Na Qin1,2, Zhenghong Li1, Nan Song1, Carmen L Wilson1, John Easton3, Heather Mulder3, Emily Plyler3, Geoffrey Neale4, Emily Walker4, Xin Zhou3, Haitao Pan5, Melissa M Hudson1,6, Yutaka Yasui1, Leslie L Robison1, Jinghui Zhang3, Kirsten K Ness1, Zhaoming Wang1,3. 1. Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA. 2. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China. 3. Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA. 4. Hartwell Center, St Jude Children's Research Hospital, Memphis, TN, USA. 5. Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA. 6. Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
Abstract
BACKGROUND: Mounting evidence supports the occurrence of accelerating aging among long-term survivors of childhood cancer. We aimed to investigate epigenetic age acceleration (EAA) in survivors and evaluate associations between EAA, treatment exposures, health behaviors, and chronic health conditions (CHCs). METHODS: Genome-wide methylation data were generated with Infinium EPIC BeadChip on blood-derived DNA from 2139 survivors and 282 frequency matched controls from the St Jude Lifetime Cohort Study. EAAs were estimated as residuals from a linear regression of epigenetic age (Levine's clock) against chronological age. Adjusted least square mean (ALSM) of EAA was calculated and compared between survivors and controls, across treatment exposures and health behaviors. Associations of EAA with 20 clinically assessed CHCs were evaluated with multivariable piecewise-exponential models. All statistical tests for P values below were 2-sided. RESULTS: EAA was statistically significantly higher in survivors than controls (ALSM = 0.63, 95% confidence interval [CI] = 0.26 to 1.01 vs -3.61, 95% CI = -4.43 to 2.80). In a multivariable model among survivors, statistically significantly higher EAA (P < .05) was observed in those exposed to chest radiotherapy, abdomen or pelvic radiotherapy, alkylating agents, glucocorticoids, or epipodophyllotoxins. Compared with survivors with favorable health behaviors (ALSM = 0.26, 95% CI=-0.36 to 0.87), EAA was statistically significantly higher among survivors with intermediate (ALSM = 1.07, 95% CI = 0.59 to 1.54) or unfavorable health behaviors (ALSM = 1.45, 95% CI = 0.60 to 2.30). In time-to-event analyses, statistically significant associations were identified between EAA tertiles and incidence of 7 CHCs: hypertension (3rd vs 1st tertile, relative rate [RR] = 1.83, 95% CI = 1.17 to 2.83), myocardial infarction (RR = 2.91, 95% CI = 1.27 to 7.21), obesity (RR = 1.39, 95% CI = 1.17 to 1.66), obstructive pulmonary deficit (RR = 1.86, 95% CI = 0.95 to 3.77), peripheral motor neuropathy (RR = 2.89, 95% CI = 1.24 to 6.97), peripheral sensory neuropathy (RR = 2.04, 95% CI = 0.99 to 4.26), and pulmonary diffusion deficits (RR = 2.75, 95% CI = 0.95 to 7.63). CONCLUSIONS: EAA is statistically significantly higher in survivors of childhood cancer than in noncancer controls and is associated with specific treatment exposures, unfavorable health behaviors, and presence of specific CHCs.
BACKGROUND: Mounting evidence supports the occurrence of accelerating aging among long-term survivors of childhood cancer. We aimed to investigate epigenetic age acceleration (EAA) in survivors and evaluate associations between EAA, treatment exposures, health behaviors, and chronic health conditions (CHCs). METHODS: Genome-wide methylation data were generated with Infinium EPIC BeadChip on blood-derived DNA from 2139 survivors and 282 frequency matched controls from the St Jude Lifetime Cohort Study. EAAs were estimated as residuals from a linear regression of epigenetic age (Levine's clock) against chronological age. Adjusted least square mean (ALSM) of EAA was calculated and compared between survivors and controls, across treatment exposures and health behaviors. Associations of EAA with 20 clinically assessed CHCs were evaluated with multivariable piecewise-exponential models. All statistical tests for P values below were 2-sided. RESULTS: EAA was statistically significantly higher in survivors than controls (ALSM = 0.63, 95% confidence interval [CI] = 0.26 to 1.01 vs -3.61, 95% CI = -4.43 to 2.80). In a multivariable model among survivors, statistically significantly higher EAA (P < .05) was observed in those exposed to chest radiotherapy, abdomen or pelvic radiotherapy, alkylating agents, glucocorticoids, or epipodophyllotoxins. Compared with survivors with favorable health behaviors (ALSM = 0.26, 95% CI=-0.36 to 0.87), EAA was statistically significantly higher among survivors with intermediate (ALSM = 1.07, 95% CI = 0.59 to 1.54) or unfavorable health behaviors (ALSM = 1.45, 95% CI = 0.60 to 2.30). In time-to-event analyses, statistically significant associations were identified between EAA tertiles and incidence of 7 CHCs: hypertension (3rd vs 1st tertile, relative rate [RR] = 1.83, 95% CI = 1.17 to 2.83), myocardial infarction (RR = 2.91, 95% CI = 1.27 to 7.21), obesity (RR = 1.39, 95% CI = 1.17 to 1.66), obstructive pulmonary deficit (RR = 1.86, 95% CI = 0.95 to 3.77), peripheral motor neuropathy (RR = 2.89, 95% CI = 1.24 to 6.97), peripheral sensory neuropathy (RR = 2.04, 95% CI = 0.99 to 4.26), and pulmonary diffusion deficits (RR = 2.75, 95% CI = 0.95 to 7.63). CONCLUSIONS: EAA is statistically significantly higher in survivors of childhood cancer than in noncancer controls and is associated with specific treatment exposures, unfavorable health behaviors, and presence of specific CHCs.
