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PubMed2026

Epigenetic Profiling for Early Detection and Treatment Response Monitoring in Non-Small Cell Lung Cancer: Protocol for a Prospective Translational Biomarker Study.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide and continues to have poor survival outcomes, with most patients diagnosed at advanced stages of disease. In New Zealand, NSCLC contributes substantially to cancer inequities, with Māori communities experiencing disproportionately high incidence and mortality rates. Although low-dose computed tomography screening can improve early detection, major limitations remain, including false-positive findings, overdiagnosis, high infrastructure costs, and limited accessibility for rural and underserved populations. Liquid biopsy approaches using circulating tumor DNA (ctDNA), particularly DNA methylation profiling, have emerged as promising, minimally invasive strategies for improving cancer detection, treatment monitoring, and precision oncology. OBJECTIVE: This study aims to establish integrated genomic and epigenomic predictive and prognostic biomarkers using ctDNA, tumor tissue, and transcriptomic profiling to improve early detection, risk stratification, treatment selection and response prediction, and longitudinal monitoring, with particular emphasis on identifying molecular mechanisms associated with treatment resistance and disease progression. METHODS: This prospective observational translational biomarker study is being conducted through the University of Otago and associated respiratory and oncology services in New Zealand. The study will recruit participants with NSCLC (including squamous and nonsquamous subtypes), individuals referred to fast-track lung nodule assessment clinics, and nonmalignant respiratory controls. Serial peripheral blood sampling will be performed in selected participants at predefined clinical follow-up time points to evaluate treatment response and disease progression. The availability of formalin-fixed paraffin-embedded archival tissues will be recorded, but will not be mandatory for enrollment. Genome-scale DNA methylation profiling will be performed using cell-free reduced representation bisulfite sequencing (cfRRBS), while targeted genomic profiling and transcriptomic analyses will be conducted using targeted sequencing panels and RNA sequencing. Integrative bioinformatic analyses will be used to identify molecular biomarkers associated with early-stage disease, advanced disease, treatment response, and therapeutic resistance. RESULTS: Ethics approval for the study has been obtained from the New Zealand Health and Disability Ethics Committee (2022 EXP 12566). This study commenced in 2022, and recruitment and biospecimen collection are ongoing. The study aims to recruit approximately 450 participants, including patients with NSCLC, individuals referred through respiratory diagnostic pathways, and nonmalignant controls. As of July 31, 2026, 205 participants have been recruited, with recruitment continuing until the target sample size is reached. Molecular and data analyses are ongoing, with additional publications expected as the cohort matures. CONCLUSIONS: This study will generate one of the first integrated genomic, epigenomic, and transcriptomic liquid biopsy datasets for NSCLC in New Zealand. The findings are expected to support the development of sensitive, accessible, and equitable blood-based biomarkers for NSCLC detection and treatment monitoring while also contributing to improved precision oncology approaches and reducing NSCLC inequities among Māori populations.

Humans↗
PubMed2003

Profiling aberrant DNA methylation in hematologic neoplasms: a view from the tip of the iceberg.

Cancer is also an epigenetic disease. The main epigenetic modification in humans is DNA methylation. Transformed cells undergo a dramatic change in their DNA methylation patterns: certain CpG islands located in the promoter regions of tumor-suppressor genes become hypermethylated and the contiguous gene rests silenced and this phenomenon occurs in an overall genomic environment of DNA hypomethylation. The profile of CpG island hypermethylation in hematologic malignancies is an epigenetic signature unique for each subtype of leukemia or lymphoma. Although the most widely studied genes are the cell-cycle inhibitors p15INK4b and p16INK4a (specially in AML and ALL), the list of methylation-repressed genes in these neoplasms is expanding very rapidly, including MGMT, RARB2, CRBP1, SOCS-1, CDH1, DAPK1, and others. A necessary cross-talk between genetic alterations and DNA methylation exists: certain chromosomal translocations may induce hypermethylation, such as the PML-RARa, or attract methylation, such as BCR-ABL, but DNA hypomethylation can be the culprit behind the genesis of certain abnormal recombination events. From a translational standpoint, hypermethylation can be used as a marker of recurrent disease or progression, for example, in MDS, or response to chemotherapy, such as MGMT methylation in B-cell non-Hodgkin's lymphoma. Furthermore, promising studies using DNA demethylating agents and histone deacetylase inhibitors are underway to awake these dormant tumor-suppressor genes for a better treatment of the patient with a hematologic malignancy.

