We investigated the genetic and epigenetic regulation of the UBASH3A gene and its association with early-onset sepsis. Using matched whole blood DNA methylation, gene expression, genotypes and immune cell counts from the EPIC-HIPC newborn cohort, we report promoter methylation was negatively correlated (Pearson's r = -0.5, p < 2.2×10-16) with ontogenetic changes in UBASH3A gene expression and circulating CD3+ T-cell numbers. Higher promoter methylation at birth was associated with lower UBASH3A expression and reduced early onset sepsis risk (OR = 0.26, p = 0.015). Genetic variation significantly influenced variations in baseline UBASH3A methylation (132 cis-meQTL, FDR < 0.05).

Road traffic noise exposure and blood DNA methylation at birth and in childhood: An epigenome-wide meta-analysis.

Flow cytometry studies have reported an association between lower regulatory T cells (Treg) in cord blood and subsequent food allergy. Flow cytometry, however, is a resource-intensive technique. We therefore aimed to develop an epigenetic biomarker (nTregepi) that correlates with the proportion of naïve regulatory T cells (nTreg) in cord blood white cells (CBWCs) measured by flow cytometry. We then investigated the association between nTregepi and subsequent food allergy. The Barwon Infant Study (BIS) is a prebirth cohort study (n = 1074 infants). Illumina Infinium MethylationEPIC v1.0 BeadChips were used to assess DNA methylation in cord whole blood (n = 936). In a subgroup, flow cytometry was used to measure the proportion of nTregs (CD4 + CD45RA + FOXP3+) in CBWCs (n = 450). In a training set (n = 338), we assessed the correlation between methylation at 78 probes in the FOXP3 and TIGIT genes and the proportion of nTregs in CBWCs. LASSO regression was then used to develop a linear methylation predictor of nTregs as a proportion of CBWCs, denoted 'nTregepi', which was then tested in a validation set (n = 112). The association between nTregepi and subsequent IgE-mediated food allergy was evaluated using logistic regression. Methylation levels of 23/78 sites in FOXP3 and TIGIT were associated with the proportion of nTregs in CBWCs (q < 0.05 for each). LASSO regression of methylation levels for these 21 probes was used to derive a linear predictor (nTregepi) which correlated with the log proportion of nTregs in the validation set (R2 = 0.22, p < 0.001). In the complete cohort with relevant data available (n = 693), a higher nTregepi was associated with decreased odds of food allergy (odds ratio 0.65 (95% CI 0.48-0.88, p = 0.005)). A composite epigenetic biomarker in cord whole blood correlates with the proportion of nTreg in CBWCs and is strongly associated with the absence of subsequent food allergy.

