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Gene Variant Increases Stroke Risk in Childhood Survivors Given CRT

Samson, Kurt

doi: 10.1097/01.COT.0000559648.60992.0a
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ATLANTA—A common genetic mutation may help determine whether or not cranial radiation therapy will increase the risk of stroke in survivors of childhood cancer, a researcher told the annual meeting of the American Association for Cancer Research (Abstract 4909).

It is well-known that long-term childhood cancer survivors face an increased risk of stroke attributed to the dose of cranial radiation therapy (CRT) received, and while radiation-induced vasculopathy is thought to be the likely mechanism, there is a variation in the dose-risk association, said Yadav Sapkota, PhD, a clinical research scientist at St. Jude Children's Research Hospital in Memphis.

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Study Details

Sapkota and his colleagues conducted a retrospective cohort study, with prospective clinical follow-up and ongoing enrollment, in 686 pediatric cancer patients of European ancestry, 5 years of age and older. The data was collected as part of the St. Jude Lifetime Cohort (SJLIFE) study, which includes whole genome data on 4,500 patients.

The researchers found a significant genome-wide association between the single-nucleotide polymorphism (SNP) on the 5p15.33 locus and CRT-associated stroke.

Among the survivors, 17 percent developed clinically diagnosed stroke. Those with the SNP had nearly 5 times greater risk of stroke if they had received 25-50 Gy of intracranial radiation, and 3 times the risk if they had been treated with less than 25 Gy or more than 50 Gy.

The researchers replicated the finding in two independent groups of survivors from the SJLIFE study: survivors of African ancestry who received CRT and survivors of European descent who did not. Analyses of common variants were performed, adjusting for age at cancer diagnosis, gender, age at follow-up, CRT dose, and principal genotype components.

“This is the first comprehensive genetic study of stroke among long-term survivors of pediatric cancers,” Sapkota told a press briefing. “We have identified a genetic risk factor that confers a high risk of stroke among childhood cancer survivors treated with cranial radiation therapy.”

He said the findings might be used to better identify survivors at the highest risk of stroke and formulate intervention strategies to minimize this risk.

Past studies have shown that, compared to survivors who have not received CRT, those given between 30 and 50 Gy have a six-fold increase in stroke risk, and an eleven-fold risk if they received more than 50 Gy, Sapkota said.

“However, the stroke risk seems to vary within the same CRT dose group, even after accounting for other clinical and demographic factors,” he noted. “This indicated to us that there may be genetic predisposition that influences a CRT-exposed survivor's risk for developing stroke.”

Results of the replication analysis suggested that a combination of CRT treatment and genetic factors can greatly increase childhood cancer survivors' risk for developing stroke, according to Sapkota.

“Survivors treated with CRT who carry this genetic variant can benefit from being monitored and counseled to minimize their modifiable cardiovascular risk factors,” he added.

The small sample size is one limitation of the study, and will require validation in additional cohorts, Sapkota noted. Functional experiments are also needed to gain mechanistic insights underlying the link between the common SNP and risk of stroke among survivors treated with CRT—thereby informing potential intervention-based approaches, he said.

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Commentary

“This is the first time that a genetic variant has been identified to further increase the chance of stroke in this high-risk population,” said Weili Sun, MD, PhD, a pediatric hematologist/oncologist and Director of the Pediatric Leukemia Program at City of Hope Comprehensive Cancer Center in Duarte, Calif.

“Interestingly, this association is strongest in patients who received a moderate dose of CRT, suggesting the genetic effect is modest, and the association is less significant if patients received higher doses of CRT,” she told Oncology Times.

“In addition to cancer therapy, genetic variants can also influence the long-term health risk of cancer survivors, so it is important for patients to be followed at a comprehensive survivorship clinic to understand their risk of long-term effects, and to monitor these risks.”

Sun acknowledged that the finding needs to be validated in a different and larger cohort to better understand the underlying mechanism by which this variant contributes to increased stroke risk.

“Among survivors who received a moderate dose of CRT and who carry this variant, do we need additional monitoring and screening? Can we decrease the risk of stroke through early detection, lifestyle changes, or medication?” she questioned.

Her colleague Anna Pawlowska, MD, a City of Hope pediatric hematologist/oncologist, told Oncology Times that these findings show precision medicine allows for better identification of childhood survivors at a high risk of stroke.

“The findings guide oncologists in ordering and analyzing whole-genome sequencing to identify patients who will benefit from very close monitoring due to this genetic predisposition,” she said.

“These findings are also very significant for patients. Knowledge and understanding of stroke risk related to previous treatment can enable them to modify their lifestyle and be more committed to a stroke prevention program.

“The findings suggest the use of novel individual genetic information for disease prevention, introducing a new era of medicine to cancer survivorship.”

Kurt Samson is a contributing writer.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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