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Gene Variant Linked to Childhood Cancer Drug's Cardio Side Effects

NEW YORK (GenomeWeb) – In Nature Genetics, an international team described a gene variant that dials up the risk of heart problems in children treated with the cancer drug anthracycline.

Members of the Canadian Pharmacogenomics Network for Drug Safety Consortium, University of British Columbia researchers, and others did a multi-stage genome-wide association study involving more than 450 anthracycline-treated childhood cancer patients from more than a dozen Canadian centers. Some of the patients had developed cardiotoxicity-related symptoms while others did not.

Their analysis revealed a SNP known as rs2229774 in the retinoic acid receptor-gamma gene RARG that's estimated to bump up cardiotoxicity risk by roughly five times in those receiving the drug.

The study's authors argued that the SNP "provides a clinical tool that may be used to predict genetic risk for [anthracycline-induced cardiotoxicity] and improve risk stratification."

"This new finding merits further exploration of the role of RARG in [anthracycline-induced cardiotoxicity] and of the clinical usefulness of the rs2229774 variant in RARG for predictive testing to inform [anthracycline-induced cardiotoxicity] risk assessment," corresponding author Colin Ross, a medical genetics and pediatrics researcher affiliated with the University of Vancouver, the Child and Family Research Institute, and colleagues added.

Although available treatments have extended the lives of many children with cancer, drug-related side effects can cause long-term health problems in a subset of these patients. For instance, the team noted, as many as 57 percent of anthracycline-treated children develop asymptomatic cardiac dysfunction, while an estimated 16 percent experience congestive heart failure.

Consequently, there's ongoing interest in using genetic approaches to dig for factors that mediate the risk of drug-related complications in children treated with anthracycline or other cancer drugs.

For the current study, the researchers started by using the Illumina HumanOmniExpress array to genotype 280 Canadian individuals of European ancestry who'd been treated with anthracycline at one of 13 Canadian centers, including 32 individuals who experienced cardiotoxicity symptoms within five years of treatment and 248 who didn't.

When the team compared patterns at more than 650,000 SNPs in the cases and controls, it turned up 18 variants — falling in nine blocks of linkage disequilibrium — that appeared more common in those with anthracycline-induced cardiotoxicity.

The researchers then attempted to replicate these findings in 22 cases and 74 controls of Dutch European ancestry, focusing on nine SNPs representing each of the linkage disequilibrium blocks detected in the initial cohort.

That analysis pointed to significant ties between toxicity and the RARG SNP rs2229774. A similar association turned up when the team tested 80 non-European, anthracycline-treated childhood cancer patients. This group, which included individuals of African, Aboriginal Canadian, Hispanic, and East Asian ancestry, contained 19 children with cardiotoxicity-related symptoms and 61 controls.

Available data suggest the risky retinoic acid receptor allele occurs in more than one-fifth of South Asians and more than one-tenth of African Americans. On the other hand, just 6 percent of Europeans and 5 percent of Hispanics carry the allele, while virtually no East Asians have it.

The results could explain the higher-than-usual cardiotoxicity that's been described in anthracycline-treated individuals in India and Pakistan or in African Americans in the US, the study's authors noted, though more work is needed to get to the heart of the RARG-anthracycline relationship.

In their follow-up cell-line experiments, they saw hints that the rs2229774 variant may diminish activity of the resulting RARG receptor subunit protein, altering its associations with other proteins, including the anthracycline-interacting enzyme topoisomerase II-beta.