Authors: Gregory T Armstrong; Toana Kawashima; Wendy Leisenring; Kayla Stratton; Marilyn Stovall; Melissa M Hudson; Charles A Sklar; Leslie L Robison; Kevin C Oeffinger Journal: J Clin Oncol Date: 2014-03-17 Impact factor: 44.544
Authors: Yang Zhang; Maria F Lorenzi; Karen Goddard; John J Spinelli; Carolyn Gotay; Mary L McBride Journal: Int J Cancer Date: 2013-09-14 Impact factor: 7.396
Authors: Gregory T Armstrong; Yan Chen; Yutaka Yasui; Wendy Leisenring; Todd M Gibson; Ann C Mertens; Marilyn Stovall; Kevin C Oeffinger; Smita Bhatia; Kevin R Krull; Paul C Nathan; Joseph P Neglia; Daniel M Green; Melissa M Hudson; Leslie L Robison Journal: N Engl J Med Date: 2016-01-13 Impact factor: 91.245
Authors: Daniel M Green; Vikki G Nolan; Pamela J Goodman; John A Whitton; DeoKumar Srivastava; Wendy M Leisenring; Joseph P Neglia; Charles A Sklar; Sue C Kaste; Melissa M Hudson; Lisa R Diller; Marilyn Stovall; Sarah S Donaldson; Leslie L Robison Journal: Pediatr Blood Cancer Date: 2013-08-12 Impact factor: 3.167
Authors: Kirsten K Ness; Kevin R Krull; Kendra E Jones; Daniel A Mulrooney; Gregory T Armstrong; Daniel M Green; Wassim Chemaitilly; Webb A Smith; Carmen L Wilson; Charles A Sklar; Kyla Shelton; Deo Kumar Srivastava; Sabeen Ali; Leslie L Robison; Melissa M Hudson Journal: J Clin Oncol Date: 2013-11-18 Impact factor: 44.544
Authors: Katrina L Piercy; Richard P Troiano; Rachel M Ballard; Susan A Carlson; Janet E Fulton; Deborah A Galuska; Stephanie M George; Richard D Olson Journal: JAMA Date: 2018-11-20 Impact factor: 157.335
Authors: Riccardo E Marioni; Sarah E Harris; Sonia Shah; Allan F McRae; Thomas von Zglinicki; Carmen Martin-Ruiz; Naomi R Wray; Peter M Visscher; Ian J Deary Journal: Int J Epidemiol Date: 2016-04-13 Impact factor: 7.196
Authors: Natassia Robinson; John Casement; Marc J Gunter; Inge Huybrechts; Antonio Agudo; Miguel Rodríguez Barranco; Fabian Eichelmann; Theron Johnson; Rudolf Kaaks; Valeria Pala; Salvatore Panico; Torkjel M Sandanger; Matthias B Schultze; Ruth C Travis; Rosario Tumino; Paolo Vineis; Elisabete Weiderpass; Roderick Skinner; Linda Sharp; Jill A McKay; Gordon Strathdee Journal: Br J Cancer Date: 2022-03-30 Impact factor: 9.075
Authors: Joanna Sulicka-Grodzicka; Andrzej Surdacki; Michał Seweryn; Tomasz Mikołajczyk; Krzysztof Rewiuk; Tomasz Guzik; Tomasz Grodzicki Journal: Cancer Med Date: 2021-02-19 Impact factor: 4.452
Authors: Cheng Chen; Nan Song; Qian Dong; Xiaojun Sun; Heather L Mulder; John Easton; Jinghui Zhang; Yutaka Yasui; Smita Bhatia; Gregory T Armstrong; Hui Wang; Kirsten K Ness; Melissa M Hudson; Leslie L Robison; Zhaoming Wang Journal: JAMA Netw Open Date: 2022-08-01