Social‐epigenetic mediators for racial disparities in pulmonary impairment among childhood cancer survivors

Background: Prior research suggests that social determinants of health (SDOH) may influence health through an epigenetic mechanism. However, the social epigenomic approach has not yet been applied to childhood cancer survivors, a population at high risk for chronic health conditions. We aim to investigate how SDOH factors contribute to racial disparity in pulmonary impairment with survivors from the St. Jude Lifetime Cohort Study. Methods: DNA methylation (DNAm) profile was generated with EPIC BeadChip using blood derived DNA. SDOH factors included educational attainment and personal income self-reported using a survey, and socioeconomic area deprivation index (ADI) geocoded using full home addresses. Clinically assessed pulmonary impairment included pulmonary diffusion deficits (PDD), restrictive pulmonary deficits (RPD) and obstructive pulmonary deficits (OPD). Epigenome-wide association study (EWAS) was performed to evaluate the association between DNAm at each CpG and each SDOH factor. Mediation analysis was conducted by treating each SDOH-associated CpG as a mediator, SDOH factor as an exposure, and specific pulmonary condition as the outcome. Genetically inferred races, i.e. survivors of European ancestry (EA) and African ancestry (AA), were considered. Results: The study included 258 AA (median time from cancer diagnosis [MTD]=25.2 years, interquartile range [IQR]=19.9-32.1 years) and 1,618 EA survivors (MTD=27.3, IQR=21.1-33.7 years). Compared to EA survivors, AA survivors had lower educational attainment (P<0.0001), lower personal income (P<0.0001), and higher ADI (P<0.0001). Compared to EA survivors, incidence of PDD (25.2% in AA vs 18.2% in EA, P=0.03) and RPD (14.2% in AA vs 7.5% in EA, P=0.002) were significantly higher in AA survivors, whereas OPD were comparable between groups (9.8% vs 13.1%, P=0.21). However, the racial disparity in PDD became nonsignificant after adjusting for SDOH. EWAS identified 130 SDOH-CpG associations at epigenome-wide significance (P<9×10-8) including 88 for educational attainment, 23 for personal income, and 19 for ADI. Thirteen CpGs, commonly associated with all three SDOH factors, resided at pleiotropic loci featuring cigarette smoking genes, e.g. CPOX and AHRR among others. Three independent SDOH-associated CpGs (cg04180924, cg1120500, and cg27470486) had a significant combined mediation effect for educational attainment (%mediation = 48.9%), and a single mediator cg08064403 had a significant mediation effect for personal income (25.9%) and ADI (24.1%) on PDD risk. Conclusions: DNAm signatures, many resembling the effect of tobacco use, are associated with educational attainment, personal income, and ADI. Our findings suggest that these DNAm are potential mechanistic mediators for the effects of SDOH factors on PDD risk. Through this mechanism, poor SDOH factors in AA survivors led to racial disparity in PDD. Citation Format: Nan Song, Jin-ah Sim, Qian Dong, Yinan Zheng, Lifang Hou, Zhenghong Li, Chia-Wei Hsu, Haitao Pan, Heather Mulder, John Easton, Emily Walker, Geoffrey Neale, Carmen L. Wilson, Kirsten K. Ness, Kevin R. Krull, Deo Kumar Srivastava, Yutaka Yasui, Jinghui Zhang, Melissa M. Hudson, Leslie L. Robison, I-Chan Huang, Zhaoming Wang. A social epigenomic investigation of racial disparity in pulmonary impairment among aging survivors of childhood cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 685.

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.