BackgroundAdvancing chronological age is a strong contributor to Alzheimer's disease (AD) risk, yet individual variability exists in aging trajectories. Novel AD biomarkers are needed to better stratify AD risk, especially in preclinical stages. To this end, we computed epigenetic “clocks,” a measure of biological age based on DNA methylation markers, and tested associations with dementia and AD biomarkers.MethodWe leveraged whole blood and brain DNA methylation data collected from the EFIGA aging and AD cohort along with the Methylclock R package to compute Horvath and Hannum aging clocks (N = 731). Next, we calculated age acceleration, by residualizing the regression of biological age on chronological age. We ran linear regression models testing associations between biological age and age acceleration with a panel of plasma dementia and AD biomarkers. All regressions were adjusted for multiple comparisons (false‐discovery rate [FDR]).ResultBiological age was significantly correlated with chronological age (R2Horvath=0.18, pHorvath =4.74x10‐33; R2Hannum=0.17, pHannum=3.48x10‐30) and with sex (βHorvath=0.21, pHorvath=8.44x10‐3; βHannum=0.27, pHannum=7.32x10‐4). We replicated correlations in brain (R2Horvath=0.52, pHorvath=6.27x10‐89; R2Hannum=0.21, pHannum=6.46x10‐30), and in an independent aging and AD cohort, ROS/MAP (in brain ‐ R2Horvath=0.49, pHorvath=6.51x10‐78; R2Hannum=0.34, pHannum=1.03x10‐47). Seven plasma biomarkers were significantly associated with biological age calculated with the Horvath clock, the Hannum clock, or both: p‐tau217 (βHorvath=0.13, p.FDRHorvath=2.69x10‐3; βHannum=0.19 p.FDRHannum=1.35x10‐5), p‐tau181 (βHorvath=0.13, p.FDRHorvath=1.75x10‐3; βHannum=0.14 p.FDRHannum=1.75x10‐3), GFAP (βHorvath=0.09, p.FDRHorvath=2.07x10‐2; βHannum=0.15 p.FDRHannum=5.77x10‐4), p‐tau231 (βHorvath=0.11, p.FDRHorvath=9.87x10‐3), NfL (βHannum=0.11, p.FDRHannum=9.87x10‐3), NfL (βHannum=0.11, p.FDRHannum=9.87x10‐3), Aβ40 (βHorvath=0.09, p.FDRHorvath=2.07x10‐2; βHannum=0.11, p.FDRHannum=1.66x10‐2), and total‐tau (βHorvath=0.09, p.FDRHorvath=2.07x10‐2).ConclusionWe demonstrated that biological age is a predictor of AD pathology in preclinical and clinical stages, and we will next evaluate biological age acceleration as a predictor of pathology. In addition, we will be replicating all biomarker associations in brain by testing associations with autopsy measures of neuropathology. Future directions will include conducting models stratified by sex and by APOE‐ε4 carrier status to identify if the relationship between biological aging and AD biomarkers is modulated by biological sex or APOE‐ε4 genotype.

BackgroundDementia is a progressive neurodegenerative disease and studies of peripheral blood DNA methylation biomarkers, which may have utility for early risk detection or monitoring progression, have been limited by sample size. We analyzed cognitive impairment and DNA methylation in the United States Health and Retirement Study (HRS), a large longitudinal cohort study nationally representative of US adults over the age of 50.MethodSite specific DNA methylation was measured in blood collected in the 2016 HRS wave. We performed cross‐sectional analysis using 2016 HRS methylation and cognitive data, comparing participants with cognitive impairment but not dementia (CIND) and with dementia to those with normal cognition, adjusting for age, sex, education, cell proportions, genetic principal components, and APOE‐ε4 carrier status. Second, we performed prospective analysis restricted to persons with normal cognition at baseline and examined association between baseline DNA methylation and any cognitive impairment with up to four years of follow‐up.ResultIn cross‐sectional analysis (n = 3,395), most methylation sites nominally associated (p <0.01) with CIND (sites=5,962) or dementia status (sites=10,115) had higher DNA methylation compared to those with normal cognition (80.4% and 81.6%, respectively). CIND associated sites were enriched (adjusted‐p<0.05) for pathways related to cell connectivity and ion transport. Dementia associated sites were enriched in pathways related to cell movement, neuron cell structure, and transcription. In prospective analysis (n = 2,424 cognitively normal at baseline), among sites nominally associated with development of any cognitive impairment (sites=7,228), 85.2% had higher DNA methylation compared to those retaining normal cognition. These sites were enriched in pathways related to cell connectivity. Between the cross‐sectional CIND and dementia, and prospective any impairment analyses, 22 CpGs were nominally associated in all analyses. The site cg25144382, which is not annotated to a gene, had 1.3% higher methylation in prevalent CIND (p = 5.1x10‐5), 2.7% higher methylation in prevalent dementia (p = 6.0x10‐5), and 1.8% higher methylation in incident impairment (p = 1.3x10‐5).ConclusionBlood DNA methylation may be a potential biomarker for incident cognitive status in older adults.

