Abstract 904: Epigenome-wide association study of dyslipidemia in survivors of childhood cancer: A report from the St. Jude lifetime cohort
Authors: Dong Qian , Song Nan , Sapkota Yadav , Zheng Yinan , Huang I-Chan , Srivastava Deo Kumar , Easton John , Mulder Heather , Neale Geoffrey , Walker Emily , Zhang Jinghui , Hudson Melissa M. , Robison Leslie L. , Wang Zhaoming 
Published: July 2021

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&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&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.