Current research in epigenetic age acceleration (EAA) is limited to non-Hispanic White individuals. It is imperative to improve inclusivity by considering racial and ethnic minorities in EAA research. To compare non-Hispanic Black with non-Hispanic White survivors of childhood cancer by examining the associations of EAA with cancer treatment exposures, potential racial and ethnic disparity in EAA, and mediating roles of social determinants of health (SDOH). In this cross-sectional study, participants were from the St Jude Lifetime Cohort, which was initiated in 2007 with ongoing follow-up. Eligible participants included non-Hispanic Black and non-Hispanic White survivors of childhood cancer treated at St Jude Children's Research Hospital between 1962 and 2012 who had DNA methylation data. Data analysis was conducted from February 2023 to May 2024. Three treatment exposures for childhood cancer (chest radiotherapy, alkylating agents, and epipodophyllotoxin). DNA methylation was generated from peripheral blood mononuclear cell-derived DNA. EAA was calculated as residuals from regressing Levine or Horvath epigenetic age on chronological age. SDOH included educational attainment, annual personal income, and the socioeconomic area deprivation index (ADI). General linear models evaluated cross-sectional associations of EAA with race and ethnicity (non-Hispanic Black and non-Hispanic White) and/or SDOH, adjusting for sex, body mass index, smoking, and cancer treatments. Adjusted least square means (ALSM) of EAA were calculated for group comparisons. Mediation analysis treated SDOH as mediators with average causal mediation effect (ACME) calculated for the association of EAA with race and ethnicity. Among a total of 1706 survivors including 230 non-Hispanic Black survivors (median [IQR] age at diagnosis, 9.5 [4.3-14.3] years; 103 male [44.8%] and 127 female [55.2%]) and 1476 non-Hispanic White survivors (median [IQR] age at diagnosis, 9.3 [3.9-14.6] years; 766 male [51.9%] and 710 female [48.1%]), EAA was significantly greater among non-Hispanic Black survivors (ALSM = 1.41; 95% CI, 0.66 to 2.16) than non-Hispanic White survivors (ALSM = 0.47; 95% CI, 0.12 to 0.81). Among non-Hispanic Black survivors, EAA was significantly increased among those exposed to chest radiotherapy (ALSM = 2.82; 95% CI, 1.37 to 4.26) vs those unexposed (ALSM = 0.46; 95% CI, -0.60 to 1.51), among those exposed to alkylating agents (ALSM = 2.33; 95% CI, 1.21 to 3.45) vs those unexposed (ALSM = 0.95; 95% CI, -0.38 to 2.27), and among those exposed to epipodophyllotoxins (ALSM = 2.83; 95% CI, 1.27 to 4.40) vs those unexposed (ALSM = 0.44; 95% CI, -0.52 to 1.40). The association of EAA with epipodophyllotoxins differed by race and ethnicity (β for non-Hispanic Black survivors, 2.39 years; 95% CI, 0.74 to 4.04 years; β for non-Hispanic White survivors, 0.68; 95% CI, 0.05 to 1.31 years) and the difference was significant (1.77 years; 95% CI, 0.01 to 3.53 years; P for interaction = .049). Racial and ethnic disparities in EAA were mediated by educational attainment (<high school vs ≥college, ACME = 0.13; high school vs ≥college, ACME = 0.07; mediation = 22.71%) and ADI (ACME = 0.24; mediation = 22.16%). In this cross-sectional study of childhood cancer survivors, race and ethnicity moderated the association of EAA with epipodophyllotoxin exposure and racial and ethnic differences in EAA were partially mediated by educational attainment and ADI, indicating differential treatment toxic effects by race and ethnicity. These findings suggest that improving social support systems may mitigate socioeconomic disadvantages associated with even greater accelerated aging and reduce health disparities among childhood cancer survivors.

