Persistent Variations of Blood DNA Methylation Associated with Treatment Exposures and Risk for Cardiometabolic Outcomes in Childhood Cancer Survivors
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PROVIDER: PRJNA715452 | ENA |
REPOSITORIES: ENA
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Project description:Background: It is well-established that cancer treatment substantially increases risk of long-term adverse health outcomes among childhood cancer survivors. However, there is limited research on the underlying mechanisms. To elucidate the pathophysiology and a possible causal pathway from treatment exposures to cardiometabolic conditions, we conducted epigenome-wide association studies (EWAS) to identify DNA methylation (DNAm) sites associated with cancer treatment exposures and examined whether treatment-associated DNAm sites mediate associations between specific treatments and cardiometabolic conditions. Methods: We included 2,052 survivors (median age 33.7 years) of European ancestry from the St. Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Cumulative doses of chemotherapy and region-specific radiation were abstracted from medical records. Seven cardiometabolic conditions were clinically assessed. DNAm profile was measured using MethylationEPIC BeadChip with blood-derived DNA. Results: By performing multiple treatment-specific EWAS, we identified 935 5’-cytosine-phosphate-guanine-3′ (CpG) sites mapped to 538 genes/regions associated with one or more cancer treatments at epigenome-wide significance level (P<9×10-8). Among the treatment-associated CpGs, 8 were associated with obesity, 63 with hypercholesterolemia, and 17 with hypertriglyceridemia (False-Discovery-Rate-Adjusted P<0.05). We observed substantial mediation by methylation at four independent CpGs (cg06963130, cg21922478, cg22976567, cg07403981) for association between abdominal field radiotherapy (abdominal-RT) and risk of hypercholesterolemia (70.3%) and by methylation at three CpGs (cg19634849, cg13552692, cg09853238) for association between abdominal-RT and hypertriglyceridemia (54.6%). In addition, three CpGs (cg26572901, cg12715065, cg21163477) partially mediated the association between brain-RT and obesity with 32.9% mediation effect and two CpGs mediated the association between corticosteroids and obesity (cg22351187, 14.2%) and between brain-RT and hypertriglyceridemia (cg13360224, 10.5%). Notably, several mediator CpGs reside in the proximity of well-established dyslipidemia genes: cg21922478 (ITGA1) and cg22976567 (LMNA). Conclusions: In childhood cancer survivors, cancer treatment exposures are associated with DNAm patterns present decades following the exposure. Treatment-associated DNAm sites may mediate the causal pathway from specific treatment exposures to certain cardiometabolic conditions, suggesting the utility of DNAm sites as risk predictors and potential mechanistic targets for future intervention studies.
2021-03-19 | GSE169156 | GEO
Project description:Long-term survivors of childhood cancer experience treatment-related cardiotoxicity among a broad spectrum of chronic health conditions, which may be further aggrevated by suboptimal life-course social/behavioral/environmental exposures. Epigenetic mechanisms, particularly DNA methylation (DNAm), provide a potential link through which these exposures become biologically embedded and subsequently influence long-term health outcomes. Epigenome-wide association studies (EWAS) identified DNAm signatures associated with both treatment effects as well as life-course exposures. In parallel, DNAm variations were also evaluated in relation to cardiometabolic risk factors, cardiovascular diseases, and other chronic health conditions, revealing individual CpG sites or genes/geomic regions where these CpGs reside linked to clinically relevant phenotypes. Together, these findings support DNAm as a molecular interface connecting diverse exposures to adverse health outcomes. In addition, epigenetic age acceleration, assessed using DNAm-based aging biomarkers, was observed among survivors exposed to cancer treatments. Epigenetic age acceleration mediated a substantial proportion of the associations between cancer treatment exposures and cardiometabolic risk factors or cardiovascular diseases, supporting accelerated biological aging as a key pathway linking cancer treatment to long-term morbidity. Lifestyle and health behaviors, as well as social vulnerability and psychosocial stress, were also associated with variations in epigenetic age acceleration, highlighting the potential modifiability of aging-related pathways in ameliorating late-effects among childhood cancer survivors. In conclusion, these findings establish DNAm—captured through EWAS signatures and epigenetic age acceleration—as central molecular mechanisms linking treatment effects and life-course exposures to cardiotoxicity along with other chronic health conditions in childhood cancer survivors. This integrative epigenetic framework supports the use of DNAm-based biomarkers for risk stratification and nominates modifiable pathways as potential intervention targets to improve long-term survivorship outcomes.