CpG Islands↗
PubMed2002

Genome-wide profiling of DNA methylation reveals transposon targets of CHROMOMETHYLASE3.

DNA methylation has been implicated in a variety of epigenetic processes, and abnormal methylation patterns have been seen in tumors. Analysis of methylation patterns has traditionally been conducted either by using Southern analysis after cleavage with methyl-sensitive restriction endonucleases or by bisulfite sequencing. However, neither method is practical for analyzing more than a few genes. Here, we describe a simple technique for genome-wide mapping of DNA methylation patterns. Fragmentation by a methyl-sensitive restriction endonuclease is followed by size fractionation and hybridization to microarrays. We demonstrate the utility of this method by characterizing methylation patterns in Arabidopsis methylation mutants. This analysis reveals that CHROMOMETHYLASE3 (CMT3), which was previously shown to maintain CpXpG methylation, preferentially methylates transposons, even when they are present as single copies within the genome. Methylation profiling has potential applications in disease research and diagnostic screening.

Arabidopsis↗
PubMedDate not supplied

Methylation profiling of urothelial carcinoma in bladder biopsy and urine.

OBJECTIVE: To test DNA methylation profiling in detection of urothelial carcinoma in urine. STUDY DESIGN: Thirty-three bladder specimens were analyzed for the DNA p16INK4a, RASSF1, APC, GSTP, E-Cad and CyclinD2 genes to determine if there is a difference in gene methylation between benign and malignant cases. Urine samples were analyzed in a feasibility study. Finally, methylation profiles of urine samples were obtained and compared with follow-up biopsy diagnoses. RESULTS: We found methylated genes in 18% benign, 37% urothelial carcinoma in situ and 93% infiltrating urothelial carcinoma cases (p = 0.001). Methylation profiles from the 18 urine samples revealed a significantly higher prevalence of methylated genes in carcinoma cases than benign cases (100% vs. 50%, p = 0.025). We analyzed methylation profiles in 37 cytologically atypical urine samples with malignant or benign diagnosis on surgical follow-up andfound that only APC (55% in malignant vs. 0% in benign, p=0.025) and CyclinD2 were differentially methylated (35% in malignant vs. 0% in benign, p=0.2) while p14ARF, p16INK4a, RASSF1, GSTP and E-Cad had similar methylation profiles. CONCLUSION: These results suggest that methylation of p14ARF, p16INK4a, RASSF1, GSTP and E-Cad genes may not accurately identify carcinoma, but methylated APC and CyclinD2 might be useful biomarkers for urothelial carcinoma in urine.

Aged↗
PubMed2004

DNA methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking apolipoprotein E.

The present work investigates the occurrence and significance of aberrant DNA methylation patterns during early stages of atherosclerosis. To this end, we asked whether the genetically atherosclerosis-prone APOE-null mice show any changes in DNA methylation patterns before the appearance of histologically detectable vascular lesion. We exploited a combination of various techniques: DNA fingerprinting, in vitro methyl-accepting assay, 5-methylcytosine quantitation, histone post-translational modification analysis, Southern blotting, and PCR. Our results show that alterations in DNA methylation profiles, including both hyper- and hypomethylation, were present in aortas and PBMC of 4-week-old mutant mice with no detectable atherosclerotic lesion. Sequencing and expression analysis of 60 leukocytic polymorphisms revealed that epigenetic changes involve transcribed genic sequences, as well as repeated interspersed elements. Furthermore, we showed for the first time that atherogenic lipoproteins promote global DNA hypermethylation in a human monocyte cell line. Taken together, our results unequivocally show that alterations in DNA methylation profiles are early markers of atherosclerosis in a mouse model and may play a causative role in atherogenesis.

Animals↗
PubMed2004

DNA methylation of multiple promoter-associated CpG islands in meningiomas: relationship with the allelic status at 1p and 22q.