Our published studies demonstrated that epigenetic age acceleration (EAA) is significantly higher in childhood cancer survivors than non-cancer controls. Additionally, EAA is associated with germline genetics, cancer treatments, unfavorable health behaviors, and chronic health conditions. However, our previous studies were limited to non-Hispanic whites (NHW). We aimed to investigate and compare the EAA between non-Hispanic blacks (NHB) and NHW, and evaluate the contribution of social determinants of health (SDOH) to potential racial disparity in EAA. Methylation profiling was generated using Infinium EPIC BeadChips on blood derived DNA from 460 NHB and 2,052 NHW from the St. Jude Lifetime Cohort. EAA was estimated as the residual from the fit of a simple linear regression of epigenetic age (EA, using Levine’s clock) on chronological age (CA, i.e., age at DNA sampling). Cumulative doses of chemotherapy and region-specific radiation exposures were abstracted from medical records. Educational attainment was categorized into 3 levels (&amp;lt; high school, high school, ≥ college). Personal income was categorized into 3 levels (none, &amp;lt; $40,000 and ≥ $40,000). For socioeconomic area deprivation index (ADI), we considered &amp;gt;75th percentile, 40th to 75th percentile, and &amp;lt;40th percentile as high, moderate, and low deprivation, respectively. Multivariable linear regression evaluated associations of EAA with race and SDOH adjusting for sex and cancer treatments. Mediation analysis treated SDOH as mediators, EAA as an outcome, and race as an exposure. The Pearson r between EA and CA was 0.85 and 0.58, and the age slope of EA (i.e., annual change rate of EA) was 1.21 and 0.91, for NHW and NHB, respectively. EAA was much higher in NHB (mean, 5.31; sd, 7.21) than NHW (mean, -1.19; sd, 12.48) with significance in a multivariable regression model adjusting for sex and cancer treatment (NHB vs. NHW: β = 1.90, P = 9.24×10-5). EAA was also associated with educational attainment (high school vs. &amp;lt;high school: β = -2.84, P = 3.22×10-5; college vs. &amp;lt;high school: β = -3.75, P = 2.03×10-7) and ADI (moderate vs. low: β= 1.07, P = 0.026; high vs. low: β = 1.58, P = 2.26×10-3), but not personal income. Notably, after adjusting for SDOH, the association between EAA and race was moderately attenuated (β = 1.50, P = 8.37×10-3). Both educational attainment (15.5%) and ADI (21.4%) mediated the association between race and EAA. We found racial disparity in EAA, with both personal and geographic SDOH as mediators of the association between race and EAA. These data indicate that changes in the social support system at both a personal and community level are needed to reduce socioeconomic disadvantage (e.g., lower education and poor living conditions) and hence the biological aging trajectory. In addition, moderate correlation between EA and CA among NHB suggests that further refined measurement of EA for NHB survivors is needed. Citation Format: Noel-Marie Plonski, Cheng Chen, Qian Dong, Na Qin, Nan Song, John Easton, Heather Mulder, Emily Walker, Geoffrey Neale, Jinghui Zhang, Kevin Krull, Kirsten K. Ness, Melissa M. Hudson, Leslie L. Robison, I-Chan Huang, Zhaoming Wang. Racial disparity and roles of social determinants of health in epigenetic age acceleration among survivors of childhood cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3503.

Social epigenomics is an emerging field in which social scientist collaborate with computational biologists, especially epigeneticists, to address the underlying pathway for biological embedding of life experiences. This social epigenomics study included long-term childhood cancer survivors enrolled in the St. Jude Lifetime Cohort. DNA methylation (DNAm) data were generated using the Illumina EPIC BeadChip, and three social determinants of health (SDOH) factors were assessed: self-reported educational attainment, personal income, and an area deprivation index based on census track data. An epigenome-wide association study (EWAS) was performed to evaluate the relation between DNAm at each 5’-cytosine-phosphate-guanine-3’ (CpG) site and each SDOH factor based on multivariable linear regression models stratified by ancestry (European ancestry, n = 1,618; African ancestry, n = 258). EWAS among survivors of European ancestry identified 130 epigenome-wide significant SDOH–CpG associations (P < 9 × 10−8), 25 of which were validated in survivors of African ancestry (P < 0.05). Thirteen CpGs were associated with all three SDOH factors and resided at pleiotropic loci in cigarette smoking–related genes (e.g., CLDND1 and CPOX). After accounting for smoking and body mass index, these associations remained significant with attenuated effect sizes. Seven of 13 CpGs were associated with gene expression level based on 57 subsamples with blood RNA sequencing data available. In conclusion, DNAm signatures, many resembling the effect of tobacco use, were associated with SDOH factors among survivors of childhood cancer, thereby suggesting that biologically distal SDOH factors influence health behaviours or related factors, the epigenome, and subsequently survivors’ health.

