Yadav Sapkota1, Matthew J Ehrhardt1,2, Na Qin1, Zhaoming Wang1,3, Qi Liu4, Weiyu Qiu4, Kyla Shelton1, Ying Shao3, Emily Plyler3, Heather L Mulder3, John Easton3, J Robert Michael3, Paul W Burridge5, Xuexia Wang6, Carmen L Wilson1, John L Jefferies7, Eric J Chow8, Kevin C Oeffinger9, Lindsay M Morton10, Chunliang Li11, Jun J Yang12, Jinghui Zhang3, Smita Bhatia13, Daniel A Mulrooney1,2, Melissa M Hudson1,2, Leslie L Robison1, Gregory T Armstrong1, Yutaka Yasui1. 1. Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA. 2. Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA. 3. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. 4. School of Public Health, University of Alberta, Edmonton, AB, Canada. 5. Department of Pharmacology, Northwestern University, Chicago, Il, USA. 6. Department of Mathematics, University of North Texas, Denton, TX, USA. 7. Division of Cardiovascular Disease, The University of Tennessee Health Science Center, Memphis, TN, USA. 8. Clinical Research Division, Fred Hutchinson Cancer Research Center, WA, USA. 9. Department of Community and Family Medicine, Duke University, Durham, NC, USA. 10. Raditional Oncology Branch, National Cancer Institute, Bethesda, MD, USA. 11. Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. 12. Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA. 13. Institute of Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, AL, USA.
Abstract
BACKGROUND: Adult survivors of childhood cancer are at increased risk of cardiac late effects. METHODS: Using whole-genome sequencing data from 1870 survivors of European ancestry in the St. Jude Lifetime Cohort (SJLIFE) study, genetic variants were examined for association with ejection fraction (EF) and clinically assessed cancer therapy-induced cardiac dysfunction (CCD). Statistically significant findings were validated in 301 SJLIFE survivors of African ancestry and 4020 survivors of European ancestry from the Childhood Cancer Survivor Study. All statistical tests were 2-sided. RESULTS: A variant near KCNK17 showed genome-wide significant association with EF (rs2815063-A: EF reduction = 1.6%; P = 2.1 × 10-8) in SJLIFE survivors of European ancestry, which replicated in SJLIFE survivors of African ancestry (EF reduction = 1.5%; P = .004). The rs2815063-A also showed a 1.80-fold (P = .008) risk of severe or disabling or life-threatening CCD and replicated in 4020 Childhood Cancer Survivor Study survivors of European ancestry (odds ratio = 1.40; P = .04). Notably, rs2815063-A was specifically associated among survivors exposed to doxorubicin only, with a stronger effect on EF (3.3% EF reduction) and CCD (2.97-fold). Whole blood DNA methylation data in 1651 SJLIFE survivors of European ancestry showed statistically significant correlation of rs2815063-A with dysregulation of KCNK17 enhancers (false discovery rate <5%), which replicated in 263 survivors of African ancestry. Consistently, the rs2815063-A was associated with KCNK17 downregulation based on RNA sequencing of 75 survivors. CONCLUSIONS: Leveraging the 2 largest cohorts of childhood cancer survivors in North America and survivor-specific polygenomic functional data, we identified a novel risk locus for CCD, which showed specificity with doxorubicin-induced cardiac dysfunction and highlighted dysregulation of KCNK17 as the likely molecular mechanism underlying this genetic association.
BACKGROUND: Adult survivors of childhood cancer are at increased risk of cardiac late effects. METHODS: Using whole-genome sequencing data from 1870 survivors of European ancestry in the St. Jude Lifetime Cohort (SJLIFE) study, genetic variants were examined for association with ejection fraction (EF) and clinically assessed cancer therapy-induced cardiac dysfunction (CCD). Statistically significant findings were validated in 301 SJLIFE survivors of African ancestry and 4020 survivors of European ancestry from the Childhood Cancer Survivor Study. All statistical tests were 2-sided. RESULTS: A variant near KCNK17 showed genome-wide significant association with EF (rs2815063-A: EF reduction = 1.6%; P = 2.1 × 10-8) in SJLIFE survivors of European ancestry, which replicated in SJLIFE survivors of African ancestry (EF reduction = 1.5%; P = .004). The rs2815063-A also showed a 1.80-fold (P = .008) risk of severe or disabling or life-threatening CCD and replicated in 4020 Childhood Cancer Survivor Study survivors of European ancestry (odds ratio = 1.40; P = .04). Notably, rs2815063-A was specifically associated among survivors exposed to doxorubicin only, with a stronger effect on EF (3.3% EF reduction) and CCD (2.97-fold). Whole blood DNA methylation data in 1651 SJLIFE survivors of European ancestry showed statistically significant correlation of rs2815063-A with dysregulation of KCNK17 enhancers (false discovery rate <5%), which replicated in 263 survivors of African ancestry. Consistently, the rs2815063-A was associated with KCNK17 downregulation based on RNA sequencing of 75 survivors. CONCLUSIONS: Leveraging the 2 largest cohorts of childhood cancer survivors in North America and survivor-specific polygenomic functional data, we identified a novel risk locus for CCD, which showed specificity with doxorubicin-induced cardiac dysfunction and highlighted dysregulation of KCNK17 as the likely molecular mechanism underlying this genetic association.
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