The ST. Jude lifetime cohort study - the number of survivors of childhood/adolescent cancer in the US will approach 580,000 by 2040

This growing population is at risk for a spectrum of physical and psychosocial effects that are multifactorial in etiology. Recognition of associations of treatment-related complications with poor quality of survival and premature mortality has motivated the evolution to risk-stratified therapeutic strategies and introduction of novel therapeutics. Concurrently, the spectrum and magnitude of adverse effects have changed, calling for continued follow-up across the lifespan to inform childhood cancer and survivorship care. The ST. Jude lifetime cohort (sjlife; U01 CA195547; MPI: hudson/ness), established in 2007, provides an unparalleled resource for survivorship research through longitudinal clinical assessment of health outcomes. Accomplishments from sjlife include: enrollment of 6,525 of 10,328 potentially eligible 5-year survivors of childhood cancer; completion of >1 comprehensive clinical assessments by 5,720 and >2 by 3,637 survivors; banking of biospecimens for >90% of participants; completion of germline whole genome sequencing of >4,400 survivors; award of 41 active investigator-initiated funded grants utilizing the cohort; implementation of >20 active intervention-based trials; participation in numerous collaborations involving data sharing; implementation of a public access data portal on the ST. Jude cloud; and publication of >280 manuscripts. Findings from sjlife have highlighted potential pathways to accelerated aging, chronic health conditions (CHC) and mortality as well as contributions of health behaviors and personal, environmental and social factors to adverse outcomes. In this application we propose to leverage continued longitudinal follow-up in sjlife to address important knowledge gaps about factors contributing to multimorbidity and premature mortality among childhood cancer survivors by 1) performing deeper phenotyping of sjlife participants with established chcs (i.e., neurocognitive and neuromuscular impairments) to advance understanding of mechanisms contributing to pathophysiology of disease progression and identify novel targets for future interventions; 2) performing deeper phenotyping of sjlife participants at risk of chcs (i.e., atherosclerotic cardiovascular disease, subsequent malignancies, neurocognitive or neuromotor impairment) to facilitate early detection of pathophysiologic targets appropriate for remediation; and 3) enhancing characterization of longitudinal social determinants of health (SDOH) to examine how living conditions (e.g., local resources and infrastructure, persistent poverty) and neighborhood characteristics interact with personal social integrations (i.e., social connectedness) to influence the progression of chcs and contribute to health disparities. By elucidating the interaction of biological, social and psychological factors underpinning adverse health outcomes in survivors of childhood cancer as they age, sjlife offers the potential to novel biomarkers predictive of disease risk and inform risk-stratified survivorship care.