Genetic Variants Associated with Therapy-Related Cardiomyopathy among Childhood Cancer Survivors of African Ancestry
| Autor: | Gregory T. Armstrong, Zhaoming Wang, Daniel A. Mulrooney, Yutaka Yasui, Jeremie H. Estepp, Carmen L. Wilson, Parul Rai, Yadav Sapkota, Melissa M. Hudson, John L. Jefferies, Matthew J. Ehrhardt, Leslie L. Robison, Yan Chen, Na Qin, Jinghui Zhang, Jane S. Hankins, Paul W. Burridge |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Oncology Male Cancer Research Cardiomyopathy Ethnic group 0302 clinical medicine Cancer Survivors Neoplasms Anthracyclines Prospective Studies Child education.field_of_study Ejection fraction Antibiotics Antineoplastic Incidence Middle Aged 030220 oncology & carcinogenesis Child Preschool Cohort Female Cardiomyopathies Adult medicine.medical_specialty Adolescent Childhood cancer Population Polymorphism Single Nucleotide Article White People 03 medical and health sciences Young Adult Internal medicine medicine Humans education Aged Retrospective Studies Therapy related Whole Genome Sequencing business.industry Genetic variants Infant Newborn Infant medicine.disease Black or African American 030104 developmental biology business Follow-Up Studies |
| Zdroj: | Cancer Res |
| ISSN: | 1538-7445 |
| Popis: | Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial or ethnic disparities, and none have assessed potential genetic factors contributing to this outcome. In this study, childhood cancer survivors of African ancestry exposed to cardiotoxic therapies (anthracyclines and/or heart radiotherapy; n = 246) were compared with cardiotoxic-exposed survivors of European ancestry (n = 1,645) in the St. Jude Lifetime Cohort. Genetic variants were examined using whole-genome sequencing data among survivors of African ancestry, first based on ejection fraction (EF) as a continuous outcome, followed by clinical history of cardiomyopathy. Survivors of African ancestry showed 1.53- and 2.47-fold risks of CTCAE grade 2–4 and grade 3–4 cardiomyopathy than survivors of European ancestry. A novel locus at 1p13.2 showed significant association with EF (rs6689879*C: EF reduction = 4.2%; P = 2.8 × 10−8) in 246 survivors of African ancestry, which was successfully replicated in 1,645 survivors of European ancestry but with attenuated magnitude (EF reduction = 0.4%; P = 0.042). In survivors of African ancestry, rs6689879*C showed a 5.43-fold risk of cardiomyopathy and 1.31-fold risk in those of European ancestry. Among survivors of African ancestry with rs6689879*C and CTCAE grade 2–4 cardiomyopathy, the PHTF1 promoter region was hypomethylated. Similar results were observed in survivors of European ancestry, albeit with reduced magnitudes of hypomethylation among those with rs6689879*C and CTCAE grade 2–4 cardiomyopathy. PHTF1 was upregulated in human-induced pluripotent stem cell-derived cardiomyocytes from patients with doxorubicin-induced cardiomyopathy. These findings have potential implications for long-term cardiac surveillance and up-front cancer care for patients of African ancestry. Significance: Childhood cancer survivors of African ancestry are at higher risk of cardiomyopathy than those of European ancestry, and a novel locus at 1p13.2 is associated with therapy-related cardiomyopathy specifically in African-American survivors. See related commentary by Brown and Richard, p. 2272 |
| Databáze: | OpenAIRE |
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