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Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline‐induced cardiotoxicity in children
Author(s) -
Visscher H.,
Ross C.J.D.,
Rassekh S.R.,
Sandor G.S.S.,
Caron H.N.,
van Dalen E.C.,
Kremer L.C.,
van der Pal H.J.,
Rogers P.C.,
Rieder M.J.,
Carleton B.C.,
Hayden M.R.
Publication year - 2013
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.24505
Subject(s) - medicine , cohort , cardiotoxicity , oncology , anthracycline , odds ratio , cohort study , replication (statistics) , chemotherapy , cancer , breast cancer , virology
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 = 1.6 × 10 −5 and P = 3.0 × 10 −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. © 2013 Wiley Periodicals, Inc.