Abstract 2260: Social vulnerability and epigenetic signatures in adult survivors of childhood cancer with African ancestry: An epigenome-wide association study

Abstract Background: Social determinants of health (SDOH) are increasingly recognized as critical factors in shaping long-term adverse health outcomes among childhood cancer survivors (survivors) because long-lasting toxicities from cancer treatment may be exacerbated by social adversity. Our previous epigenetic study of SDOH primarily focused on survivors of European ancestry, using measures such as educational attainment, personal income, and the Area Deprivation Index. This study aims to enhance understanding of the biological embedding of social adversity in survivors of African ancestry using the Social Vulnerability Index (SVI). The SVI provides a more comprehensive representation of SDOH, capturing neighborhood-level social vulnerabilities and aligning with the objectives of Healthy People 2030. Methods: Survivors of African ancestry from the St. Jude Lifetime Cohort were included. DNA methylation (DNAm) profiles were generated with EPIC BeadChip v1 using blood-derived DNA. SDOH factors included social vulnerability (four domains from the SVI: socioeconomic, household composition/disability, minority status/language, and housing/transportation), educational attainment, and personal income. An epigenome-wide association study (EWAS) was used to evaluate the association between DNAm at each CpG and SDOH factors, adjusting for attained age, sex, cancer treatment exposures, and leukocyte composition. Results: The study included 367 survivors (50.0% males; median age at blood draw for DNAm = 32.75 and interquartile range = 27.9-38.5 years). EWAS identified an epigenome-wide significant association between cg25793377 and overall SVI (beta=0.18, SD=0.033, p=8.73×10-8). Specifically, this association was significant for the socioeconomic domain of the SVI (beta=0.14, SD=0.035, p=8.11×10-5), but not significant for three other domains of SVI). Moreover, this CpG was not associated with personal-level SDOH factors, including educational attainment and personal income. This CpG maps to FFAR4, which encodes a G protein-coupled receptor (GPR) belonging to the rhodopsin family of GPRs and is a receptor for free fatty acids, including omega-3s, indicated in suppression of anti-inflammatory responses and insulin sensitizing; cg25793377 is also associated with protein levels in whole blood, including GZMK and TNFRSF17, both implicated in immune function and pro-inflammation. Conclusion: This study highlights the potential impact of neighborhood-level socioeconomic status in epigenome alteration among childhood cancer survivors with African ancestry, suggesting that socioeconomic vulnerability has molecular effects. These findings support the hypothesis that distal social factors become biologically embedded through epigenetic modulation, potentially influencing health trajectories in childhood cancer survivors. Citation Format: Yoonji Kim, Xiaoxi Meng, Jaesung Choi, Tiffany Eulalio, Noel-Marie Plonski, Heather Mulder, John Easton, Emily Walker, Geoff Neale, Kirsten Ness, Melissa M. Hudson, Gregory T. Armstrong, I-Chan Huang, Zhaoming Wang. Social vulnerability and epigenetic signatures in adult survivors of childhood cancer with African ancestry: An epigenome-wide association study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2260.