Hepatocellular carcinoma (HCC) development in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern, but the underlying mechanisms are not fully understood. Epigenetic aging biomarkers, reflecting cellular and tissue aging, have been linked to various age-related pathologies, but their association with MASLD-HCC is unknown. We investigated associations between five epigenetic aging biomarkers and MASLD-HCC risk. We performed whole blood DNA methylation assay (Infinium 850k array) and calculated principal components-based (PC) versions of HorvathAge, HannumAge, PhenoAge and GrimAge and the DunedinPACE aging rate. We further calculated relative age accelerations for PCHorvathAge, PCHannumAge, PCPhenoAge and PCGrimAge. The aging biomarkers were modelled as continuous variables and categorised into tertiles based on distributions among controls. Associations between each aging biomarker and MASLD-HCC were examined using logistic regression, calculating odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for covariates. Data on 272 MASLD-HCC cases and 316 cancer-free MASLD controls recruited from six sites and matched on chronological age, sex and study site were analysed. Higher relative age accelerations of PCPhenoAge (ORT3 vs. T1 = 2.25, 95% CI: 1.45-3.50; ORcontinuous = 1.04, 95% CI: 1.02-1.07, p = 0.009), PCGrimAge (ORT3 vs. T1 = 3.97, 95% CI: 2.41-6.64; ORcontinuous = 1.16, 95% CI: 1.10-1.24, p = 8.76 × 10-07) and DunedinPACE (ORT3 vs. T1 = 3.45, 95% CI: 2.17-5.55; ORcontinuous = 1.72, 95% CI: 1.43-2.10, p = 2.58 × 10-08) were associated with MASLD-HCC, but not PCHorvathAge or PCHannumAge. Higher relative age accelerations of PCPhenoAge, PCGrimAge and DunedinPACE aging rate are associated with risk of MASLD-HCC. These aging biomarkers could improve HCC risk assessment and facilitate risk stratification in patients with MASLD.

Epigenetic differences across racial/ethnic groups can provide insights into health disparities, including likely mechanisms and multifactorial upstream exposures at play. We compared the blood DNA methylome of Native Hawaiian (NatH) women, an understudied group with high chronic disease burden, with that of White women. Blood genome-wide DNA methylation profiling was performed in generally healthy, non-smoking NatH (n = 143) and White (n = 181) postmenopausal women in the Multiethnic Cohort. CpGs showing significant (Bonferroni p < 0.05) and substantial (delta-beta > 0.1) differential methylation in NatH compared to White women (CpGs-NatH) were identified through linear regression of methylation, adjusted for potential confounders. The CpGs-NatH were examined for gene pathways and for associated dietary patterns and metabolic biomarkers. We identified 736 CpGs-NatH, which presented more frequent CpG island hypermethylation than expected. Many corresponding CpGs-NatH genes (61%) were functionally implicated in liver disease etiology, and 15 CpGs-NatH were correlated with MRI-quantified liver fat content. 168 of the 736 CpGs were associated with adherence to the Dietary Approaches to Stop Hypertension (DASH) diet. The CpGs-NatH were also associated with several blood biomarkers of key metabolism, including adiponectin, triglycerides, and sex hormone-binding globulin. Our findings suggest marked racial differences in DNA methylation, suggesting epigenetic mechanisms underlying racial metabolic health disparities, such as the higher propensity for ectopic fat accumulation and higher incidence of liver disease and cancer among NatH, compared to Whites. These results support further investigation of the epigenome across racial and ethnic populations in relation to lifestyle factors and metabolism.

