMT inhibitors have not yet been identified. Improving methods will certainly lead to the prediction of novel directly binding inhibitors in the future.     

Synthetic lethality strategies: Beyond BRCA1/2 mutations in pancreatic cancer

Cancer cells are often characterized by abnormalities in DNA damage response including defects in cell cycle checkpoints and/or DNA repair. Synthetic lethality between DNA damage repair (DDR) pathways has provided a paradigm for cancer therapy by targeting DDR. The successful example is that cancer cells with BRCA1/2 mutations are sensitized to poly(adenosine diphosphate [ADP]‐ribose)polymerase (PARP) inhibitors. Beyond the narrow scope of defects in the BRCA pathway, “BRCAness” provides more opportunities for synthetic lethality strategy. In human pancreatic cancer, frequent mutations were found in cell cycle and DDR genes, including P16, P73, APC, MLH1, ATM, PALB2, and MGMT. Combined DDR inhibitors and chemotherapeutic agents are under preclinical or clinical trials. Promoter region methylation was found frequently in cell cycle and DDR genes. Epigenetics joins the Knudson's “hit” theory and “BRCAness.” Aberrant epigenetic changes in cell cycle or DDR regulators may serve as a new avenue for synthetic lethality strategy in pancreatic cancer.