Epigenetic studies of blood lipid traits have identified genes underlying lipid metabolism in the general population. However, investigation of this association has not been conducted in survivors of childhood cancer, a population with a much higher burden of dyslipidemia and other cardiometabolic conditions due to exposures of genotoxic cancer therapies. We performed epigenome-wide association studies (EWAS) to identify blood DNA methylation (DNAm) 5’-cytosine-phosphate-guanine-3′ (CpGs) associated with lipid concentrations, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG), for childhood cancer survivors from the St. Jude Lifetime (SJLIFE) cohort. DNAm was generated with blood derived DNA using Illumina MethylationEPIC BeadChip array. Adjusted M-value of DNAm for each CpG was calculated based on a linear regression of M-value against a set of covariates, including sex, age at DNA sampling, leukocyte subtype proportions, top four significant genetic principal components, and top four methylation principal components. In the exposure EWAS, a linear regression model was used for lipid levels prior to DNA sampling as an exposure variable and DNAm as an outcome variable, adjusting for cancer treatments, age at lipid measurement, BMI, cigarette smoking and lipid lowering medicine use. In the outcome EWAS, a linear regression model was used for DNAm as an exposure variable and lipid levels after DNA sampling as outcome variables, adjusting for cancer treatments, age at lipid measurement, BMI, smoking, lipid lowering medicine use, lipid levels measured at DNA sampling, age at DNA sampling, and polygenic risk score for specific lipid levels. Among survivors of European ancestry (N=2052), we identified 43 significant CpGs (P&amp;lt;9×10-8) associated with HDL (n=7), TC (n=3) and TG (n=33) as exposures; and 106 CpGs associated with HDL (n=5), LDL (n=3), TC (n=4), and TG (n=94) as outcomes. Among survivors of African ancestry (N=370), we identified 3 CpGs associated with TG as an exposure, and 5 CpGs associated with LDL (n=1) and TC (n=4) as outcomes. A comparison of effect sizes of significant CpGs between survivors of European and African ancestry suggests moderate to substantial racial differences in epigenetic associations with lipid exposures (14/46 with I2&amp;gt;50) and lipid outcomes (106/111 with I2&amp;gt;50). Additionally, no overlap between CpGs associated with lipid exposures and lipid outcomes suggests that the DNAm levels of these CpGs could be either the cause or consequence of lipid levels. Examination of the EWAS catalog and recent literature, suggests that most of the lipid associated CpGs identified in our study are novel. Blood lipid associated CpGs may be epigenetic biomarkers for identification of survivors with higher risk of dyslipidemia and may inform potential drug targets for future interventions. Citation Format: Qian Dong, Nan Song, Cheng Chen, Zhenghong Li, John Easton, Heather Mulder, Jinghui Zhang, Geoffrey Neale, Emily Walker, I-Chan Huang, Kirsten K. Ness, Melissa M. Hudson, Leslie L. Robison, Zhaoming Wang. Epigenome-wide association study of blood lipids among survivors of childhood cancer in the St. Jude Lifetime Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3764.

