Abstract 4514: Variations of blood DNA methylation associated with cancer treatment exposures among childhood cancer survivors of African ancestry
Authors: Dong Qian , Das Sarmistha , Chen Cheng , Easton John , Mulder Heather L. , Walker Emily , Neale Geoffrey , Srivastava Deo Kumar , Huang I-Chan , Zhang Jinghui , Hudson Melissa M. , Robison Leslie L. , Ness Kirsten K. , Song Nan , Wang Zhaoming 
Published: April 2023

Abstract
We previously showed that cancer treatment associated DNA methylation (DNAm) signatures were present decades following the cancer diagnosis in childhood cancer survivors (CCS) of European ancestry (EA) and that treatment associated DNAm sites mediated the causal pathway from specific treatment exposures to increased risk of chronic health conditions (CHCs). This new analysis further evaluated and compared the treatment and DNAm associations in CCS of African ancestry (AA) from the St. Jude Lifetime Cohort Study. Cancer treatments were abstracted from medical records. DNAm was measured using MethylationEPIC BeadChip with blood-derived DNA. Among 370 AA CCS (53.2% female, median age at blood draw=31.2 [range=18.4-65.1] years), treatments included alkylating agents (54.6%), anthracyclines (48.6%), epipodophyllotoxins (29.2%), corticosteroids (33.0%), and vincristine (61.6%), and radiation therapy (RT) to brain (26.5%), chest (27.6%), abdomen (22.7%), and pelvis (21.6%). Epigenome-wide association study (EWAS) for each treatment, using multivariable linear regression adjusting for sex, age at blood draw, leukocyte cell subtype proportions, genotype principal components and DNAm principal components, showed little inflation with genomic control (GC) factor between 1.1 (brain-RT) and 1.2 (chest-RT). A total of 93 5′-cytosine-phosphate-guanine-3′ (CpG) was associated with one or more cancer treatments (GC-adjusted P&lt;9 × 10−8), including epipodophyllotoxins (n=46), alkylating agents (n=38), corticosteroids (n=3), anthracyclines (n=3), abdominal-RT (n=3), chest-RT (n=2), and pelvic-RT (n=1). A total of 60 differentially methylated regions (DMRs) was identified using DMRcate R package, including alkylating agents (n=28), epipodophyllotoxins (n=22), corticosteroids (n=3), abdominal-RT (n=4), chest-RT (n=2), and anthracyclines (n=1). A total of 39 CpGs from EWAS were nested within 21 DMRs. 92.1% (650/706) chemo-associated CpGs in EA were replicated in AA CCS, and 98.9% (86/87) chemo-associated CpGs in AA were replicated in EA CCS. In contrast, 66.7% (4/6) RT-associated CpGs in AA were replicated in EA CCS, and 71.7% (638/890) RT-associated CpGs in EA were replicated in AA CCS. Moreover, the four CpGs that partially mediated the effect of abdominal-RT on hypercholesterolemia in EA were not associated with abdominal-RT in AA CCS, further suggesting substantial difference in RT-associated CpGs as compared to chemo-associated CpGs between AA and EA CCS. Future studies by including a larger sample size of AA CCS are warranted to assess the difference in treatment-associated DNAm alterations and subsequent disparity in risk of treatment-related CHCs between AA and EA CCS. The DNAm sites can be used as predictors for risk management (treatment decision-making) and potential mechanistic targets for intervention for those at the greatest risk of CHCs.
Citation Format: Qian Dong, Sarmistha Das, Cheng Chen, John Easton, Heather L. Mulder, Emily Walker, Geoffrey Neale, Deo Kumar Srivastava, I-Chan Huang, Jinghui Zhang, Melissa M. Hudson, Leslie L. Robison, Kirsten K. Ness, Nan Song, Zhaoming Wang. Variations of blood DNA methylation associated with cancer treatment exposures among childhood cancer survivors of African ancestry. [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 4514.