1. Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors
- Author
-
Marie A. Chaix, James Ellis, Cedric Manlhiot, Emily Lam, Paul C. Nathan, Neha Parmar, Anne Christie, Jane Lougheed, Paul F. Kantor, Guoliang Meng, Luc Mertens, Anastasia Miron, Leonard S. Sender, Stacey Marjerrison, Shayna Zelcer, Ashok Kumar Manickaraj, David C. Hodgson, Rejane Dillenburg, Seema Mital, Oyediran Akinrinade, Herschel Rosenberg, Roderick Yao, Caroline Kinnear, Myriam Lafreniere-Roula, Mylene Bassal, and Pediatrics
- Subjects
H2AX, H2A family member X ,Oncology ,Cardiac & Cardiovascular Systems ,PREDICTION ,VARIANT ,Cardiomyopathy ,DMSO, dimethyl sulfoxide ,THERAPY ,Pediatrics ,LVEF - Left ventricular ejection fraction ,AUC, area under the curve ,risk prediction ,GSEA, gene set enrichment analysis ,IC50, half-maximal inhibitory concentration ,TUMOR ,LVEF, left ventricular ejection fraction ,echocardiography ,Genetic risk ,Original Research ,mRNA, messenger RNA ,PGP, Personal Genome Project ,RF, random forest ,machine learning ,Cardiology and Cardiovascular Medicine ,Life Sciences & Biomedicine ,Clinical risk factor ,Cancer survivorship ,SKAT, sequence kernel association test ,medicine.medical_specialty ,DOXORUBICIN ,Anthracycline ,MAF, minor allele frequency ,anthracycline ,MECHANISMS ,Internal medicine ,genomics ,medicine ,GENOME-WIDE ASSOCIATION ,LV, left ventricular ,SNV, single-nucleotide variant ,Cardiotoxicity ,Science & Technology ,CARDIOMYOPATHY ,hiPSC-CM, human induced pluripotent stem cell–derived cardiomyocyte ,business.industry ,medicine.disease ,DOX, doxorubicin ,Pediatric cancer ,CI, confidence interval ,OR, odds ratio ,cancer survivorship ,Cardiovascular System & Cardiology ,RISK-FACTORS ,business ,cardiomyopathy - Abstract
Background Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging. Objectives This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. Methods We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (≤250 mg/m2), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin >250 mg/m2 were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell–derived cardiomyocytes, and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed. Results Thirty-one genes were differentially enriched for variants between case patients and control patients (p < 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 × 10–15). A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical-only model. In vitro inhibition of gene-associated pathways (PI3KR2, ZNF827) provided protection from cardiotoxicity in cardiomyocytes. Conclusions Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs. (Preventing Cardiac Sequelae in Pediatric Cancer Survivors [PCS2]; NCT01805778), Central Illustration
- Published
- 2020
- Full Text
- View/download PDF