Background: Epigenetic research of blood lipids has been conducted in the general population with some robust findings. However, there is lack of similar studies that explore epigenetic effects among childhood cancer survivors who have elevated risk of dyslipidemia. We aimed to utilize epigenome-wide approach to search for DNA methylation (DNAm) sites influencing lipid metabolism among survivors of childhood cancer. Methods: Epigenome-wide methylation data were generated with Infinium EPIC BeadChip on blood derived DNA of survivors from the St. Jude Lifetime Cohort Study. Chemotherapy agents and region-specific radiation exposures were abstracted from medical records. Two forms of dyslipidemia, i.e. hypertriglyceridemia (HTG) or hypercholesteremia (HCL) were clinically assessed. Multivariable logistic regression was used to evaluate associations between each DNAm site with incident cases of HTG or HCL adjusting for age, sex, and cancer treatment exposures. Analysis was stratified by genetically determined races, i.e. survivors of European ancestry (EA) and survivors of African ancestry (AA). Significant DNAm sites were correlated with mRNA expression of the mapped genes using RNA sequencing data available for blood samples of 87 survivors. Results: 2,052 EA (median age=34.7 years, 47.1% female, 26.6% HTG, 32.0% HCL) and 370 AA survivors (median age=32.1 years, 53.2% female, 15.9% HTG, 26.8% HCL) were included. Among EA survivors, six DNAm sites were associated with HTG risk at epigenome-wide significance level (P&amp;lt;9×10-8): CPT1A (cg00574958, cg05325763, cg17058475, cg09737197), SLC43A1 (cg11376147), and LINC01934 (cg22050199). These DNAm sites were also associated with HCL with P value ranging from 1.9×10-4 to 2.1×10-7. There was no single DNAm site associated with HCL risk reaching over epigenome-wide significance level. Search of differentially methylated regions for HTG status identified one additional statistically significant (PFDR&amp;lt;0.05) genomic region of chr1:120255941-120256112 encompassing PHGDH with three DNAm sites (cg16246545, cg14476101, cg26457483). Furthermore, DNAm of cg00574958 and cg14476101 located in CPT1A and PHGDH, respectively, were both inversely correlated with gene expression (CPT1A: r = -0.33, P=2.0×10-3; PHGDH: r=-0.46, P=9.1×10-6). In contrast, none of these DNAm sites showed associations with risk of HTG or HCL among AA survivors. Conclusion: We identified one or more DNAm sites, residing in each of CPT1A, SLC43A1, and PHGDH genes, associated with dyslipidemia among EA survivors. Lack of associations among AA survivors may partially contribute to lower risk of dyslipidemia among AA survivors. The findings demonstrated epigenetic roles in dyslipidemia among survivors, suggesting epigenetic biomarkers for identification of survivors with higher dyslipidemia risk and new targets for future interventions. Citation Format: Qian Dong, Nan Song, Yadav Sapkota, Yinan Zheng, I-Chan Huang, Deo Kumar Srivastava, John Easton, Heather Mulder, Geoffrey Neale, Emily Walker, Jinghui Zhang, Melissa M. Hudson, Leslie L. Robison, Zhaoming Wang. Epigenome-wide association study of dyslipidemia in survivors of childhood cancer: A report from the St. Jude lifetime cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 904.

The incidence of childhood, adolescent, and young adult (AYA) cancers have been increasing since 1975.[1][1] In 2014, an estimated 10 450 and 5330 new cancers will be diagnosed among children aged birth–14 and adolescents aged 15 to 19 years old, respectively.[2][2] For young adults aged 20 to 34

Understanding Social Determinants of Brain Health During Development.

Social Determinants of Health and Traumatic Brain Injury: Implications for Rehabilitation Service Delivery and Outcomes.

