Polymorphisms in candidate genes in patients with congestive heart failure (CHF) after childhood cancer: A Report from the Childhood Cancer Survivor Study (CCSS)

Abstract

9004 Background: In cancer survivors, CHF associated with the use of anthracyclines is an important clinical complication. Risk factors for anthracycline associated cardiac toxicity, including cumulative dose, gender, and age, have been described. However, these risk factors do not fully explain the observed clinical variability. Notably, the potential role of genetic risk factors has not been studied. A recent “unifying hypothesis” postulates that the early cardiac damage is mediated mostly by oxidative stress while the more chronic type of toxicity is induced by anthracycline alcohol metabolites synthesized by carbonyl reductases (CBRs). Therefore we hypothesized that genetic polymorphisms in genes encoding for enzymes involved in oxidative stress pathways, and the metabolism of anthracyclines may impact on the risk of anthracycline-related cardiotoxicity. Methods: We conducted a nested case-control study within a cohort of 5,739 patients enrolled in the CCSS. Forty-seven cases with CHF and 195 matched controls (matched for demographics, follow-up and treatment) were genotyped for 10 genetic polymorphisms in 7 genes: catalase (CAT), GSTP, GSTT, GSTM, superoxide dismutase (SOD 1), NQO1, and CBR3. Results: In the subjects who received anthracyclines, multivariable analyses of CHF risk, adjusted for gender, smoking history, recurrence, and family history of heart disease, showed the GSTP +313A>G polymorphism was a significant risk factor, HR = 5.0, p = 0.01 for the A/G genotype vs. A/A; HR = 3.3, p = 0.19 for the G/G genotype vs. A/A. In addition, a suggested association between CBR3 V244M polymorphism and the risk of CHF after treatment with anthracyclines, HR=10.2, p=0.06 for G/G vs. A/A; HR = 4.0, p=0.18 for G/A vs. A/A was seen in an identical multivariable analysis. Conclusions: These data suggest that specific polymorphic genetic variants on a panel of candidate genes relevant to the anthracycline pharmacodynamics may modify the risk of CHF in childhood cancer survivors. Future studies to further refine the role of these novel genetic risk factors affecting a large population are warranted. No significant financial relationships to disclose.