2.ABSTRACTBackgroundCarotid-intima media-thickness predicts cardiovascular events and informs mechanistic research on cardiovascular diseases (CVD). However, CVD research remains Eurocentric despite etiological differences across ancestries. Incorporating Asian populations— who face substantial CVD burden with distinct etiological landscape— can enhance our understanding of cIMT biology and subclinical processes linked to CVD. This study aimed to elucidate methylation-based mechanisms of cIMT through DNA methylation profiling integrated with multi-omics data and clinically informative cIMT thresholds, leveraging an Asian cohort to enhance discovery.MethodsWe conducted an epigenome-wide association study (EWAS) of cIMT using peripheral blood DNA methylation at ∼850,000 CpG sites in the Asian Health for Life in Singapore (HELIOS) cohort (n=1,357), followed by targeted trans-ancestry meta-analysis with European cohorts (overall n=2,765). Causal inference analyses (summary data-based Mendelian Randomisation [SMR] and colocalisation) evaluated methylation-mediated effects on cIMT, CVD and proximal gene expression. We derived a methylation risk score (MRS) and tested its association with cIMT thresholds indicative of elevated cardiovascular risk (≥75thpercentile for age, sex and ethnicity).ResultsThree novel CpG-cIMT associations were identified (P<9.35E-07). Causal analyses supported cg08227773 methylation-mediated effects on both coronary artery disease risk (PSMR=2.91E-05, coloc PP.H4 =0.91) andNBEAL2(Neurobeachin-like 2) expression (PSMR=9.13E-08, coloc PP.H4=0.69), a gene implicated in immune dysregulation. MRS of cIMT aggregating the three sentinel CpGs was associated with clinically-informative cIMT elevation (Odds Ratio=2.75 for Q4 vs Q1, 95% CI: 1.47-5.13).ConclusionsThrough Asian-led discovery, this study identifies three novel DNA methylation markers for cIMT that are linked to cIMT elevation above clinically meaningful risk thresholds. Causal inference analyses suggest methylation-mediated CAD risk viaNBEAL2regulation, nominating biologically relevant targets while underscoring the need for larger multi-omics resources to refine mechanisms.

Preterm birth and very low birth weight (VLBW; <1500 g) increase risks for poor health outcomes, potentially mediated by epigenetic modifications such as DNA methylation (DNAm). We hypothesized that DNAm differs between VLBW adults and their siblings in blood and adipose tissue. We studied 75 adults born preterm with VLBW and 73 same-sex sibling controls from the Adults Born Preterm Sibling Study. DNAm at cytosine-guanine dinucleotide (CpG) sites in blood and adipose tissue was assessed using Illumina EPIC 850K at a mean age of 29 years. Biological pathways were investigated with QIAGEN ingenuity pathway analysis (IPA). No differences were observed in blood DNAm. In adipose tissue, 458 CpG sites were differentially methylated (FDR p < 0.05) between VLBW and siblings. Top sites were annotated to genes related to lipid metabolism (cg00264176 (FADS2), 0.077 (0.007), FDR p = 3.24 × 10-14) and neural development (cg08277679 (KIF26A), 0.053 (0.005), FDR p = 8.22 × 10-12). IPA identified enrichment for 81 pathways (FDR p < 0.05). Our results suggest tissue-specific DNAm differences in VLBW adults compared to their siblings. The changes cluster in pathways related to lipid metabolism, neurodevelopment, and cardiometabolic regulation, suggesting lasting tissue-specific epigenetic modifications in VLBW adults.

