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Genetic Loci Influence Risk of Cardiomyopathy in Pediatric Cancer Survivors of African Ancestry

NEW YORK — Genetic variants contribute to the increased risk of treatment-linked heart problems among pediatric cancer survivors of African ancestry, a new study has found. 

Children who have survived cancer are at increased risk of cardiomyopathy, particularly if they were treated with anthracycline chemotherapy or radiation therapy that involved the heart. But most analyses have relied on children of European ancestry.

In a new study, researchers from St. Jude Children's Research Hospital analyzed data from a large cohort of childhood cancer survivors to find survivors of African ancestry are 2.5 times more likely to develop cardiomyopathy than survivors of European ancestry. As they reported Monday in the journal Cancer Research, the researchers further homed in on two genetic variants that boost that risk.

"Childhood cancer survivors are a unique population," first author Yadav Sapkota from St. Jude said in a statement. "But within that group, survivors of African ancestry are an even more specific population, who, until now, have generally been excluded from studies looking into the genetic mechanisms behind health outcomes among pediatric cancer survivors."

The researchers examined the incidence of cardiomyopathy among patients exposed to cardiotoxic therapies within the St. Jude Lifetime Cohort, a retrospectively constructed cohort with prospective clinical follow-up. This cohort included 246 childhood cancer survivors of African ancestry and 1,645 survivors of European ancestry who underwent such therapy.

Overall, survivors of African ancestry had 1.53-fold higher risk of grade 2 to 4 cardiomyopathy and 2.47-fold higher risk of grade 3 to 4 cardiomyopathy, as compared to survivors of European ancestry.

Through a genome-wide analysis, the researchers identified two genetic loci among survivors of African ancestry associated with ejection fraction, which is reduced in cardiomyopathy. Minor alleles at one locus at 1p13.2 were each linked to a 4 percent decline in ejection fraction, while a minor allele at the other locus, 15q25.3, leads to a 5.9 percent reduction in ejection fraction.

These loci were similarly associated with increased risk of cardiomyopathy among survivors of African ancestry. The locus at 1p13.2 was linked to a 3.71-fold increased risk of grade 2 to 4 cardiomyopathy and a 5.43-fold increased risk of grade 3 to 4 cardiomyopathy. Meanwhile, the locus at 15q25.3 is linked to a 5.24-fold and 4.51-fold increased risk of grade 2 to 4 cardiomyopathy and grade 3 to 4 cardiomyopathy, respectively.

Among childhood cancer survivors of European ancestry, the locus at 1p13.2 was also associated with an increased risk of cardiomyopathy, but did not reach statistical significance.

Together, the researchers estimate that the loci at 1p13.2 and 15q25.3 account for 17.6 percent and 13.0 percent of the racial disparity in cardiomyopathy risk, at the different grade levels, between African and European childhood cancer survivors.

Additionally, the researchers found that the risk allele at the 1p13.2 locus was linked to decreased methylation at two sites within the promoter region of the PHTF1 gene, which encodes a putative homeodomain transcription factor, among survivors of African ancestry. Among survivors of European ancestry, one of those two sites was also significantly hypomethylated, but the other was not.

Dysregulation at this site could, researchers said, be behind some of the genetic associations they uncovered and inform risk analyses.

"All childhood cancer survivors should be monitored for cardiac late effects, but as we gain a more granular understanding of cardiomyopathy risk among different populations, we can start to focus interventions on those individuals with the greatest need," co-author Melissa Hudson from St. Jude said.