Our assessment of epigenetic age acceleration (EAA), calculated with DNA methylation (DNAm) data generated from bulk DNA derived from peripheral blood mononuclear cells (PBMC), supports accelerated aging in childhood cancer survivors (CCS). It is challenging to disentangle variation of DNAm at cell-type specific levels from the effects of age-dependent cell type composition, and bulk measurements may obfuscate the links between EAA and age-related outcomes (e.g., cardiomyopathy). Methylation profiling was generated using Infinium EPIC BeadChips on PBMC-derived DNA from CCS in the St. Jude Lifetime Cohort. Tensor composition analysis was employed to deconvolute bulk DNAm and infer DNAm at each leukocyte subtype level, i.e., a single n (individuals) by m (DNAm sites) matrix of observed DNAm data was deconvoluted into multiple n by m matrices of DNAm data. Epigenetic age (EA, using Levine’s clock) and EAA (residuals from the fit of a simple linear regression of EA on chronological age at blood draw) were calculated for bulk PBMCs and each cell subtype (CD4T, CD8T, B, natural killer, and monocyte). Cardiomyopathy (CMP) was assessed by echocardiography, and severity graded (2 = moderate, 3 = severe/disabling, 4 = life-threatening and 5 = fatal) using a modified version of the National Cancer Institute Common Terminology Criteria for Adverse Events. Cumulative doses of anthracyclines and mean heart radiation doses (heart-RT) calculated through radiation dosimetry were abstracted from medical records. Associations between EAA and CMP were evaluated by multivariable Cox regression. Cell-type specific EA was highly correlated with bulk EA with Pearson r2 between 0.63 (CD8T) and 0.79 (CD4T), but the linear regression lines of cell-type specific EA against bulk EA differed in both intercept and slope, suggesting heterogeneity across leukocyte subtypes. Cell-type specific EAA was moderately correlated with bulk EAA with Pearson r2 between 0.23 (monocyte) and 0.29 (CD8T). Among 2,044 CCS (median age = 33.7 years), 104 (5.1%) developed CMP (≥grade 3). Among bulk EAA and five cell-type specific EAAs, monocyte EAA was the only one significantly associated with CMP (hazard ratio per standard deviation increase in EAA = 1.25, 95% CI = 1.04-1.50, P = 0.018). Cell sorting of PBMC followed by DNAm is currently underway for further validation. We showed an in-depth view of the variability of EAA across leukocyte subtypes, and more importantly, demonstrated that monocyte EAA was associated with CMP risk. Our novel finding is plausible and consistent with the literature implicating monocyte-derived cardiac macrophages in cardiac remodeling, which can be induced by cardiotoxic cancer treatment exposures in CCS. Therapeutic strategies that prevent deleterious effects of monocytes contributing to adverse cardiac remodeling, while sparing their essential immune functions, may prevent or ameliorate CMP among CCS. Citation Format: Cheng Chen, Qian Dong, Qin Na, Nan Song, John Easton, Heather L. Mulder, Emily Walker, Geoffrey Neale, Emily R. Finch, Qian Li, Yutaka Yasui, Daniel A. Mulrooney, Melissa M. Hudson, Kirsten K. Ness, Jinghui Zhang, Xiang Chen, Hui Wang, Leslie L. Robison, Zhaoming Wang. Monocyte-specific epigenetic age acceleration and cardiomyopathy risk among survivors of childhood cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4363.

Social determinants of racial health inequities

e20554 Background: Significant progress has been made in the screening, diagnosis, and treatment of squamous cell carcinomas of the lung (LUSC). Despite the advancements, African American populations continue to experience worse disease burden and poorer overall survival, even after controlling for patient and tumor characteristics. While the interplay of various social determinants of health is well known to contribute to racial disparities in cancers, the molecular basis of racial disparity is less understood. Given the diversity of the US population that comprise of genetically admixed groups, understanding the role of ancestry and its influence on biology of cancers that drive incidence and prognosis is paramount to reducing racial disparities. Therefore, in this study, we aimed to investigate the influence of African (AFR) ancestry in genetic mutations of LUSC. Methods: We utilized The Cancer Genome Ancestry Atlas (TCGAA) to obtain data on the genetic ancestry and ancestral composition of 504 LUSC patients. The dataset contained 459 self-reported whites, 32 blacks, and 11 Asians. The percentage of each patient’s ancestral composition (European, AFR, Asian, and Native American) was revealed via the LAMP technique. The dominant ancestry was defined as those with genetic composition of ≥50% from one of four ancestral backgrounds. Genetic alteration profiles and clinical data of patients were obtained from LUSC TCGA PanCancer Atlas through GDC data portal. Of those with AFR dominant ancestry, we analyzed the differences in the gene mutation frequency based upon the proportion of AFR ancestry. Results: Ancestry analysis uncovered 30 AFR ancestry dominant cases with a mean AFR composition of 78.4%. We found 14 subjects with &gt; 80% AFR ancestry and 16 subjects with 50-80% AFR ancestry. Two patients from the &gt; 80% were excluded from the mutational analyses due to absence of genetic profiles in the data portal. TP53 was the most frequently mutated gene with a rate of 91.7% and 87.5% in &gt; 80% and 50-80% AFR groups, respectively. Evaluation of the classic genetic mutations that drive disease pathology in LUSC (EGFR, ALK, PIK3CA, NRAS, KRAS) revealed 25% of &gt; 80% AFR ancestry subjects carried mutations in at least one of these genes compared to 6.3% in the 50-80% AFR ancestry subjects. Also, a trend towards worse overall survival (OS) was seen in those with greater proportion of AFR ancestry (median OS of 27.2 months in &gt; 80% group vs 43.9 months in 50-80% group). Conclusions: Despite the limited sample size, our study highlights substantial heterogeneity in tumor biology even within those of AFR ancestry and that genetic ancestry may impact tumor and host biology that contribute to disparities. Moving forward, engagement of the African American community into clinical trials and genomic studies are needed to explore ancestral influence on tumorigenesis, and to facilitate discovery of new actionable targets to help eradicate racial disparities in lung cancer.