The purpose of this research was to examine the DNA methylation profile of meningiomas. Accordingly, we examined the DNA methylation status of ten tumor-related genes (RB1, p16(INK4a), p73, MGMT, ER, DAPK, TIMP-3, p14(ARF), THBS1, and Caspase-8) in 98 meningiomas (68 grade I; 27 grade II; and 3 grade III samples) using methylation-specific PCR and sequencing. The most frequently methylated genes were THBS1 (30%), TIMP-3 (24%), p16(INK4a) (17%), MGMT (16%), p73 (15%), ER (15%), and p14(ARF) (13%), whereas methylation was relatively rare in the other genes (<10%). Methylation occurred in at least one gene in 77.5% of the cases and in three or more genes in 25.5%. Methylation was tumor specific since it was absent in the controls: two non-neoplastic meningeal samples and two non-neoplastic brain samples. The frequency of aberrant gene methylation in grade I versus grade II-III tumors showed some differences for TIMP-3, THBS1, MGMT, p16(INK4a) and p73; these differences reached statistical significance for TIMP-3: 18% in grade I versus 40% in grade II-III (P < 0.02). Our previous loss of heterozygosity studies provided the allelic constitution at 1p and 22q for 60 of the 98 meningiomas included in this report. The level of aberrant promoter methylation increased in tumors (30 samples) displaying 1p loss (either isolated or as concurrent deletion at 1p/22q; P = 0.014). These meningiomas primarily accumulated the epigenetic changes of THBS1 (14/30; 47%; P < 0.005), TIMP-3 (12/30; 40%; P < 0.05), p73 (10/30; 26%; P < 0.02) and p14(ARF) /p16(INK4a)(7/30 each one; 23%; not significant). Our findings indicate that aberrant DNA methylation of promoter-associated CpG islands in meningiomas contributes to the development of these tumors.

Adolescent↗
PubMed2003

A systematic profile of DNA methylation in human cancer cell lines.

Human cancer cell lines are commonly used in basic cancer research to understand the behavior of primary tumors. Aberrations in the DNA methylation patterns are nowadays recognized as a hallmark of the cancer cell. However, no comprehensive study defines the DNA methylation environment present in the established cancer cell lines used in everyday laboratory-based research. To address this matter, we have analyzed 70 widely used human cancer cell lines of 12 different tumor types for CpG island promoter hypermethylation of 15 tumor suppressor genes, global 5-methylcytosine genomic content, chemical response to the demethylating agent 5-aza-2'-deoxycytidine, and their genetic haplotype for methyl-group metabolism genes. Several conclusions arise from our study: (a) a specific profile of CpG island hypermethylation exists for each tumor type, allowing its classification within hierarchical clusters according to the originating tissue; (b) cancer cell lines generally have higher levels of CpG island hypermethylation than primary tumors, because of the contribution of particular CpG islands and tumor types; and (c) there are no major differences between cell lines in their 5-methylcytosine DNA content, efficacy of 5-aza-2'-deoxycytidine treatment, and distribution of allelotypes of methyl-group metabolism genes. Our data provide a basis for a better use of human cancer cell lines in basic and translational research with respect to their DNA methylation environment.

5-Methylcytosine↗
PubMed2003

CpG island methylation in sporadic and neurofibromatis type 2-associated schwannomas.

PURPOSE: The purpose of this research was to examine the DNA methylation profile of schwannomas. EXPERIMENTAL DESIGN: We examined the DNA methylation status of 12 tumor-related genes (NF2, RB1, p14(ARF), p16(INK4a), p73, TIMP-3, MGMT, DAPK, THBS1, caspase-8, TP53, and GSTP1) in 44 sporadic and/or NF2-associated schwannomas using methylation-specific PCR. RESULTS: The most frequently methylated genes were THBS1 (36%), p73 (27%), MGMT (20%), NF2 (18%), and TIMP-3 (18%). The RB1/p16INK4a gene pair displayed aberrant methylayed alleles in 15% of cases, whereas methylation was relatively rare in the other genes (<5%). Methylation was tumor specific because it was absent in two nonneoplastic nerve sheath samples and two nonneoplastic brain samples studied as controls. CONCLUSIONS: Our findings indicate that aberrant methylation seems to be a mechanism for NF2 gene inactivation, considered an early step in schwannoma tumorigenesis, and as well, aberrant hypermethylation of other tumor-related genes might represent secondary events that also contribute to the development of these tumors.

Adult↗
PubMed2026

Spinal low-grade ependymal tumors harboring telomerase reverse transcriptase promoter mutation and chromosome 7 gain with methylation profile of spinal subependymoma.

