Title: Health-Related Quality of Life and DNA Methylation-Based Aging Biomarkers among Survivors of Childhood Cancer

Abstract

Background: Childhood cancer survivors are at high risk for morbidity and mortality and poor patient-reported outcomes, typically health-related-quality-of-life (HRQOL). However, associations between DNA methylation (DNAm)-based aging biomarkers and HRQOL have not been evaluated.

Methods: DNAm was generated with Infinium EPIC BeadChip on blood-derived DNA (median[range] for age at blood draw=34.5[18.5-66.6] years) and HRQOL was assessed with age at survey (32.3[18.4-64.5] years) from 2,206 survivors in the St. Jude Lifetime Cohort. DNAm-based aging biomarkers, including epigenetic age using multiple clocks (e.g., GrimAge) and others (e.g., DNAmB2M: beta-2-microglobulin; DNAmADM: adrenomedullin), were derived from the DNAm Age Calculator (https://dnamage.genetics.ucla.edu). HRQOL was assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey to capture eight domains, and physical and mental component summaries (PCS and MCS). General linear models evaluated associations between HRQOL and epigenetic age acceleration (EAA, e.g., EAA_GrimAge) or other age-adjusted DNAm-based biomarkers (e.g., ageadj_DNAmB2M) after adjusting for age at blood draw, sex, cancer treatments, and DNAm-based surrogate for smoking pack-years. All P values were 2-sided.

Results: Worse HRQOL was associated with greater EAA_GrimAge (PCS: β[95%CI]=-0.18[-0.251,-0.11] years, P=1.85×10^-5; and four individual HRQOL domains), followed by ageadj_DNAmB2M (PCS: -0.08[-0.124,-0.037], P=0.003; and three individual HRQOL domains), and ageadj_DNAmADM (PCS: -0.082[-0.125,-0.039], P=0.002; and two HRQOL domains). EAA_Hannum (Hannum clock) was not associated with any HRQOL.

Conclustion: Overall and domain-specific measures of HRQOL are associated with DNAm measures of biological aging. Future longitudinal studies should test biological aging as a potential mechanism.