Hypertension-A Social Disease in Need of Social Solutions.

Background: Cancer treatments engender the risk of long-term cardiometabolic and cardiac conditions among survivors of childhood cancer. However, the underlying biological mechanisms remain unclear. This study aimed to identify DNA methylation (DNAm) CpG sites associated with cardiometabolic risk factors (CMRFs) and adverse cardiac outcomes, and to assess if these DNAm CpG sites mediate associations between specific cancer treatments and these outcomes. Methods: We included 3, 044 survivors (median age at blood draw: 29.6 years) from the St. Jude Lifetime Cohort. Blood-derived DNA was profiled using the EPIC BeadChip. Associations between DNAm and seven clinically assessed outcomes were examined: five CMRFs (abnormal glucose metabolism, hypercholesterolemia, hypertriglyceridemia, hypertension, and obesity), and two cardiac outcomes (cardiomyopathy and myocardial infarction). Treatment-specific epigenome-wide association studies (EWAS) evaluated associations with 10 chemotherapeutic agents and four region-specific radiotherapies. Results: EWAS identified 1, 833 CpG sites associated with cardiometabolic outcomes (p &amp;lt; 9x10-8), including obesity (N=1, 709), abnormal glucose metabolism (N=141), and hypertriglyceridemia (N=134). A moderate number of CpG sites mapped to CPT1A, a key gene in fatty acid metabolism linked to metabolic disorders, with 23 outcome-CpG associations involving 7 unique CpG sites. Most (71%) outcome-associated CpG sites were also associated with cancer treatments, particularly chest- (N=610) and abdominal-radiotherapy (N=599), suggesting potential causal mediation for the treatment-related genotoxicity. Mediation analyses identified 386 CpG sites mediating treatment effects on cardiometabolic outcomes. Asparaginase treatment was significantly associated with abnormal glucose metabolism (Odds ratio [95% CI] = 1.09 [1.06-1.13]). Eighteen CpG sites collectively mediated 26.7% of this effect, with 14 previously implicated in type-2 diabetes. Similarly, alkylating agents were associated with hypertriglyceridemia (1.11 [1.07-1.14]) mediated by DNAm at 46 CpG sites; five independent CpG sites accounted for a substantial 79.8% of such mediation effect. Notably, 39 of these mediator CpG sites were previously associated with C-reactive protein (CRP) levels (two-sided Fisher’s test, p=2.2x10-30), suggesting potential DNAm-mediated inflammatory pathways connecting alkylating agents to triglyceride dysregulation. Conclusion: Our findings suggest that DNAm changes may mediate the association between cancer treatments and cardiometabolic risks. These results implicate inflammatory and metabolic pathways in treatment-related adverse outcomes. These insights may inform risk stratification and targeted interventions to improve cardiometabolic and cardiac health in childhood cancer survivors. Citation Format: Tiffany Eulalio, Yoonji Kim, Peggy Meng, Qian Dong, Noel-Marie Plonski, Heather Mulder, John Easton, Emily Walker, Geoffrey Neale, Deokumar Srivastava, Stephanie Dixon, Kirsten K. Ness, Melissa M. Hudson, Gregory T. Armstrong, Zhaoming Wang. Epigenome-wide analysis of DNA methylation mediators linking cancer treatments to cardiometabolic risks in survivors of childhood cancer [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 703.