Spinal intramedullary tumors comprise a heterogeneous group of entities with diverse histopathological features, making their diagnosis particularly challenging. With the introduction of DNA methylation profiling, the underlying biological diversity of these tumors has been increasingly clarified and systematized; however, owing to the rarity of these tumors, case accumulation remains limited, and significant challenges persist. In this study, we identified two cases of spinal ependymal tumors exhibiting a methylation profile of spinal (SP-) subependymoma (SEPN). Both cases occurred in elderly patients and demonstrated circumscribed growth consistent with low-grade ependymal tumors; however, these tumors did not exhibit the typical histopathological features required for a diagnosis of SEPN in the 2021 WHO classification of central nervous system (CNS) tumors, showing indistinct cluster formation, an astrocytic immunohistochemical profile suggested by Olig2 expression, and relatively elevated Ki-67 labeling indices of 4.5% and 3.1%. At the molecular level, both cases harbored telomerase reverse transcriptase promoter mutations and whole chromosome 7 gain. On two-dimensional t-distributed stochastic neighbor embedding analysis, both clustered within the SP-SEPN methylation class at its periphery, with low classifier calibration scores (0.70 and 0.69). According to the current WHO classification, these cases are designated as low-grade ependymal tumors (CNS WHO grade 2) with methylation profile of SP-SEPN because they do not meet the essential WHO histopathological criteria. Ependymal tumors exhibiting a methylation profile consistent with SEPN, but discordant histopathological features have been increasingly recognized, and the appropriate classification of such tumors remains a subject of ongoing debate. These cases provide important insights into the histopathological diversity of ependymal tumors and contribute to establishing a more comprehensive and systematic classification of ependymal tumors.

Aged↗
PubMed2026

DNA Methylation and Proteomic Profiling of Postmortem Brain Tissue Reveals Epigenetic Dysregulation and Neuroinflammatory in Fragile X-associated Tremor/Ataxia Syndrome (FXTAS).

BACKGROUND: Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by FMR1 premutation CGG repeat expansions (55-200 repeats). The epigenetic landscape of the FXTAS brain remains uncharacterized. We performed genome-wide DNA methylation profiling of postmortem prefrontal cortex tissue to identify differentially methylated positions (DMPs) and candidate genes, and sought protein-level support for a neuroinflammatory signal. METHODS: DNA methylation was profiled in postmortem prefrontal cortex (Brodmann area 9) from 27 male FXTAS cases and 29 male controls using the Illumina MethylationEPIC array (EPICv1 and EPICv2 platforms), merging 721,802 common probes. Surrogate variable analysis (SVA) controlled for confounders. DMPs were defined by |&#x394;&#x3b2;| > 0.10 and FDR < 0.05; exploratory Reactome 2024 pathway analysis was performed on the DMP-associated gene list. Targeted proteomic profiling was performed in the same brain region using the Olink (proximity extension assay) Inflammation panel in 9 FXTAS cases and 12 controls, with SVA-adjusted differential abundance analysis, and concordance assessment against a prior mass spectrometry dataset. RESULTS: We identified 108 significant cg-type DMPs mapping to 80 genes (50 hypermethylated, 58 hypomethylated in FXTAS). The strongest signal was CYP2E1 (7 concordant hypomethylated DMPs, mean &#x394;&#x3b2; = -0.143), an oxidative stress gene also implicated in Parkinson's disease. FTCD, a one-carbon cycle enzyme, carried 5 hypermethylated DMPs (mean &#x394;&#x3b2; = +0.210). A cluster of DMP-associated genes with established roles in innate immune and NF-&#x3ba;B signaling, TRAF3 (the single most significant DMP among the inflammation genes, hypermethylated), BATF, RCOR1, and MSI2; they pointed toward neuroinflammatory dysregulation. Additional genes included LINGO1 (myelination inhibitor), SYT3 (synaptic vesicle), and SLC39A4 (zinc transporter). Exploratory Reactome enrichment using the DMP-associated gene set nominated themes including neuroinflammation resolution, axonal growth inhibition, zinc homeostasis, and CYP2E1 metabolism at nominal significance (p<0.05); however, the gene-to-pathway mapping rate was low and no pathway survived correction for multiple testing. Olink proteomic analysis independently identified 60 significantly altered inflammation proteins (59 downregulated), including CXCL8, CXCL10, IL6, IL15, IL18, TLR3, IRAK1/4, and complement C1QA, which were directionally concordant with prior mass spectrometry data. CONCLUSIONS: This integrated study reveals a genome-wide epigenetic signature in the FXTAS prefrontal cortex implicating oxidative stress, myelination failure, zinc dysregulation, one-carbon cycle disruption, and most notably a coordinated set of epigenetically altered genes governing innate immune and NF-&#x3ba;B signaling. Convergence of TRAF3 hypermethylation with independent downregulation of TLR3 and NF-&#x3ba;B-pathway proteins at the protein level supports a coherent, cross-platform model of dysregulated neuroinflammatory signaling in FXTAS, identified here through individual gene- and protein-level convergence rather than formal pathway enrichment. FTCD hypermethylation proposes a self-reinforcing epigenetic loop via SAM depletion. These multi-omic findings establish FXTAS as a disorder of pervasive epigenetic reprogramming and nominate candidate genes for future mechanistic and therapeutic investigation.

