Yadav Sapkota, Ph.D., Gregory Armstrong, M.D., MSCE and Yutaka Yasui, Ph.D., all of the St. Jude Department of Epidemiology and Cancer Control.
Scientists from St. Jude Children’s Research Hospital have identified a genetic variant associated with substantially increased risk of heart disease in survivors of childhood cancer treated with the chemotherapy doxorubicin. This connection was discovered in participants in the St. Jude Lifetime Cohort Study (St. Jude LIFE) and validated in another major cancer cohort, the Childhood Cancer Survivor Study (CCSS). The results were published today in the Journal of the National Cancer Institute.
“In this study, we have identified a new region in the genome that increases risk of cardiotoxicity in childhood cancer survivors,” said first and corresponding author Yadav Sapkota, Ph.D., St. Jude Department of Epidemiology and Cancer Control. “This particular variant has never been identified before as a contributor to the mechanisms underlying cardiotoxicity.”
Childhood cancer survivors often experience treatment-related toxicities later in life. The researchers observed that some survivors developed cardiac problems, while some did not, even when they received the same treatment. This gave them a hint that genetics may be responsible for developing cardiac problems later in life.
The heart-breaking variant and treatment combination
The scientists found a strong relationship in children with a particular genetic variant, the common chemotherapy agent doxorubicin and cardiac dysfunction later in life. Doxorubicin belongs to the anthracycline family of chemotherapy agents used to treat pediatric cancer. The newly identified genetic variant could help guide pediatric cancer treatment.
“Patients who carry this variant may not have yet developed cardiotoxicity, but they could develop cardiotoxicity in the future,” Sapkota said. “When we performed the analysis among those survivors who were exposed to doxorubicin as a pediatric cancer treatment without chest radiotherapy and daunorubicin, we see that cardiotoxicity risk was much higher in somebody who carries at least one copy of this particular variant. With just a single copy, a survivor will have a 3-times larger risk of developing cardiotoxicity compared to someone else who does not have the risk allele.”
“But if somebody carries two copies of the variant,” he said, “Then, that person will have a 9-times higher risk for development of cardiotoxicity compared to those who did not carry the allele.”
St. Jude LIFE provides answers
To find the variants most associated with later cardiac problems, researchers compared genetic variants from 1,870 survivors who are part of those enrolled in St. Jude LIFE. St. Jude LIFE is a long-running study tracking the health of five-year survivors who were treated for childhood cancer at St. Jude. The study aims to reduce treatment side effects later in life in childhood cancer survivors. The researchers were able to “rediscover” several known variants associated with cardiac dysfunction, verifying that their approach worked.
In the same analysis, the group found a new variant near the gene KCNK17 associated with cardiac dysfunction. The researchers repeated the analysis in 301 St. Jude LIFE survivors of African descent and confirmed the discovery in this population.
“The whole genome sequencing data was key to finding this variant,” said co-senior author Yutaka Yasui, Ph.D., St. Jude Department of Epidemiology and Cancer Control. “Whole genome sequencing data of over 4,500 survivors that we have in St. Jude LIFE are an exceptional resource for scientific research. We use this precious genomic data in combination with treatment and health outcome data collected through clinical assessment from survivors as adults to identify risk of major late effects of childhood treatment, including cardiomyopathy.”
Validating results
Sometimes genetic findings only apply to the sample of patients used in the study. The scientists wanted to see if their finding could be replicated in an unrelated cohort. So, they ran their analysis with 4,020 survivors of European ancestry enrolled in the CCSS. This cohort includes childhood cancer survivors at least five years post-therapy who were treated at one of 31 participating institutions in the US and Canada. The researchers were able to find the same variant associated with cardiac dysfunction in this population too, validating their results.
The data used to discover the variant in the St. Jude LIFE cohort is freely available to other scientists on the St. Jude Cloud.
Authors and funding
The other co-senior authors is Gregory Armstrong of St. Jude. The other authors from St. Jude are Matthew J Ehrhardt, Na Qin, Zhaoming Wang, Kyla Shelton, Ying Shao, Emily Plyler, Heather L Mulder, John Easton, Robert Michael, Carmen Wilson, Chunliang Li, Jun Yang, Jinghui Zhang, Daniel Mulrooney, Melissa Hudson and Leslie Robison. Additional authors are Qi Liu and Weiyu Qiu, University of Alberta; Paul Burridge, Northwestern University; Xuexia Wang, University of North Texas; John Jefferies, The University of Tennessee Heath Science Center; Eric J Chow, Fred Hutchinson Cancer Research Center; Kevin Oeffinger, Duke University; Lindsay Morton, National Cancer Institute; and Smita Bhatia, University of Alabama at Birmingham.
The study was supported by grants from the National Cancer Institute (CA21765, R01CA261898 and R01CA216354) and ALSAC, the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease, and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.