Abstract 6384: DNA methylation based aging biomarkers mediate the association between patient-reported symptoms and all-cause late-mortality: A report from the St. Jude Lifetime Cohort
Authors: Li Qian , Pan Yue , Zhang Xijun , Plonski Noel-Marie , Chen g , Dong Qian , Shelton Kyla , Easton John , Mulder Heather , Zhang Jinghui , Neale Geoffrey , Walker Emily , Srivastava Deo Kumar , Armstrong Greg T. , Ness Kirsten , Huang I-Chan , Wang Zhaoming 
Published: March 2024

Abstract
Background: Long-term survivors of childhood cancer experience high rates of patient-reported symptoms and evidence for accelerated molecular aging. Both are established to increase the risk for late-mortality (&gt;5 years from cancer diagnosis). We aim to investigate if accelerated molecular aging mediates the association between symptoms and all-cause late-mortality.
Methods: DNA methylation (DNAm)-based aging biomarkers were derived from the DNAm Age Calculator, including epigenetic age acceleration (EAA) using multiple clocks (e.g., GrimAge and PhenoAge) and other DNAm-predicted biomarkers (e.g., DNAmB2M: beta-2-microglobulin, DNAmTL: telomere length) adjusted for age and standardized. Survivors self-reported the presence of 10 symptom domains (cardiac, pulmonary, sensory, motor/movement, nausea, pain, fatigue, memory, anxiety, and depression) that were aggregated into a total symptom burden score. Multiple linear regression tested the association between each aging biomarker and symptom prevalence, adjusting for the age of symptom survey, sex, and cancer treatment exposures. Cox regression tested the association of each aging biomarker or symptom domain with mortality. Aging biomarkers mediation for the symptom-mortality association was assessed by using the Accelerated Failure Time model and the mediation R package. False discovery rate was controlled for multiple testing.
Results: Among 2,206 survivors (47% males) who had DNAm measured on (52%) or after the survey, the median duration from the symptom survey to DNA sampling were 0.48 years (IQR: 0.09-4.27 years). EAA_GrimAge was the aging biomarker most closely associated with total symptom burden (beta [95%CI] = 0.576 [0.455, 0.697] years, P=2.89×10-18) and eight of ten domain-specific symptoms except for motor/movement and memory. Seven aging biomarkers (e.g., DNAmB2M: 1.91 [1.48, 2.48], P=1.87×10-5; EAA_GrimAge: HR [95%CI] = 1.17 [1.09, 1.26], P=3.1×10-4 ) and five symptom domains (e.g., pulmonary: 2.54 [1.44, 4.49], P=0.004; cardiac: 2.25[1.28, 3.97], P=0.01; total symptom burden: 1.47 [1.18, 1.82], P=0.0019) were associated with mortality risk. EAA (e.g., EAA_GrimAge) mediated the association between symptoms (cardiac: % mediation =0.13 [0.044, 0.379], P=0.008; pulmonary: 0.186 [0.075, 0.486], P=0.008; and total symptoms: 0.206 [0.078, 0.503], P=0.012) and late mortality. In addition, the association between symptoms and mortality was mediated by DNAmB2M and DNAmTL (e.g., pulmonary: 0.152 [0.046, 0.378], P=0.008; 0.12 [0.031, 0.373], P=0.021).
Conclusions: EAA, DNAmB2M and DNAmTL mediated the association between the presence of specific symptom domains and late-mortality, suggesting that accelerated molecular aging may be an underlying biological pathway explaining the associations between symptom burden and mortality.
Citation Format: Qian Li, Yue Pan, Xijun Zhang, Noel-Marie Plonski, g Chen, Qian Dong, Kyla Shelton, John Easton, Heather Mulder, Jinghui Zhang, Geoffrey Neale, Emily Walker, Deo Kumar Srivastava, Greg T. Armstrong, Kirsten Ness, I-Chan Huang, Zhaoming Wang. DNA methylation based aging biomarkers mediate the association between patient-reported symptoms and all-cause late-mortality: A report from the St. Jude Lifetime Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6384.