CYP2E1↗
PubMed2006

Accumulation of DNA methylation is associated with tumor stage in gastric cancer.

BACKGROUND: The authors purpose in this study was to clarify the difference in terms of clinicopathologic features between gastric cancer (GC) with high numbers of DNA methylated genes and CpG island methylator phenotype (CIMP)-positive GC as originally defined. METHODS: We analyzed DNA methylation of 12 tumor-related genes (hMLH1, MGMT, p16(INK4a), CDH1, RAR-beta, HLTF, RIZ1, TM, FLNc, LOX, HRASLS, HAND1) in 75 samples of GC from 75 patients, 25 samples of corresponding nonneoplastic mucosa from 25 patients, and 10 samples of normal gastric mucosa from 10 healthy young individuals by methylation-specific polymerase chain reaction (PCR) and bisulfite PCR. We also investigated CIMP status by examining the methylation of five MINT loci and p53 mutation status by PCR single-strand conformation polymorphism. We measured levels of expression of mRNAs for these 12 genes by quantitative reverse transcription PCR in 50 GC specimens. RESULTS: The average number of methylated genes per tumor was 4.83. DNA methylation of each gene was correlated with low expression of the respective mRNA. High methylation (GC with 5 or more methylated genes) was detected in 39 (52.0%) of 75 GCs. Twenty-nine (37.8%) of 75 GCs were CIMP-positive. DNA methylation of each of the 12 genes was observed more frequently in the high-methylation group than in the low-methylation group. Methylation of 6 specific genes occurred more frequently in CIMP-positive GC than in CIMP-negative GC. Methylation of the remaining 6 genes was not correlated with CIMP-status. High methylation was found more frequently in Stage III/IV GC (26 of 40 cases, 65.0%) than in Stage I/II GC (13 of 35 cases, 37.1%, P = 0.029).CONCLUSIONS.These findings indicate that GCs with higher numbers of methylated genes have more distinct DNA methylation profiles than the originally defined CIMP-positive GCs. DNA methylation of tumor-related genes accumulates in conjunction with tumor progression.

Adult↗
PubMed2002

DNA Methylation Database "MethDB": a user guide.

The DNA Methylation Database (MethDB; http://www.methdb.net) is a public database dedicated to DNA methylation. It attempts to store all data about DNA methylation in a common source. MethDB can be searched in different ways, ranging from a simple browse mode to detailed queries for sequence-specific DNA methylation profiles and patterns, total methylation content data or environmental conditions that can influence the methylation state of DNA. Currently, the database contains 2570 values for methylation content and 5278 methylation patterns and profiles for a total of 83 genes or loci. MethDB is an annotated database, and the scientific community is invited to submit their own data (submit@methdb.de).

Computer Graphics↗
PubMed2026

A stratified urine-based molecular diagnostic and prognostic model for non-muscle-invasive bladder cancer management.

