期刊
PEDIATRIC BLOOD & CANCER
卷 60, 期 8, 页码 1375-1381出版社
WILEY
DOI: 10.1002/pbc.24505
关键词
anthracyclines; cardiotoxicity; genetic association study; pharmacogenomics
资金
- Canadian Institutes of Health Research
- Canada Foundation for Innovation
- Genome Canada
- Genome British Columbia
- Genome Quebec
- Child & Family Research Institute (Vancouver, BC)
- Faculties of Pharmaceutical Sciences and Medicine, University of British Columbia
- University of Western Ontario
- Canada Gene Cure Foundation
- Canadian Society of Clinical Pharmacology
- C17 Research Network
- Childhood Cancer Foundation-Candlelighters Canada
- Canadian Paediatric Society
- Merck Frosst
- Janssen-Ortho
- Illumina
- Eli Lilly
- Pfizer
- Canada Foundation for Innovation/Canadian Institutes of Health Research Regional/National Clinical Research Initiatives
- Genome British Columbia Translational Program for Applied Health
- Michael Smith Foundation for Health Research
- Child & Family Research Institute
- Stichting Kindergeneeskundig Kankeronderzoek (Foundation for Pediatric Cancer Research)
Background . The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity. Multiple genetic variants predictive of anthracycline-induced cardiotoxicity (ACT) in children were recently identified. The current study was aimed to assess replication of these findings in an independent cohort of children. Procedure . Twenty-three variants were tested for association with ACT in an independent cohort of 218 patients. Predictive models including genetic and clinical risk factors were constructed in the original cohort and assessed in the current replication cohort. Results . We confirmed the association of rs17863783 in UGT1A6 and ACT in the replication cohort (P=0.0062, odds ratio (OR) 7.98). Additional evidence for association of rs7853758 (P=0.058, OR 0.46) and rs885004 (P=0.058, OR 0.42) in SLC28A3 was found (combined P=1.6x10-5 and P=3.0x10-5, respectively). A previously constructed prediction model did not significantly improve risk prediction in the replication cohort over clinical factors alone. However, an improved prediction model constructed using replicated genetic variants as well as clinical factors discriminated significantly better between cases and controls than clinical factors alone in both original (AUC 0.77 vs. 0.68, P=0.0031) and replication cohort (AUC 0.77 vs. 0.69, P=0.060). Conclusions . We validated genetic variants in two genes predictive of ACT in an independent cohort. A prediction model combining replicated genetic variants as well as clinical risk factors might be able to identify high- and low-risk patients who could benefit from alternative treatment options. Pediatr Blood Cancer 2013;601375-1381. (c) 2013 Wiley Periodicals, Inc.
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