Epigenetic Age in Peripheral Blood Among Children, Adolescent, and Adult Survivors of Childhood Cancer.
Noel-Marie Plonski, Cheng Chen, Qian Dong, Na Qin, Nan Song, Hemang M Parikh, Kyla Shelton, Emily R Finch, John Easton, Heather Mulder, Jinghui Zhang, Geoffrey Neale, Emily Walker, Hui Wang, Kevin Krull, Kirsten K Ness, Melissa M Hudson, Leslie L Robison, Qian Li, AnnaLynn Williams, Zhaoming Wang
Author Information
Noel-Marie Plonski: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
Cheng Chen: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
Qian Dong: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
Na Qin: Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
Nan Song: College of Pharmacy, Chungbuk National University, Cheongju, Korea.
Hemang M Parikh: Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa.
Kyla Shelton: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
Emily R Finch: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
John Easton: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee.
Heather Mulder: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee.
Jinghui Zhang: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee.
Geoffrey Neale: Hartwell Center, St Jude Children's Research Hospital, Memphis, Tennessee.
Emily Walker: Hartwell Center, St Jude Children's Research Hospital, Memphis, Tennessee.
Hui Wang: School of Public Health, Shanghai Jiaotong University, Shanghai, China.
Kevin Krull: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
Kirsten K Ness: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
Melissa M Hudson: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
Leslie L Robison: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
Qian Li: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee.
AnnaLynn Williams: Division of Supportive Care in Cancer, Department of Surgery, University of Rochester Medical Center, Rochester, New York.
Zhaoming Wang: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
Importance: Certain 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. Objective: To 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 Participants: Study 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 Measures: Early-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). Results: Among 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 Relevance: The 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.
