Chronic Health Conditions in Childhood Cancer Survivors: Is it All Treatment-Related—or Do Genetics Play a Role?

Abstract

BACKGROUND: High-intensity, risk-based therapeutic strategies for childhood cancer have resulted in long-term survival rates that now approach 80%. However, the growing population of survivors is at a substantial risk for treatment-related complications that can significantly impact quantity and quality of survival. It is increasingly recognized that many of these complications result from complex interactions between therapeutic exposures and genetic susceptibility.OBJECTIVE: This review is designed to increase general clinician awareness of the ongoing efforts by investigators to understand the interactions between therapeutic exposures and genetic susceptibility to therapy-related complications.RESULTS: Most studies have relied on a biologically plausible candidate gene approach to evaluate genetic susceptibility. This has resulted in the identification of unique genetic polymorphisms that could alter metabolic pathways of therapeutic agents associated with specific adverse events. We highlight some of these findings and discuss their implications for future prevention strategies, as well as their role in elucidating the pathophysiology of these complex diseases. CONCLUSION:Research exploring the role of genetic susceptibility in the development of therapy-related adverse outcomes is still in its infancy. There is a need for continued efforts to study these outcomes in the context of complex gene-gene and gene-environment interactions unique to cancer survivors. A better understanding of the pathogenesis of these outcomes will help develop effective targeted prevention strategies.

Prediction of cardiovascular disease among hematopoietic cell transplantation survivors

“…We and others have shown that despite the strong association between certain variables (eg, anthracycline dose, age, hypertension) and post-HCT HF, there is marked inter-individual variability in risk that is not explained exclusively by these factors alone. 29,51,52 For example, susceptibility due to inherited genetic variations in pathways involved in anthracycline-related toxicity have been shown to account for up to 10% of the HF risk after HCT, 38,39 and may need to be accounted for in future risk prediction estimates. As for CAD, the long latency (;10 years) between HCT and CAD may necessitate longer follow-up of our cohort, allowing us to further refine our risk estimates.…”

Children's Oncology Group's 2013 blueprint for research: Survivorship and outcomes

“…A subsequent study evaluating genetic modifiers of early-and late-occurring cardiotoxicity in a different cohort of childhood cancer survivors identified multiple variants of the SLC28A3 gene as important modifiers of anthracyclinerelated cardiotoxicity risk [40]. Information obtained from these studies add to the emerging body of literature [13] that genetic susceptibility could play an important role in modifying risk of developing adverse health-related outcomes in survivors of childhood cancer. Importantly, these results will facilitate the development of enhanced surveillance and/or prevention strategies among survivors at increased risk of cardiomyopathy.…”

“…However, doses as low as 150 mg/m 2 result in cardiomyopathy in some patients, suggesting a role for inter-individual variability in anthracycline pharmacodynamics [37]. Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites [13]. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites [38].…”

“…For a given therapeutic exposure, marked heterogeneity exists in the prevalence and severity of many of the long-term adverse outcomes experienced by cancer survivors. There is emerging data to suggest that genetic susceptibility influences individual response to therapeutic exposures [10][11][12][13].…”

Disparities in cancer outcomes: Lessons learned from children with cancer

“…Many of these genetic variants when fully established, could potentially play an important role in understanding the pathogenesis of the subsequent therapy‐related adverse events, and facilitate implementation of targeted prevention strategies. The current knowledge regarding established associations between therapeutic exposures and these genomic variables has been reviewed recently 60. While understanding the molecular underpinning of treatment‐related adverse events will allow a better understanding of the pathogenesis of these life‐threatening complications, it will be equally important to explore whether any racial/ethnic differences exist in the frequencies of the at risk variants that would place a sub‐population at a particularly high risk of complications, impacting long‐term survival.…”