As survival rates for many childhood cancers increase, more attention is being focused on health problems that survivors of childhood cancer may face after their recovery. 

Many children with cancer are prescribed anthracyclines, but these drugs can induce cardiomyopathy, particularly in patients exposed to high doses. 

Anthracyclines are known to be metabolised to alcohol-containing compounds such as doxorubicinol, and it is these that are cardiotoxic. Polymorphisms in the genes for the enzymes involved in this metabolic process, carbonyl reductases, are likely to affect metabolite formation and therefore the probability of developing cardiotoxicity.

Single nucleotide polymorphisms have been identified in two human carbonyl reductases, a non-coding polymorphism in CBR1 (1096GàA) and a missense mutation in CBR3 that leads to the amino acid substitution V244M. A large team of researchers led by Smita Bhatia from City of Hope, Duarte, California, USA on behalf of the Children’s Oncology Group has now conducted a case-control study to investigate the effect of these mutations on the development of cardiomyopathy in survivors of childhood cancer.

Bhatia and her co-workers identified 170 patients, defined as survivors of a primary cancer diagnosed before the age of 21 who had gone on to develop cardiomyopathy. Each patient was matched with between one and four controls who were also survivors of childhood cancer but with no cardiomyopathy, giving a total of 317 controls. 

Cases and controls were matched for primary cancer diagnosis, year of diagnosis, race or ethnicity and length of follow-up, and each case and control contributed a sample of cells for genotyping. The total exposure to anthracyclines for each participant was calculated from medical records. For all participants, the risk of developing cardiomyopathy was found to increase with cumulative anthracyclin dose.

The prevalence of the CBR1 (1096GàA) and CBR3 V244M genotypes in the group of childhood cancer survivors as a whole were similar to those observed in the general population.

 No association was observed between the CBR1 (1096GàA) mutation and the risk of cardiomyopathy. However, individuals carrying at least one allele for the V244M CBR3 variant were at statistically greater risk of developing cardiomyopathy than those with no such allele (odds ratio 1.79; P=0.02). There was an increase in cardio-myopathy risk for those individuals who carried the mutations in both genes, but this was not statistically significant.

The researchers then investigated the variation in cardiomyopathy with anthracycline dose in all groups. High cumulative doses of anthracyclines ((> 250 mg/m²) were associated with increased cardiomyopathy risk, independent of either CBR1 or CBR3 genotype. 

The risk associated with low to moderate doses of anthracyclines, however, was strongly genotype dependent. Individuals who were homozygous for the V244M allele of CBR3 (GG) were found to be at much greater risk of developing cardio-myopathy after these doses compared to individuals who were heterozygous at this position or homozygous for the wild type (V) allele., i.e. who carried the AG or AA genotype (odds ratio 5.48; P > 0.003). Further adjustment for CBR1 (1096GàA) genotype did not change this association pattern.

The researchers concluded that children who were homozygous for the V244M mutation in CBR3 and who were diagnosed with cancer would be at risk of developing cardiomyopathy after anthracycline use irrespective of dose, so much so that no anthracycline dose should be considered safe to use in these individuals. 

Thus, they recommended that close monitoring, prevention strategies or alternative cancer therapies be used with these children.

Reference

Blanco, J.G., Sun, C-L., Landier, W. and 13 others (2011). Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes — A report from the Children’s Oncology Group.  J. Clin. Oncology, published online ahead of print 28 November 2011. doi: 10.1200/JCO.2011.34.8987