Grant Number:	5R01CA261752-05 Interpret this number
Primary Investigator:	Zebrack, Bradley
Organization:	University Of Michigan At Ann Arbor
Project Title:	Social Genomic Mechanisms of Health Disparities Among Adolescent and Young Adult (AYA) Cancer Survivors
Fiscal Year:	2025

Survivors of cancer diagnosed in adolescence or young adulthood (AYA) have an elevated risk of multiple health problems. They also experience specific and unique psychosocial stressors and life disruptions having ramifications for their health, mental health, and quality of life (QOL). These outcomes, and disparities in these outcomes (by demographic factors, socioeconomic status (SES), geographic location), may be partially a function of social determinants of health, including socioeconomic gradients or early childhood experiences of adversity. Yet, little is known about these effects including the biological pathways through which the known effects of social-environmental risk factors on population health and well-being influence outcomes in post- treatment AYA cancer survivors, particularly with regard to treatment-related late effects and QOL. Therefore, the research proposed here is intended to identify and define functional genomic pathways through which current and past psychosocial and social environmental risk and resilience factors influence gene regulation in AYAs, and thus contribute to a greater understanding of health disparities in post-treatment survivorship. We propose a 5-year longitudinal prospective cohort study of 350 AYA cancer survivors recruited within three years following completion of treatment for Hodgkin or non-Hodgkin lymphomas or acute lymphocytic leukemia (ALL). Using repeated measures of risk and resilience factors and blood assays, we will evaluate the extent to which biological, psychological and social indicators are associated with, and potentially predict treatment-related late effects (morbidity) and QOL in AYA cancer survivors over two years after completion of therapy. In collaboration with the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) research infrastructure and the National Cancer Institute Community Oncology Research Program (NCORP), this study will 1) identify the genome-wide transcriptional impact of social-environmental RISK factors (i.e., adverse living conditions, childhood adversity, and social isolation) and define the relationships of those genomic profiles to AYA survivor morbidity (including cancer recurrence and QOL; 2) identify the genome-wide transcriptional impact of individual RESILIENCE factors (i.e., social support, sense of purpose/meaning-making, self-efficacy) and define the relationships of those genomic profiles to AYA morbidity and QOL; and, 3) identify the genome-wide molecular correlates of vulnerable populations, as structured by demographic factors, SES, and geography (e.g., rural vs. urban), and define the relationships of those genomic profiles to AYA survivor morbidity and QOL. The study results may inform the conceptualization and development of new biological / molecular targets for future interventions to reduce risks for treatment-related late effects and maximize likelihood of long-term health and QOL for AYA cancer survivors. Modified Specific Aims The body of literature on pediatric, adolescent, and young adult cancer survivorship is replete with studies documenting the effects of cancer, cancer treatment, and other cancer-related processes on morbidity, mortality, and quality of life (QOL) outcomes. Markedly less is known, however, about the biological pathways by which disruptions in psychosocial maturation, deleterious social conditions, and individual coping behaviors may affect future health outcomes for adolescent and young adult cancer survivors (AYAs). The research proposed here will identify and define functional genomic pathways through which psychosocial and social environmental risk and resilience factors influence gene regulation in AYA cancer survivors and thus contribute to a greater understanding of health disparities in post-treatment survivorship. Research in human social genomics has begun to map molecular pathways through which psychological factors and social environment regulate gene expression in immune cells and tumor tissue, and thus impact chronic disease progression, symptom development, antiviral resistance, morbidity, and mortality. In many cases, these pathways involve social and psychological processes that impact neural and endocrine function to regulate the expression of genes that influence cancer progression (e.g., inflammation, metastasis, treatment resistance) and immune function (e.g., stimulating inflammatory genes and suppressing antiviral gene transcription, as observed in the “Conserved Transcriptional Response to Adversity” / CTRA transcriptome signature). However, nothing is known about how such effects impact AYA cancer survivors. Defining effects of psychosocial and social environmental conditions on gene expression and their role in health outcomes for AYA survivors will fill a critical gap in the knowledge base that informs risk-based models for cancer survivorship care. Our experienced, strong, and disciplinarily-diverse investigative team is uniquely positioned to address this critical gap in AYA oncology research through the conduct of a 5-year longitudinal cohort study of 350 AYA survivors. To achieve parsimony and minimize heterogeneity and complexity of analyses, we will focus this initial investigation on survivors of Hodgkin and non-Hodgkin lymphomas and Acute Lymphocytic Leukemia. Our overarching goal is to develop a general analytic approach that can later be generalized to other AYA cancer survivors. Working in collaboration with the National Cancer Institute’s Community Oncology Research Program (NCORP), we will collect blood samples and patient reports of psychosocial and social environmental conditions over two years after completion of therapy. These data will form a novel dataset needed to identify the biological mechanisms through which social risk factors and individual resilience factors influence health outcomes and QOL in AYA survivorship, thereby identifying new targets for future interventions to improve AYA survivorship outcomes. To this end, we propose the following three sequential yet independent specific aims: Specific Aim #1: To identify the genome-wide transcriptional impact of SOCIAL-ENVIRONMENTAL RISK factors (i.e., adverse living conditions, childhood adversity, and social isolation) and define the relationships of those genomic profiles to AYA survivor outcomes (i.e., morbidity/late effects, QOL). We hypothesize that key social-environmental risk factors will be associated with greater expression of CTRA indicator genes (i.e., increased inflammatory biology and reduced Type I interferon biology), and that CTRA gene expression will in turn be associated with increased risk of morbidity (e.g., cancer recurrence) and reduced QOL. Specific Aim #2: To identify the genome-wide transcriptional impact of INDIVIDUAL RESILIENCE factors (i.e., social support, sense of purpose/meaning attribution, self-efficacy) and define the relationships of those genomic profiles to AYA survivor health outcomes (i.e., morbidity, QOL). We hypothesize that individual resilience factors will be associated with reduced expression of CTRA indicator genes and thereby moderate associations between social-environmental risk factors and morbidity and QOL. Specific Aim #3: To identify the genome-wide molecular correlates of vulnerable populations, as structured by demographic factors, socioeconomic status, geography (e.g., rural vs. urban) and define the relationships of those genomic profiles to AYA survivor health outcomes. We hypothesize that vulnerable populations will show greater CTRA gene expression and worse outcomes. Impact: This work is critical for an age-defined population of AYA cancer survivors, most of whom will survive cancer and look forward to decades of life. Yet, every AYA survivor has significantly increased risks for deleterious physical and mental health challenges. This study will be significant in that it will inform the conceptualization and development of targeted medical and supportive care interventions that reduce risks for morbidity and mortality and improve the QUALITY of life for AYAs.




A Developmental Science Approach to Informing Age Subgroups in Adolescent and Young Adult Cancer Research.
Authors: Siembida E.J. , Fladeboe K.M. , Ip E. , Zebrack B. , Snyder M.A. , Salsman J.M. .
Source: The Journal Of Adolescent Health : Official Publication Of The Society For Adolescent Medicine, 2023-06-08 00:00:00.0; , .
EPub date: 2023-06-08 00:00:00.0.
PMID: 37294255
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Social Genomics as a Framework for Understanding Health Disparities Among Adolescent and Young Adult Cancer Survivors: A Commentary.
Authors: Ghazal L.V. , Cole S. , Salsman J.M. , Wagner L. , Duan F. , Gareen I. , Lux L. , Parsons S.K. , Cheung C. , Loeb D.M. , et al. .
Source: Jco Precision Oncology, 2022 Jun; 6, p. e2100462.
PMID: 35772048
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