Keunsoo Kang | PubMed Health

PubMed2026

Transcriptome-based epigenetic screening identifies DNA hypermethylation signatures as prognostic biomarkers in oral squamous cell carcinoma.

Promoter DNA hypermethylation is a key epigenetic mechanism of gene silencing in cancer, yet the DNA hypermethylome of oral squamous cell carcinoma (OSCC) and its prognostic relevance remain poorly characterized. Here, we systematically identified and validated novel hypermethylated genes with prognostic significance in OSCC using a genome-wide discovery and multi-platform validation strategy. Candidate genes were first identified by pharmacologic demethylation combined with RNA sequencing across OSCC cell lines, then validated by quantitative RT-PCR, methylation-specific PCR, and bisulfite sequencing in OSCC cell lines, normal oral mucosa, and primary OSCC tumors, with independent confirmation in the TCGA-HNSC dataset. Immunohistochemistry confirmed protein-level silencing, and Kaplan-Meier survival analysis assessed prognostic significance across both cohorts. This pipeline identified five candidate genes, GPX3, ANG, CTGF, GPRC5B, and BAMBI, exhibiting cancer-specific promoter hypermethylation associated with transcriptional and protein silencing in OSCC. Validation in oral cavity tumor samples extracted from the TCGA-HNSC dataset confirmed tumor-specific hypermethylation and revealed significant inverse correlations between methylation and expression for GPX3, GPRC5B, and CTGF. Notably, CTGF hypermethylation was independently associated with poor overall survival in both cohorts (institutional cohort, p=0.03; oral tumor subset from TCGA-HNSC, p=0.01), and a combined ANG+CTGF methylation signature showed superior and reproducible prognostic performance across both platforms. Pathway analysis linked these genes to epithelial-mesenchymal transition and interferon response signaling. This study establishes the first validated DNA methylation biomarker panel for OSCC prognosis, identifying CTGF hypermethylation as a robust prognostic driver with translational potential for clinical risk stratification.

Humans↗

PubMed2024

Molecular genomic and epigenomic characteristics related to aspirin and clopidogrel resistance.

BACKGROUND: Mediators, genomic and epigenomic characteristics involving in metabolism of arachidonic acid by cyclooxygenase (COX) and lipoxygenase (ALOX) and hepatic activation of clopidogrel have been individually suggested as factors associated with resistance against aspirin and clopidogrel. The present multi-center prospective cohort study evaluated whether the mediators, genomic and epigenomic characteristics participating in arachidonic acid metabolism and clopidogrel activation could be factors that improve the prediction of the aspirin and clopidogrel resistance in addition to cardiovascular risks. METHODS: We enrolled 988 patients with transient ischemic attack and ischemic stroke who were evaluated for a recurrence of ischemic stroke to confirm clinical resistance, and measured aspirin (ARU) and P2Y12 reaction units (PRU) using VerifyNow to assess laboratory resistance 12 weeks after aspirin and clopidogrel administration. We investigated whether mediators, genotypes, and promoter methylation of genes involved in COX and ALOX metabolisms and clopidogrel activation could synergistically improve the prediction of ischemic stroke recurrence and the ARU and PRU levels by integrating to the established cardiovascular risk factors. RESULTS: The logistic model to predict the recurrence used thromboxane A synthase 1 (TXAS1, rs41708) A/A genotype and ALOX12 promoter methylation as independent variables, and, improved sensitivity of recurrence prediction from 3.4% before to 13.8% after adding the mediators, genomic and epigenomic variables to the cardiovascular risks. The linear model we used to predict the ARU level included leukotriene B4, COX2 (rs20417) C/G and thromboxane A2 receptor (rs1131882) A/A genotypes with the addition of COX1 and ALOX15 promoter methylations as variables. The linear PRU prediction model included G/A and prostaglandin I receptor (rs4987262) G/A genotypes, COX2 and TXAS1 promoter methylation, as well as cytochrome P450 2C19*2 (rs4244285) A/A, G/A, and *3 (rs4986893) A/A genotypes as variables. The linear models for predicting ARU (r = 0.291, R2 = 0.033, p < 0.01) and PRU (r = 0.503, R2 = 0.210, p < 0.001) levels had improved prediction performance after adding the genomic and epigenomic variables to the cardiovascular risks. CONCLUSIONS: This study demonstrates that different mediators, genomic and epigenomic characteristics of arachidonic acid metabolism and clopidogrel activation synergistically improved the prediction of the aspirin and clopidogrel resistance together with the cardiovascular risk factors. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03823274.

Humans↗