Purpose Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites. We examined whether single nucleotide polymorphisms in CBR1 (CBR1 1096G>A) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors. Patients and Methods One hundred seventy survivors with cardiomyopathy (patient cases) were compared with 317 survivors with no cardiomyopathy (controls; matched on cancer diagnosis, year of diagnosis, length of follow-up, and race/ethnicity) using conditional logistic regression techniques. Results A dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m2: reference; 1 to 100 mg/m2: odds ratio [OR], 1.65; 101 to 150 mg/m2: OR, 3.85; 151 to 200 mg/m2: OR, 3.69; 201 to 250 mg/m2: OR, 7.23; 251 to 300 mg/m2: OR, 23.47; > 300 mg/m2: OR, 27.59; Ptrend < .001). Among individuals carrying the variant A allele (CBR1:GA/AA and/or CBR3:GA/AA), exposure to low- to moderate-dose anthracyclines (1 to 250 mg/m2) did not increase the risk of cardiomyopathy. Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006). High-dose anthracyclines (> 250 mg/m2) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status. Conclusion This study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m2. Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low- to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele. These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy.
Deidre B. Pereira合作论文数Department of Clinical and Health Psychology, University of Florida8
Shan S. Wong合作论文数7Kacel Elizabeth L合作论文数7Chantel Ulfig合作论文数5Stephanie G. Smith合作论文数3Rachel Postupack合作论文数3Adaixa Padron合作论文数3
McCrae Christina S合作论文数Dept Clin & Hlth Psychol, Univ Florida3Laura Trinastic合作论文数2Laura Telepak合作论文数2Rachel Fox合作论文数2Michael E. Robinson合作论文数Center for Pain Research and Behavioral Health, Department of Clinical and Health Psychology, College of Public Health & Health Professions, University of Florida2
Gregory Schultz合作论文数Department of Obstetrics & Gynecology, College of Medicine, University of Florida;Institute for Wound Research, University of Florida;Center for Vision Research, University of Florida2Jacqueline C. Castagno合作论文数1Janae L. Kirsch合作论文数1
Stephanie Louise Smith合作论文数1Janae L Kirsch合作论文数1Gregory Shultz合作论文数1Alayna Ernster合作论文数1
Lori B Waxenberg合作论文数Department of Clinical and Health Psychology, College of Phhp, University of Florida1
Villaluna Doojduen合作论文数Childrens Oncol Grp1
Kevin Charles Oeffinger合作论文数Department of Community and Family Medicine, School of Medicine, Duke University;Department of Medicine, School of Medicine, Duke University;Center For Onco-Primary Care, Duke Cancer Institute, Duke University;Supportive Care and Survivorship Center, Duke Cancer Institute, Duke University1
Mary V. Relling合作论文数Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital1
Lu Chen合作论文数Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University1Ritchey A Kim合作论文数1Mays Allison合作论文数1
Smita Bhatia合作论文数Institute for Cancer Outcomes & Survivorship , School of Medicine, The University of Alabama at Birmingham1
Melissa M. Hudson合作论文数Cancer Survivorship Division, Department of Oncology, St. Jude Children's Research Hospital;Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital;Comprehensive Cancer Center, St. Jude Children's Research Hospital1
Joseph Neglia合作论文数Department of Pediatrics, University of Minnesota Medical School;M Health Fairview Masonic Children's Hospital;Division of Epidemiology and Community Health, School of Public Health, University of Minnesota1
Michael H. Antoni合作论文数Center for Psycho-Oncology Research, Department of Psychology, College of Arts and Sciences, University of Miami;Behavioral Medicine Research Center, University of Miami Miller School of Medicine;Sylvester Comprehensive Cancer Center, University of Miami Health Systems1Javier G. Blanco合作论文数1
Debra L. Friedman合作论文数Division of Pediatric Hematology/Oncology, Department of Pediatrics, Vanderbilt University Medical Center;Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center1Jill P. Ginsberg合作论文数1
Canlan Sun合作论文数Department of Supportive Care Medicine, City of Hope;Center for Cancer and Aging, City of Hope1
Wendy Leisenring合作论文数Clinical Research Division, Fred Hutchinson Cancer Center;Public Health Sciences Division, Fred Hutchinson Cancer Center1Wendy Landier合作论文数University of California-Los Angeles USA.1Linda Morgan合作论文数1