Background:In a previous study, we reported associations between space weather [galactic cosmic rays (GCRs)] and solar and geomagnetic activities (SGAs)] with shorter telomere length in a cohort of elderly men in Massachusetts. Here, we investigated the impact of space weather on epigenetic aging in the same cohort.Methods:We analyzed 1,487 blood DNA methylation measures from 771 older men in the Normative Aging Study (1999–2013). Daily space weather indicators were obtained from NASA including sunspot number (SSN) and interplanetary magnetic field as solar activity parameters, Kp-index as a geomagnetic parameter, and neutron monitors and modeled cosmic ray-induced ionization as measures of GCRs. The 30-day moving average of each parameter was prespecified as the exposure window. Four epigenetic age acceleration metrics, including HorvathAgeAccel, HannumAgeAccel, PhenoAgeAccel, and GrimAgeAccel, were derived, and exploratory epigenome-wide association study (EWAS) and pathway enrichment analyses were conducted.Results:GCRs were associated with accelerated epigenetic aging, whereas SGAs were associated with slower aging. Each interquartile range increase in SSN corresponded to a 0.61-year lower HorvathAgeAccel and 0.50-year lower PhenoAgeAccel, while higher neutron counts were associated with 0.32-year greater HorvathAgeAccel and 0.29-year greater HannumAgeAccel. EWAS identified hundreds of CpGs associated with GCRs (predominantly lower methylation) and thousands with SGAs (predominantly higher methylation), enriched in genome maintenance pathways such as P53 signaling, DNA repair, and inflammatory response, consistent with astronaut studies showing activation of similar stress and repair pathways.Conclusion:Short-term space weather fluctuations were associated with distinct epigenetic aging patterns in blood, suggesting that, as observed in astronauts, terrestrial populations may likewise show biological sensitivity to space weather variability.

BACKGROUNDPeripheral blood DNA methylation may have utility as an early dementia risk biomarker.METHODSWe analyzed DNA methylation (blood collected 2016) and cognitive impairment in the Health and Retirement Study, a longitudinal study representative of US adults over age 50 (3,921 individuals and 585,356 CpG sites). We analyzed methylation associations with cognitive status both cross-sectionally and prospectively among participants with normal cognition at baseline with four years follow-up.RESULTSCross-sectionally, 5,322 CpGs were associated (p-value<0.01) with cognitive impairment non-dementia, and 14,366 (166 genome-wide FDR<0.05) with dementia. Prospectively, 4,898 CpGs were associated with any-impairment. Enriched biologic pathways include ion transport, ligand-gated channel, and neuron differentiation. Nine CpGs overlapped all analyses including cg02583484 (HNRNPA1), cg15266133 (LOC102724084), cg24287460 (CCDC48), cg17124509 (C17orf57), and cg02553054 (SMARCD1).DISCUSSIONCpGs identified were enriched in pathways related to Alzheimer’s disease pathology and provide promising grounds for non-invasive blood biomarkers. Future studies for replication and with longer follow-up are needed.

Patients with metastatic testicular cancer (TC) treated with cisplatin-based chemotherapy (CBCT) are prone to develop metabolic syndrome (MetS). In an epigenome wide association study in patients with TC we have shown that DNA methylation was associated to CBCT. The aim of the study was to investigate whether there was a change in DNA methylation after treatment with CBCT, and if methylation status is related to the presence or development of MetS. In a prospective cohort of 67 TC patients who received CBCT, we assessed whole blood global methylation long interspersed nuclear element-1 (LINE-1) and DNA methylation at selected cytosine-phosphate-guanine dinucleotide (CpG) sites associated with MetS using targeted sequencing. Measured samples were taken before, one month after, and one year after CBCT. Development of MetS was assessed before and up to five years after CBCT. Serum platinum levels were measured to assess platinum exposure (PtAUC) within the first year after the start of CBCT. Data were used for paired comparisons, comparisons between groups, statistical modeling to account for covariates, and machine learning approaches to predict occurrence of MetS five years after diagnosis. Global methylation did not change during the first year after the start of CBCT (median 73.7% (25th -75th percentile 72.0–75.2) vs. 73.9% (72.5–75.1)). Seven out of the 16 other selected CpGs decreased. Patients with MetS before start of CBCT (N = 18) showed a larger decrease than patients without MetS (N = 49) for AC090023 (-11.6% vs. -8.2%, p = 0.008), NCAM2 (-6.5% vs. -1.6%, p = 0.030), and TOM1L2 (-5.8% vs. -2.6%, p = 0.003). The 15 patients who did not have MetS prior to CBCT, but developed MetS within five years after treatment showed an increase in global methylation (1.5% vs. − 0.6%, p = 0.008) after one year, and a decrease in TOM1L2 methylation (-4.0% vs. -1.6%, p = 0.015) when compared to patients who did not have prior to CBCT nor developed MetS (N = 34). There was no difference in PtAUC during the first year after the start of CBCT between the latter groups (70.0 vs. 67.9 days*mg/L, p = 0.206). Changes in global DNA methylation and TOM1L2 one year after the start of CBCT are associated with a higher risk for newly developing MetS within five years. This may indicate potential for tailored advice, based on epigenetic status, to patients treated with chemotherapy for TC to prevent development of MetS.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-22918-y.

