Genetic variant linked to increased risk for heart disease in cancer survivors
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Patients who received the chemotherapy drug doxorubicin for childhood cancer and harbor a specific genetic mutation near the KCNK17 gene experienced significantly greater risk for heart disease later in life, study results have shown.
A retrospective analysis by investigators at St. Jude Children’s Research Hospital suggested cancer survivors who carry a single copy of the genetic variant rs2815063-A and received treatment with doxorubicin have a three-times higher risk for developing treatment-related cardiac dysfunction later in life as those who do not carry the allele.
Background
Doxorubicin, an anthracycline-based chemotherapy, is part of the standard of care for many pediatric cancers, according to Yadav Sapkota, PhD, assistant member at St. Jude Children's Research Hospital. The therapy is also known to cause cardiac dysfunction in long-term cancer survivors, he added.
“Childhood cancer survivors have an increased risk [for] various chronic health conditions later in life, and one of them is cardiac toxicity, which is the leading cause of noncancer morbidity and mortality,” Sapkota told Healio.
Approximately 10% to 12% of cancer survivors experience cardiotoxicity after cancer treatment, Sapkota noted.
“Many childhood cancer survivors develop cardiotoxicity, but there is a variation in risk, suggesting a potential role of genetic susceptibility,” he said. “We sought to identify specific inherited genetic factors that may contribute to the increased cardiotoxicity risk.”
Methodology
Sapkota and colleagues used whole-genome sequencing data from 1,870 cancer survivors of European ancestry in the St. Jude Lifetime Cohort (SJLIFE) study to identify genetic variants associated with ejection fraction and risk of cardiotoxicity.
The investigators used two separate cohorts — including 301 survivors of African ancestry from the SJLIFE cohort and 4,020 survivors of European ancestry from the Childhood Cancer Survivor Study (CCSS) — to validate genetic variants significantly associated with risk of treatment-related cardiac dysfunction.
Key findings
A variant located near the gene KCNK17 (rs2815063-A) demonstrated significant genome-wide association with reduced ejection fraction of 1.6% (P = 2.1 × 10-8) among survivors in the SJLIFE European ancestry cohort. Researchers identified a similar association in the SJLIFE African ancestry cohort, which showed a 1.5% reduction in ejection fraction (P = .004).
The variant also correlated with a 1.8-fold (P = .008) higher risk for developing advanced treatment-related cardiac dysfunction in the SJLIFE European ancestry cohort. Again, researchers replicated the association, this time in the CCSS European ancestry cohort (OR = 1.4; P = .04).
Investigators found a stronger association among survivors in the SJLIFE European ancestry cohort who received doxorubicin only and carried the genetic variant, with a 3.3% reduction in ejection fraction (P = 5.1 × 10-5) and significantly higher risk for developing treatment-related cardiac dysfunction (OR = 2.97; P = .006).
Clinical implications
The significant association of the rs2815063-A variant with risk for cardiotoxicity among cancer survivors points toward a new mechanism or biology that will require further research, according to Sapkota.
He said that screening for patients who carry the genetic variant could help guide clinician recommendations by identifying those more likely to develop treatment-related cardiac dysfunction in the future.
“This could be very important information for clinicians to explore alternative therapies — if any are appropriate — that could possibly reduce the risk of subsequent cardiotoxicity,” Sapkota said.
For more information:
Yadav Sapkota, PhD, can be reached at Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, MS 735,
Memphis, TN 38105; email: yadav.sapkota@stjude.org.
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