2026-01-13 | GSE314261 | GEO
Project description:Childhood cancer survivors who received abdominal radiotherapy (RT) or total body irradiation (TBI) are at increased risk for cardiometabolic disease, but the underlying mechanisms are unknown. We hypothesize that RT-induced adipose tissue dysfunction contributes to the development of cardiometabolic disease in the expanding population of childhood cancer survivors. We performed bulk RNA-sequencing of abdominal subcutaneous adipose tissue from adult childhood cancer survivors previously exposed to TBI, abdominal RT, or chemotherapy alone, alongside a group of healthy controls. We find that irradiated adipose tissue is characterized by a gene expression signature indicative of a complex macrophage expansion, which is also associated with dysregulated adipokine secretion. The full cohort is 30 subjects; however, 3 participants (2 in CHM group, 1 in CTL group) declined to share their sequencing data in a public database.
2021-09-17 | GSE184148 | GEO
Project description:In this study RNA-Seq was performed in anthracycline- exposed childhood cancer survivors who had cardiomyopathy (cases) matched to those without cardiomyopathy (controls) to understand the pathogenesis of anthrcaycline-related cardiomyopathy
2023-01-31 | GSE218276 | GEO
Project description:Mass spectrometry-based proteomic profiling of cerebrospinal fluid (CSF) in large patient cohorts, particularly among childhood cancer survivors, remains scarce, limiting opportunities for benchmarking, method development, and validation. Here, we present a longitudinal CSF proteomics dataset from survivors of childhood acute lymphoblastic leukemia (ALL). Samples were collected from 178 patients enrolled in the TOTXVI therapeutic protocol at two timepoints: diagnosis (pre-treatment) and during the consolidation phase of chemotherapy (totaling 356 samples). CSF proteomes were profiled using tandem-mass-tag (TMT) labeling coupled with extensive fractionation and high-resolution liquid chromatography-tandem mass spectrometry (LC/LC-MS/MS). The dataset includes quantitative profiles for more than 3,000 confidently identified proteins. This resource enables the investigation of chemotherapy-induced alterations in the CSF proteome and provides a valuable resource for studying the molecular mechanisms of neurotoxicity, identifying biomarkers of adverse late effects, and guiding the development of neuroprotective strategies in childhood cancer survivors.
2025-11-21 | MSV000099982 | MassIVE
Project description:Background: Increased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA. Methods: Genome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2,138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability. Results: For EAA-Horvath, a genome-wide significant association was mapped to SELP gene with the strongest SNP rs732314 (meta-GWAS: β=0.57, P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed substantial heterogeneity between children and adults (meta-GWAS: β=0.97 vs. 0.51, I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31, I2=66.3%). For EAA-Hannum, an association was mapped to HLA locus with the strongest SNP rs28366133 (meta-GWAS: β=0.78, P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09, P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21, P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge. Conclusions: We identified novel genetic variants in SELP gene and HLA region associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate identification of survivors at higher risk in developing accelerated aging, and potentially inform drug targets for future intervention strategies among vulnerable survivors.
2022-03-09 | GSE197675 | GEO
Project description:Background: Increased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA. Methods: Genome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2,138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability. Results: For EAA-Horvath, a genome-wide significant association was mapped to SELP gene with the strongest SNP rs732314 (meta-GWAS: β=0.57, P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed substantial heterogeneity between children and adults (meta-GWAS: β=0.97 vs. 0.51, I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31, I2=66.3%). For EAA-Hannum, an association was mapped to HLA locus with the strongest SNP rs28366133 (meta-GWAS: β=0.78, P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09, P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21, P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge. Conclusions: We identified novel genetic variants in SELP gene and HLA region associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate identification of survivors at higher risk in developing accelerated aging, and potentially inform drug targets for future intervention strategies among vulnerable survivors.
2022-03-09 | GSE197676 | GEO
Project description:Background: Increased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA. Methods: Genome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2,138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability. Results: For EAA-Horvath, a genome-wide significant association was mapped to SELP gene with the strongest SNP rs732314 (meta-GWAS: β=0.57, P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed substantial heterogeneity between children and adults (meta-GWAS: β=0.97 vs. 0.51, I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31, I2=66.3%). For EAA-Hannum, an association was mapped to HLA locus with the strongest SNP rs28366133 (meta-GWAS: β=0.78, P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09, P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21, P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge. Conclusions: We identified novel genetic variants in SELP gene and HLA region associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate identification of survivors at higher risk in developing accelerated aging, and potentially inform drug targets for future intervention strategies among vulnerable survivors.
2022-03-09 | GSE197674 | GEO
Project description:Genome wide DNA methylation profiling of samples from adult survivors of childhood and young adult cancer, using the Illumina Infinium Human MethylationEPIC Beadchip arrays. Samples included 32 samples, all sampled at least 10 years after diagnosis . Specific therapies and duration between sampling and diagnosis varied.
2020-12-31 | GSE162559 | GEO
Project description:Mitigating Long-term Treatment-related Morbidity in Childhood Cancer Survivors
| PRJNA1167347 | ENA