Project description:BackgroundIncreased 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.MethodsGenome-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: 2138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against the 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.ResultsFor EAA-Horvath, a genome-wide significant association was mapped to the 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 a 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 the 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.ConclusionsWe identified novel genetic variants in the 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 the identification of survivors at higher risk in developing accelerated aging and potentially inform drug targets for future intervention strategies among vulnerable survivors.

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.

Project description:ImportanceCertain cancer therapies are risk factors for epigenetic age acceleration (EAA) among survivors of childhood cancer, and EAA is associated with chronic health conditions (CHCs). However, small numbers of younger survivors (aged <20 years) previously evaluated have limited the ability to calculate EAA among this age group.ObjectiveTo evaluate the change rate of epigenetic age (EA) and EAA in younger compared with older survivors and the possible association of EAA with early-onset obesity (aged <20 years), severity/burden of CHCs, and late mortality (>5 years from cancer diagnosis).Design, setting, and participantsStudy participants were from the St Jude Lifetime Cohort, initiated in 2007 with ongoing follow-up. The present study was conducted from April 17, 2022, to March 23, 2023. Survivors in this cohort of European ancestry with DNA methylation data were included. Cross-sectional annual changes in EA and EAA were compared across 5 different chronologic age groups: age 0 to 9 (children), 10 to 19 (adolescents), 20 to 34 (younger adults), 35 to 49 (middle-aged adults), and greater than or equal to 50 (older adults) years. Logistic regression evaluated the association between EAA and early-onset obesity or severity/burden of CHCs. Cox proportional hazards regression assessed the association between EAA and late mortality.Main outcomes and measuresEarly-onset obesity, severity/burden of CHCs (graded using the Common Terminology Criteria for Adverse Events (grade 1, mild; 2, moderate; 3, severe/disabling; 4, life-threatening) and were combined into high vs low severity/burden based on frequency and grade), and late mortality were the outcomes based on follow-up until April 2020. Expanded DNA methylation profiling increased the number of survivors younger than 20 years (n = 690). Epigenetic age was calculated primarily using the Levine clock, and EAA was derived from least squares regression of EA against chronologic age and was standardized to a z score (Levine EEA).ResultsAmong 2846 participants (median age, 30.3 [IQR, 9.3-41.5] years; 53% males), the cross-sectional annual change in EA_Levine was higher in children (1.63 years) and adolescents (1.14 years), and the adjusted least-squares mean of Levine EEA was lower in children (-0.22 years) and older adults (-1.70 years). Each 1-SD increase in Levine EEA was associated with increased risk of developing early-onset obesity (odds ratio [OR], 1.46; 95% CI, 1.19-1.78), high severity/burden of CHCs (OR, 1.13; 95% CI, 1.03-1.24), and late mortality (hazard ratio, 1.75; 95% CI, 1.35-2.26).Conclusions and relevanceThe findings of this study suggest that EAA measured in children and adolescent survivors of childhood cancer is associated with early-onset obesity, severity/burden of all CHCs, and late mortality. Evaluating EAA may help identify survivors of childhood cancer at increased risk for early-onset obesity, morbidity in general, and mortality.

Project description:BackgroundNeurocognitive impairment in survivors of childhood cancer may be associated with direct neurotoxicity, as well as indirect effects of systemic health complications. We evaluated associations among treatment exposures, chronic health conditions, and neurocognitive outcomes in adult survivors of childhood cancer.MethodsParticipants included 5507 adult survivors of childhood cancer (47.1% male; mean [SD] age = 31.8 [7.6] years at evaluation; 23.1 [4.5] years postdiagnosis) in the Childhood Cancer Survivor Study who completed a self-report measure of neurocognitive function. Cardiac, pulmonary, and endocrine chronic health conditions were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Structural equation modeling was used to examine a priori hypothesized causal pathways among cancer treatment, subsequent chronic health conditions, and neurocognitive outcomes. Multivariable models were used to estimate relative risk for associations of treatments and chronic conditions on neurocognitive function. All statistical tests were two-sided.ResultsOne-third of survivors with a grade 2 or higher chronic condition reported impairments in task efficiency and memory. In addition to direct effects of cranial radiation, path analyses and multivariable models demonstrated direct effects of cardiopulmonary (β = 0.10, P = .002; relative risk [RR] = 1.27, 95% confidence interval [CI] = 1.12 to 1.44) and endocrine (β = 0.07, P = .04; RR = 1.14, 95% CI = 1.02 to 1.28) conditions on impaired task efficiency. We identified similar effects of cardiopulmonary condition on memory (P = .01) and emotional regulation (P = .01). Thoracic radiation was associated with impaired task efficiency (P = .01) and emotional regulation (P = .01) through endocrine morbidity.ConclusionsNon-neurotoxic exposures, such as thoracic radiation, can adversely impact survivors' neurocognitive function through chronic conditions. Management of chronic diseases may mitigate neurocognitive outcomes among aging survivors of childhood cancer.

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Epigenetic Age Acceleration and Chronic Health Conditions Among Adult Survivors of Childhood Cancer.

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