Persistent variations of blood DNA methylation associated with treatment exposures and risk for cardiometabolic outcomes in long-term survivors of childhood cancer in the St. Jude Lifetime Cohort

Abstract

Background It is well-established that cancer treatment substantially increases the 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 the 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 2052 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 the 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 the association between abdominal field radiotherapy (abdominal-RT) and risk of hypercholesterolemia (70.3%) and by methylation at three CpGs (cg19634849, cg13552692, cg09853238) for the 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 a 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.

Anti-cancer therapy is associated with long-term epigenomic changes in childhood cancer survivors

“…These have primarily concentrated on epigenetic ageing, and consistent with this study, have identified accelerated ageing in cancer survivors [ 43 – 46 ]. A recent study by Song et al [ 47 ] also performed an epigenome-wide association study (EWAS) to identify specific CpG sites exhibiting differential methylation in patients given specific therapies or combinations of therapies. They identified 935 CpG sites associated with individual treatments and 224 CpG sites associated with exposure to drug combinations.…”

Genome-wide association studies identify novel genetic loci for epigenetic age acceleration among survivors of childhood cancer

“…rs3093956 is a known hit for EAA-Hannum [ 15 ]; however, it has low LD ( r 2 =0.075) with rs28366133. Multiple striking DMRs were observed between survivors and controls in the HLA region, which might be due to the fact that genotoxic cancer treatments modified the epigenome among other physiological alterations in survivors and hence altered functional genomic links (e.g., eQTL, mQTL, and eQTM) [ 23 , 58 ], which may lead to either disruption or introduction of genetic associations with EAA. For the same reason, a substantial proportion (e.g., 20 out of 39 IEAA-associated SNPs) of previously reported genetic associations, including the most notable rs2736099 ( TERT ), were not replicated in our study.…”

“…The raw intensity was exported from Illumina Genome Studio and analyzed in R (version 3.6.3) using the minfi package [ 22 ]. Detailed quality controls (QCs) and data normalization were described previously [ 23 ]. After QCs, the data set comprised beta-values for 689,419 CpGs.…”

“…The DNA methylation data, demographics, and cancer treatment information generated and analyzed in this study are accessible at the NCBI GEO website under the accession number GSE197678 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE197678 ) [ 59 ]. Parts of these data have been previously published in Song et al [ 23 ] and are accessible at the NCBI GEO website under the accession number GSE169156 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE169156 ). Additional clinical data about the study participants in the St. Jude Lifetime Cohort can be accessed via the survivorship portal ( http://survivorship.stjude.cloud/ ).…”

DNA methylation under the major depression pathway predicts pediatric quality of life four-month post-pediatric mild traumatic brain injury

“…BMI represented body mass index. Principal components (PCs) decomposed from genomic methylation data have been used to control for potential confounding factors in genomic association analyses [ 42 ]. The change rate of eigenvalues suggested using the first five PCs, while PC 1 was highly collinear with buccal cell proportions (correlation r = 0.87) and PC 5 was associated with gender ( r = 0.45, p = 4.18 × 10 –11 ), race ( r = − 0.33, p = 3.17 × 10 –6 ), and PCSI at SA ( r = 0.19, p = 0.02).…”