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high recurrence rate requiring lifelong cystoscopic surveillance. Existing urine-based molecular assays mainly rely on mutations or methylation, which fail to capture large-scale genomic instability. Copy number variation (CNV) profiling offers complementary information on tumor evolution and aggressiveness, but its application in urinary diagnosis remains limited. We aimed to integrate CNV and DNA methylation signals from urinary DNA to establish a noninvasive and biologically informed stratified diagnostic model for NMIBC recurrence surveillance and risk stratification. METHODS: Urine samples were prospectively collected from 91 patients (75 evaluable) between June 2021 and August 2023. Shallow whole-genome sequencing (sWGS) was used to detect CNVs at chromosomal arm and focal gene levels, while ONECUT2 promoter methylation was quantified by qPCR. Diagnostic and prognostic performance was evaluated by ROC analysis, Kaplan-Meier survival, and stratified recurrence assessment. RESULTS: We evaluated a stratified diagnostic model combining CNV and ONECUT2 methylation testing in a cohort of 79 patients. CNV analysis alone showed high specificity (0.923) for NMIBC diagnosis. A combined model, using CNV as an initial screen followed by ONECUT2 methylation testing in CNV-positive cases, achieved a sensitivity of 0.783, specificity of 0.981, and a negative predictive value (NPV) of 0.911. This approach reduced the number of required ONECUT2 tests by 35% and identified a high proportion of true-negative patients (98.1%), which may help reduce unnecessary cystoscopy procedures. The model also demonstrated significant prognostic value, with the molecularly defined high-risk group showing significantly shorter recurrence-free survival (RFS) than the low-risk group (median RFS: 4.33 months vs. not reached; p&#x2009;<&#x2009;0.001). Additional, in patients with initially negative cystoscopy after urine sample collection, the model demonstrated a predictive accuracy of 0.922 for recurrence, with molecular positivity observed a median of 9.6 months prior to clinical diagnosis. CONCLUSIONS: Integrating CNV and DNA methylation profiling from urinary DNA provides a powerful and noninvasive molecular framework for NMIBC surveillance. By combining early epigenetic changes with genomic instability signals, this approach enhances recurrence risk assessment and enables earlier detection compared with conventional cystoscopy. It offers a practical route toward personalized and adaptive post-treatment monitoring of NMIBC. TRIAL REGISTRATION: NCT04994197.

Humans↗
PubMed2002

Methylome profiling of cancer cells by amplification of inter-methylated sites (AIMS).

Alterations of the DNA methylation pattern have been related to generalized chromosomal disruption and inactivation of multiple tumor suppressor genes in neoplasia. To screen for tumor-specific alterations and to make a global assessment of methylation status in cancer cells, we have modified the methylated CpG island amplification method to generate easily readable fingerprints representing the cell's DNA methylation profile. The method is based on the differential cleavage of isoschizomers with distinct methylation sensitivity. Specific adaptors are ligated to the methylated ends of the digested genomic DNA. The ligated sequences are amplified by PCR using adaptor- specific primers extended at the 3' end with two to four arbitrarily chosen nucleotidic residues to reduce the complexity of the product. Fingerprints consist of multiple anonymous bands, representing DNA sequences flanked by two methylated sites, which can be isolated and individually characterized. Hybridization of the whole product to metaphase chromosomes revealed that most bands originate from the isochore H3, which identifies the regions of the genome with the highest content of CpG islands and genes. Comparison of the fingerprints obtained from normal colon mucosa, colorectal carcinomas and cell lines revealed tumor-specific alterations that are putative recurrent markers of the disease and include tumor-specific hypo- and hypermethylations.

Base Sequence↗
PubMed2026

Methylation profiling in CNS tumor diagnostics: a single-centre real-world experience from Central Europe.

Genome-wide DNA methylation profiling has transformed neuro-oncology by providing an objective, machine learning-based taxonomy that mitigates interobserver variability and refines the histo-molecular criteria of the current WHO classification. We evaluate the real-world diagnostic performance and clinical utility of this modality in a prospective, consecutively accrued three-year cohort of 291 central nervous system (CNS) tumors across a mixed adult-pediatric population. Successful profiling was completed in 95.9% of cases. Using the Epignostix classifier, a high-confidence diagnostic match (calibrated score [CS]&#x2009;&#x2265;&#x2009;0.84) was achieved in 70.3% of analyzable samples, while 26.5% returned lower-confidence scores (&#x2265;&#x2009;0.3 to <&#x2009;0.84) and only 3.2% remained completely unclassifiable (CS&#x2009;<&#x2009;0.3). When integrated into a comprehensive diagnostic framework, methylation profiling provided clinically useful results in 81.1% of cases, establishing diagnoses in 70 cases submitted for molecular subclassification and resolving diagnostic uncertainty or prompting major revisions in 149 histologically challenging tumors. Within truly ambiguous lesions, integration of methylome data dictated tumor grade modifications in 38.8% of cases (upgrading in 29.4% and downgrading in 9.4%), shifting patient risk stratification. Crucially, over half (52.7%) of the lower-confidence cases yielded meaningful clinical integration when supported by histomorphology and ancillary genetic or immunohistochemical markers, demonstrating that rigid score cutoffs should not dictate assay failure. Discrepant or misleading classifications occurred in 1.9%. Updating bioinformatic pipelines from version 11b4 to 12.8 rescued multiple ambiguous entries, increasing overall clinical utility to 84.1%. These findings demonstrate that integrating computational epigenomics with classical neuropathology enhances diagnostic precision, while highlighting the ongoing need for careful clinical-pathological correlation.

