Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes—A Report From the Children's Oncology Group

Abstract

A B S T R A C T PurposeCarbonyl 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 1096GϾA) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors. Patients and MethodsOne 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. 2 ) 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 ϭ .003), as well as exposed to low-to moderate-dose anthracyclines (OR, 3.30; P ϭ .006). High-dose anthracyclines (Ͼ 250 mg/m 2 ) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status. Results ConclusionThis study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m 2 . 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.

Single-Nucleotide Polymorphisms in Aldo-Keto and Carbonyl Reductase Genes Are Not Associated with Acute Cardiotoxicity after Daunorubicin Chemotherapy

“…To the best of our knowledge of the SNPs investigated here, only rs1056892 (V244M) in CBR3 has been previously tested for association with AIC, and was found to be associated in survivors of childhood cancers by Blanco and colleagues but not by Visscher and colleagues (7,8). Similar to Visscher and colleagues, we did not find an association between the SNP and AIC in a population of adult patients with AML.…”

The use of biomarkers in detecting subclinical cardiotoxicity in doxorubicin-based treatment for paediatric patients with acute lymphoblastic leukaemia

“…After exposure to 151-200 mg/m² AC, it is associated with odds ratio of 3.69; between 201-250 mg/m² it doubles (odds ratio 7.23) and, when the total dose of doxorubicin rises above 251 mg/m², the odds ratio reaches 23.47 [7].…”

Treatment patterns, outcomes and long-term toxicity among patients with Hodgkin’s lymphoma in real world: results of a hospital based registry

“…Кардио-токсичность хорошо охарактеризована, и идентифи-цировано множество факторов, ассоциированных с ней. К наиболее важным факторам риска антрациклиновой токсичности относятся общая кумулятивная доза [21], возраст [22], женский пол [23], генетические полимор-физмы RARG (S427L), SLC28A3 (L461L) и UGT1A6*4 (V209V) [24][25][26], сочетанное применение лучевой те-рапии и антрациклинов и, наконец, срок наблюдения [27]. Если говорить о лучевой кардиотоксичности, клю-чевое значение имеют кумулятивная доза > 30 Гр [28], разовая доза > 2 Гр [29], доза облучения на область сердца [30], одновременное использование антраци-клинов [31,32], факторы риска по развитию сердечно-сосудистых заболеваний и, наконец, срок наблюдения за больными [31].…”