Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes-A Report From the Children's Oncology Group
Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes-A Report From the Children's Oncology Group
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DOI：
10.1200/jco.2011.34.8987
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发表时间：
2012-05-01
影响因子：
45.3
通讯作者：
Bhatia, Smita
中科院分区：
文献类型：
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作者：
Blanco, Javier G.;Sun, Can-Lan;Bhatia, Smita
目的羰基还原酶（CBRs）催化蒽环类药物还原为心脏毒性酒精代谢物。CBR1和CBR3的多态性影响这些代谢物的合成。我们研究了CBR1 （CBR1 1096G>A）和/或CBR3 （CBR3 V244M）的单核苷酸多态性是否改变了儿童癌症幸存者蒽环类药物相关心肌病的剂量依赖性风险。患者和方法使用条件logistic回归技术将170例心肌病幸存者（患者病例）与317例无心肌病幸存者（对照；在癌症诊断、诊断年份、随访时间和种族/民族方面匹配）进行比较。结果累积蒽环类药物暴露与心肌病风险呈剂量依赖关系(0 mg/m(2)：参考；1至100 mg/m(2)：优势比[OR]为1.65；101 ~ 150mg /m(2): OR为3.85；151 ~ 200 mg/m(2): OR值3.69；201 ~ 250mg /m(2): OR值7.23；251 ~ 300 mg/m(2): OR值23.47；>300 mg/m(2): OR值27.59；p趋势< .001)。在携带变异A等位基因（CBR1:GA/AA和/或CBR3: GA/AA）的个体中，暴露于低至中等剂量的蒽环类药物（1至250 mg/m(2)）不会增加心肌病的风险。在CBR3 V244M纯合G基因型（CBR3:GG）的个体中，与未暴露于蒽环类药物的CBR3: GA/AA基因型个体相比，暴露于低至中剂量蒽环类药物的个体（OR, 5.48; P = 0.003）以及暴露于低至中剂量蒽环类药物的个体（OR, 3.30; P = 0.006），心肌病风险增加。高剂量蒽环类药物（> 250mg /m(2)）与心肌病风险增加相关，与CBR基因型状态无关。结论：本研究表明，低至101 - 150mg /m的剂量会增加蒽环类药物相关心肌病的风险(2)。CBR3中G等位基因的纯合子导致与低至中剂量蒽环类药物相关的心肌病风险增加，因此对于CBR3 V244M G等位基因纯合子的患者似乎没有安全剂量。这些结果表明，需要对心肌病风险增加的人群进行针对性干预。
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 1096G>A) 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.ResultsA dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m(2): reference; 1 to 100 mg/m(2): odds ratio [OR], 1.65; 101 to 150 mg/m(2): OR, 3.85; 151 to 200 mg/m(2): OR, 3.69; 201 to 250 mg/m(2): OR, 7.23; 251 to 300 mg/m(2): OR, 23.47; >300 mg/m(2): OR, 27.59; P-trend < .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/m(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 = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006). High-dose anthracyclines (> 250 mg/m(2)) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status.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.