Central nervous system tumors↗
PubMed2002

Methylation profiles of sporadic ovarian tumors and nonmalignant ovaries from high-risk women.

PURPOSE: The purpose of this research was to examine the DNA methylation profiles of primary sporadic ovarian cancers and ovarian tissues from high-risk women. EXPERIMENTAL DESIGN: We analyzed the DNA methylation status of nine cancer-related genes in 49 primary ovarian tumors, 39 nonmalignant ovarian tissues obtained from 16 women with no known risk and from 23 high-risk women with a strong family history of breast and/or ovarian cancer or BRCA1 germ-line mutations, and 11 ovarian cancer cell lines, by methylation-specific PCR. RESULTS: Our findings are as follows: (a) methylation rates of four of nine genes, RASSF1A (41%), HIC1 (35%), E-cadherin (29%), and APC (18%) were significantly higher in tumors compared with controls. At least one of the four genes was methylated in 76% of the tumors; (b) a low frequency of methylation was present in nonmalignant tissues; (c) no significant differences in methylation frequencies were seen between the nonmalignant ovarian tissues from women at high-risk and those with no known risk of developing ovarian cancer; (d) methylation of the BRCA1 gene was found in 10% of sporadic tumors but in none of the samples from women with a germ-line BRCA1 mutation; and (e) ovarian cancer cell lines showed a similar frequency of methylation to ovarian tumors except for the HIC1 gene. CONCLUSIONS: Our results suggest that aberrant methylation of specific genes, including two not described previously, may be important in ovarian cancer pathogenesis but not in ovaries at risk for cancer development.

DNA↗
PubMed2026

Epigenetic alterations of AKT1 orchestrate a metabolic reprogramming in advanced lipedema: translational insights from an integrated multi-omics study.

BACKGROUND: lipedema is a chronic, progressive adipose disorder predominantly affecting women, characterized by painful, symmetrical subcutaneous fat accumulation, and typically resistant to lifestyle interventions. The pathophysiology of advanced-stage lipedema remains poorly defined, and no validated biomarkers or targeted therapies are currently available. METHODS: in this observational study, we applied a comprehensive multi-omics approach to dissect the molecular and metabolic alterations underlying late-stage lipedema. RESULTS: Genome-wide DNA methylation profiling identified over 5,000 differentially methylated CpG sites affecting genes involved in receptor tyrosine kinase signaling, phospho-metabolism, and immune pathways. Transcriptomic analysis revealed profound downregulation of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and fatty acid &#x3b2;-oxidation, alongside disruption of the sirtuin pathway and extracellular matrix remodeling. Integrative analysis pinpointed AKT1 as a central regulatory node: its promoter region was hypomethylated, correlating with increased gene expression and protein phosphorylation. Metabolomic profiling confirmed AKT1-linked metabolic dysregulation, including altered levels of L-arginine, NADP+, ATP, guanosine, glycerol, and glutamate, indicating impaired redox balance and energy metabolism. Trans-omic network analysis positioned AKT1 at the intersection of multiple dysregulated pathways, suggesting its key role in advanced-stage lipedema. CONCLUSIONS: the consistent enhancing of AKT pathway signaling across omic layers highlights its potential not only as a biomarker for disease stratification but also as a putative druggable target for therapeutic intervention. These findings offer new mechanistic insights into lipedema pathophysiology and provide a rationale for future personalized treatment strategies guided by AKT1-centric molecular profiling.

Proto-Oncogene Proteins c-akt↗