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

Nan Song,Carmen L Wilson,Kevin R Krull,Kirsten K Ness,Melissa M Hudson,Emily Walker,Leslie L Robison,I‐Chan Huang ,Yutaka Yasui,Heather L Mulder ,Jinghui Zhang,Haitao Pan,Chia‐Wei Hsu ,Deo Kumar Srivastava,Yinan Zheng,Zhenghong Li,John Easton,Lifang Hou,Geoffrey Neale,Jin Ah Sim ,Zhaoming Wang

doi:10.1186/s13073-021-00875-1

Abstract

BackgroundIt 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.MethodsWe 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.ResultsBy 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).ConclusionsIn 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.

Highlights

It is well-established that cancer treatment substantially increases the risk of long-term adverse health outcomes among childhood cancer survivors
By performing multiple treatment-specific epigenome-wide association studies (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)
In childhood cancer survivors, cancer treatment exposures are associated with DNA methylation (DNAm) patterns present decades following the exposure

Summary

Introduction

It is well-established that cancer treatment substantially increases the risk of long-term adverse health outcomes among childhood cancer survivors. Premature cellular senescence, sterile inflammation, and mitochondrial dysfunction resulting from a primary cancer diagnosis or treatment-related toxicity may contribute to adverse health outcomes [12]. Survivors of childhood cancer often develop treatment-related late effects with 60% to more than 90% of survivors experiencing one or more long-term chronic health conditions (CHCs) [13], an approximately 2fold greater burden of CHCs than community controls [4]. Treatment-related adverse health outcomes encompass a broad range of CHCs [4, 14, 15], hospitalizations [16], premature frailty [17], and early mortality [14]. Some of the most commonly observed CHCs among survivors include obesity [18, 19], diabetes mellitus [20], cardiovascular diseases [21, 22], hypertension [9, 22, 23], and subsequent neoplasms [24, 25]

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