Alcohol use disorder (AUD) is associated with widespread epigenetic alterations, including changes in DNA methylation (DNAm). This multi-cohort study validated and extended previous findings on DNAm of HECW2 and GDAP1 in AUD, assessed sex differences, and explored DNAm in blood and brain tissue in humans and rats. DNAm was measured via pyrosequencing in human blood (NCtrl = 341, NAUD = 258), postmortem frontal cortex (Brodmann area 9; discovery cohort: NCtrl = 10, NAUD = 13, replication cohort: NCtrl = 64, NAUD = 55) and rat blood and medial prefrontal cortex (NCtrl = 16, NAUD = 15). Gene expression was assessed in human postmortem brain by quantitative real-time PCR. AUD-associated DNAm differences in HECW2 and GDAP1 were replicated in human blood. While decreased GDAP1 DNAm was only observed in men, HECW2 hypomethylation was present in both sexes. In brain tissue, initial DNAm increases in AUD and HECW2 gene expression decreases were not validated in the replication cohort. In rats, HECW2 hypomethylation appeared in the prelimbic cortex but not in blood. Our findings support the involvement of HECW2 and GDAP1 DNAm in AUD, revealing sex-specific and tissue-dependent epigenetic patterns. The opposing DNAm directionality in blood and brain underscores the complexity of alcohol-related epigenetic modifications and suggests the need for multi-tissue, cross-species, and longitudinal studies to clarify causal mechanisms.

Introduction/Background: CHIP is a risk factor for cardiovascular (CV) disease, cancer, and all-cause mortality. Previous work has shown that CHIP, and particularly larger CHIP clones, are associated with adverse CV outcomes, yet the molecular pathways through which CHIP impacts CV risk are poorly defined. Hypothesis/Research Question: We hypothesize that the integration of whole blood transcriptomics and methylomics will provide novel insights into the pathophysiology of CHIP. Methods/Approach: Whole blood DNA methylation profiling, transcriptomics, and whole exome sequencing with CHIP calling for variant allele frequencies (VAF) of ≥2% (CHIP) and ≥10% (large CHIP) were performed for 507 ISCHEMIA and ISCHEMIA-CKD participants with moderate-severe ischemia. We identified transcriptomic and methylomic differences between participants with CHIP and large CHIP vs no CHIP using DESeq2 and limma, adjusted for age, sex, and race/ethnicity. Gene set enrichment analysis (GSEA) and probe set enrichment analysis (PSEA) were performed to identify pathway-level alterations in transcription and methylation, respectively. Results/Data: Clinical characteristics of study participants are described in Fig 1A . Compared to no CHIP (n=391), transcriptomics identified 6 differentially expressed genes (DEGs) in CHIP (n=116) and 27 DEGs in large CHIP (n=35) (p-adj&lt;0.05; abs(logFC)&gt;0.25) (Fig 1B) . Compared to no CHIP, methylation identified no differentially methylated probes in CHIP and 6 in large CHIP (padj&lt;0.20, abs(logFC)&gt;0.03). GSEA identified 137 pathways significantly different in both CHIP and large CHIP vs. no CHIP (padj&lt;0.05), while PSEA identified 724 and 2356 pathways (padj&lt;0.20), respectively. Given its stronger relationship with methylation and transcription, downstream analyses focused on large CHIP. Integrating these data, we found 58 pathways to be both hypomethylated and transcriptionally upregulated in large CHIP, including azurophil granule-related pathways implicated in neutrophil degranulation (Fig 1C) . Further investigation into the gene-probe pairs driving the azurophil granule pathway enrichment in large CHIP revealed hypomethylation and increased transcription of genes implicated in neutrophil extracellular trap formation, including ELANE, PTRN3, AZU1, and CTSG (Fig 1D) . Conclusions: Integration of the methylome and transcriptome suggests large CHIP is linked to neutrophil-mediated immune pathways in patients with stable coronary artery disease.

