Survivors of childhood cancer are at a significantly higher risk of developing cardiomyopathy years after completing therapy. New research from St. Jude Children’s Research Hospital reveals that the genetic contributors to this risk may differ from those found in the general population and survivors of adult cancers. The study, published in JAMA Network Open, identifies common genetic variants in TTN (rs3829746-C) and BAG3 (rs2234962-C) as being associated with a decreased risk of late-onset cancer therapy-related cardiomyopathy (CCM) in childhood cancer survivors of European ancestry.
“There are two types of dilated cardiomyopathy,” explained senior author Yadav Sapkota, PhD, an assistant member in the department of epidemiology and cancer control at St. Jude. “The first is familial, early-onset, meaning if your parents have it, then you are more likely to have it. These cases are usually associated with rare variants. The second is sporadic, late-onset, where there is generally no family history, but common variants have been identified in the general population.”
Understanding the Genetic Landscape
The study analyzed data from 205 survivors in the St. Jude Lifetime Cohort (SJLIFE) and 248 survivors from the Childhood Cancer Survivor Study (CCSS), all of whom had experienced late-onset CCM, defined as occurring at least five years after cancer treatment. These survivors had been exposed to known cardiotoxic treatments, including anthracyclines and chest-directed radiation. Researchers employed multivariable logistic regression to assess associations between genetic variants and late-onset CCM, adjusting for demographic and treatment factors.
The analysis revealed that genetic patterns observed in this cohort resemble those found in sporadic dilated cardiomyopathy (DCM) in the general population, rather than familial or early-onset DCM. This finding builds on previous research, including a study by Garcia-Pavia et al., which found rare PAVs in TTN among 7.5% of adult and pediatric cancer survivors with CCM. However, most participants had early-onset cardiomyopathy, often occurring within a year of cancer treatment.
“While cardiotoxic cancer therapies may unmask the harmful cardiac effects of rare PAVs in TTN and other DCM genes, leading to early-onset CCM, these variants may not significantly increase the risk of late-onset CCM, which typically develops years to decades after a childhood cancer diagnosis,” the researchers noted.
Implications for Genetic Screening
The findings suggest that incorporating common variants in TTN and BAG3 into genetic screening tools could help identify childhood cancer survivors at varying risks for late-onset cardiomyopathy. Notably, in survivors exposed to lower doses of cardiotoxic treatment, the protective effect of the TTN variant rs3829746-C was more pronounced, showing a 52% reduction in cardiomyopathy risk. A similar association was seen with BAG3 rs2234962-C in high-risk treatment groups.
“These observations can likely be implicated in early-onset cancer treatment–related cardiomyopathy, but not in our late-onset cancer treatment cardiomyopathy,” Sapkota stated.
Challenges and Future Directions
While the current research has identified new associations between treatments for early childhood cancer and CCM, the researchers acknowledged the inherent difficulty in studying rare variants in population-based cohorts due to their low frequency. They also noted limited findings among African ancestry participants, where associations between the variants and cardiomyopathy were not observed. Additionally, the data from CCSS were self-reported, which could have introduced reporting bias.
“The study suggests that more accurate genetic variant screens driven by this better understanding and acknowledgment of the differences between early- and late-onset health outcomes may help improve risk assessment in the future,” the researchers said.
The researchers plan to validate their findings in additional cohorts and explore whether other genetic variants beyond those identified in the TTN and BAG3 genes also play a role in long-term cardiac outcomes for childhood cancer survivors. Further work is needed to investigate how these genetic factors interact with treatment exposures and traditional cardiovascular risk.
This development represents a significant step forward in understanding the complex interplay between genetics and long-term health outcomes in childhood cancer survivors. As research continues, the hope is that these insights will lead to more personalized and effective strategies for monitoring and managing the health of these individuals.
