DNA Methylation Modification Patterns Research Articles

DNA Methylation Modification Patterns Identify Distinct Prognosis and Responses to Immunotherapy and Targeted Therapy in Renal Cell Carcinoma.

Considering the remarkable heterogeneity of biological features of renal cell carcinoma (RCC), the current clinical classification that only relies on classic clinicopathological features is in urgent need of improvement. Herein, we aimed to conduct DNA methylation modification patterns in RCC. We retrospectively curated multiple RCC cohorts, comprising TCGA-KIRC, TCGA-KICH, TCGA-KIRP, and E-MTAB-1980. DNA methylation modification patterns were proposed with an unsupervised clustering algorithm based on 20 DNA methylation regulators. Immunological features were characterized using tumor-infiltrating immune cells and immunomodulators. Sensitivity to immuno- or targeted therapy was estimated with submap and Genomics of Drug Sensitivity in Cancer (GDSC). DNA methylation score (DMS) was developed with principal component analysis. Three DNA methylation modification patterns were conducted across RCC patients, namely C1, C2 and C3. Among them, C3 displayed the most remarkable survival advantage. The three patterns presented in agreement with immune phenotypes: immune-desert, immune-excluded, and immune-inflamed, respectively. These patterns displayed distinct responses to anti-PD-1 and targeted drugs. DMS enabled the quantification of DNA methylation status individually as an alternative tool for prognostic estimation. The DNA methylation molecular patterns we proposed are an innovative complement to the traditional classification of RCC, which might contribute to precision medicine.

DNA methylation regulator-mediated modification pattern defines tumor microenvironment immune infiltration landscape in colon cancer.

Emerging evidence implies a non-negligible role of DNA methylation in tumor immunity, however, its comprehensive impact on tumor microenvironment (TME) formation and immune activation remains unclear. In this study, we integrated 24 DNA methylation regulators among 754 colon cancer patients to distinguish different modification patterns via an unsupervised clustering method, and explore their TME immune characteristics. Three DNA methylation modification patterns with distinct prognosis and biological behaviors were identified, consistent with three known phenotypes of immune-inflamed, immune-excluded, and immune-desert. We then determined a DNA methylation gene signature and constructed a DNA methylation score (DMS) to quantify modification patterns individually through principal component analysis algorithms. DMS-low group had characteristics of specific molecular subtypes, including microsatellite instability, CpG island methylator phenotype positive, and mutant BRAF, presented by increased mutation burden, activation of DNA damage repair and immune-related pathways, highly TME immune cells infiltration, and hence, a preferable prognosis. Further, low DMS was also demonstrated to be correlated to better response and prolonged survival of anti-PD-L1 antibody, indicating that DMS could be considered as an effective predictive tool for immunotherapy. In conclusion, our work presented a landscape of different DNA methylation modification patterns, and their vital role in the formation of TME diversity and complexity, which could help to enhance understanding of TME immune infiltration characteristics and more importantly, guide immunotherapy strategies more effectively and personalized.

DNA Methylation Regulator-Meditated Modification Patterns Define the Distinct Tumor Microenvironment in Lung Adenocarcinoma.

BackgroundEpigenetic changes of lung adenocarcinoma (LUAD) have been reported to be a relevant factor in tumorigenesis and cancer progression. However, the molecular mechanisms responsible for DNA methylation patterns in the tumor immune-infiltrating microenvironment and in cancer immunotherapy remain unclear.MethodsWe conducted a global analysis of the DNA methylation modification pattern (DMP) and immune cell-infiltrating characteristics of LUAD patients based on 21 DNA methylation regulators. A DNA methylation score (DMS) system was constructed to quantify the DMP model in each patient and estimate their potential benefit from immunotherapy.ResultsTwo DNA methylation modification patterns able to distinctly characterize the immune microenvironment characterization were identified among 513 LUAD samples. A lower DMS, characterized by increased CTLA-4/PD-1/L1 gene expression, greater methylation modifications, and tumor mutation burden, characterized a noninflamed phenotype with worse survival. A higher DMS, characterized by decreased methylation modification, a greater stromal-relevant response, and immune hyperactivation, characterized an inflamed phenotype with better prognosis. Moreover, a lower DMS indicated an increased mutation load and exhibited a poor immunotherapeutic response in the anti-CTLA-4/PD-1/PD-L1 cohort.ConclusionEvaluating the DNA methylation modification pattern of LUAD patients could enhance our understanding of the features of tumor microenvironment characterization and may promote more favorable immunotherapy strategies.

Comparison of DNA methylation profiles associated with spontaneous preterm birth in placenta and cord blood

BackgroundThe etiology and mechanism of spontaneous preterm birth (sPTB) are still unclear. Accumulating evidence has documented that various environmental exposure scenarios may cause maternal and fetal epigenetic changes, which initiates the focus on whether epigenetics can contribute to the occurrence of sPTB. Therefore, we conducted the current study to examine and compare the DNA methylation changes associated with sPTB in placenta and cord blood.MethodsThis hospital-based case-control study was carried out at three Women and Children’s hospitals in South China, where 32 spontaneous preterm births and 16 term births were recruited. Genome-wide DNA methylation profiles of the placenta and cord blood from these subjects were measured using the Illumina HumanMethylation EPIC BeadChip, and sPTB-associated differential methylated CpG sites were identified using limma regression model, after controlling for major maternal and infant confounders. Further Gene Ontology analysis was performed with PANTHER in order to assess different functional enrichment of the sPTB-associated genes in placenta and cord blood.ResultsAfter controlling for potential confounding factors, one differentially methylated position (DMP) in placenta and 31 DMPs in cord blood were found significantly associated with sPTB (Bonferroni corrected p < 0.05). The sPTB-associated CpG sites in placenta were mapped to genes that showed higher enrichment on biological processes including biological regulation, multicellular organismal process, and especially response to stimulus, while those in cord blood were mapped to genes that had higher enrichment on biological processes concerning cellular process, localization, and particularly metabolic process.ConclusionFindings of this study indicated that DNA methylation alteration in both placenta and cord blood are associated with sPTB, yet the DNA methylation modification patterns may appear differently in placenta and cord blood.