Analysis of mitochondrial D-loop region methylation and copy number in peripheral blood DNA of Down syndrome individuals including newborns with and without congenital heart defects

DNA methylation has been shown to play a crucial role in many diseases, including Alzheimer’s disease (AD). Although many studies have correlated DNA methylation in blood samples with risk of clinical AD diagnosis, few have examined links with AD neuropathology. Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study, we investigate the associations between peripheral blood DNA methylation and three AD-associated biomarkers in cerebrospinal fluid: amyloid-beta, phosphorylated tau-181, and total tau using an innovative multivariate approach. In our approach, we first adjusted the methylation values for covariates that have known wide-spread effects on methylation. We then developed and implemented a multivariate penalized model to find associations, jointly, between CSF biomarkers and sets of methylation residuals defined by regions around each gene. These penalized models then selected probes showing associations with one or more CSF biomarkers. We demonstrate, using both simulations and actual data, that our proposed multivariate approach is beneficial for detecting weak signals. We also provide complementary validation using data from the Canadian Longitudinal Study on Aging. Our multivariate strategy has the potential to increase feature selection accuracy among correlated predictors in epigenetic studies.

Agricultural copper pesticide exposure and DNA methylation in Central Valley of California residents with and without Parkinson's disease.

EpiClock; biological age measurement from blood DNA methylation using a minimal CpG marker set for high-throughput iPlex mass spectrometry assay for screening in drug development and population health.

Approximately 70% of ovarian cancer (OC) patients relapse after chemotherapy, underscoring the need to assess survival before second-line treatment. We previously identified PLAT-M8, an 8-CpG blood-based methylation signature linked to chemoresistance. This study validates its correlation with clinicopathological features and treatment profiles in additional cohorts. Extracted DNA from whole blood was provided from the BriTROC-1 (n = 47) and OV04 cohorts (n = 57) upon the first relapse. Additional samples from Hammersmith Hospital (n = 100) were collected during first-line chemotherapy (Cycles 3-4 and 6). Bisulphite pyrosequencing was used to quantify DNA methylation at the previously identified 8 CpG sites. The methylation data obtained were combined with previous data from ScoTROC-1D and 1V (n = 141) and OCTIPS (n = 46). Cox regression was used to assess OS after relapse concerning clinicopathological characteristics. The DNA methylation Class (Class 1 vs. 2) was determined by consensus clustering. As for results, blood DNA methylation at relapse correlates with clinical outcomes, but it has no impact during first-line treatment. Class 1 is linked to shorter survival (summary OS: HR 2.50, 1.64-3.79) and poorer prognosis on carboplatin monotherapy (OS: aHR 9.69, 95% CI: 2.38-39.47). It is associated with older (>75 years), advanced-stage, platinum-resistant patients, residual disease, and shorter PFS. In contrast, Class 2 is linked to platinum sensitivity, higher complete response rates (RECIST), and better prognosis but shows no correlation with CA-125. These findings highlight PLAT-M8's potential in guiding second-line chemotherapy decisions. The PLAT-M8 methylation biomarker is associated with survival in relapsed OC patients and may potentially predict their response to second-line platinum treatment.

Mapping DNA methylation signatures to identify epigenetic variation across subcortical regions of the human PTSD brain.