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ATLANTA -- A genomic analysis of pediatric cancer survivors revealed a genetic abnormality that significantly increased the risk of stroke in patients who had cranial irradiation, according to research presented here.

Almost half of the survivors with stroke had at least one copy of the genetic variant, which was associated with almost a threefold greater risk of stroke as compared with patients who did not have the variant, reported Yadav Sapkota, PhD, of St. Jude Children's Research Hospital in Memphis, Tennessee.

The variant was identified in children of European and African ancestry, and the highest stroke risk was seen in patients who received intermediate doses of radiation. The findings may help inform treatment decisions for patients who require cranial irradiation, as reported at the American Association for Cancer Research annual meeting.

"This is the first comprehensive genetic study of stroke among long-term survivors of pediatric cancers," Sapkota said during a press briefing. "Cranial radiation-treated survivors of European ancestry who carry the risk allele ... are nearly three times more likely to develop stroke as compared to those who did not. A cranial radiation dose-specific stroke risk was observed, with the strongest effect observed among those who received cranial radiation doses of 25 to 50 Gy."

As compared with studies of drug safety, limited data have accumulated regarding the long-term complications of radiation therapy, said Federico Innocenti, MD, PhD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.

"To my knowledge, this is the first study providing evidence for the role of genetic variation of the host for the risk of stroke in pediatric cancer patients treated with radiation," Innocenti told MedPage Today via email. "The discovery has biological plausibility, as the genetic variant associated with risk of stroke is flanking a gene involved in heart physiology."

But Innocenti explained that the study does not provide a mechanism for how this gene-flanking variant causes stroke, and said more molecular and experimental studies should be conducted to support the association, which remains only statistical at the present time.

"To move these results to the domain of clinical application, such a mechanistic link should be established," he said. "One can envision that by typing patients for this variant, clinicians could achieve a more informed decision as to the dose of radiation to be used, as the highest genetic risk was seen when higher doses of radiation were given to patients."

Adult survivors of childhood cancers have a well documented risk of treatment-related late adverse effects, including second cancers, cardiovascular complications, infertility, and others. Previous studies showed that long-term survivors of cancer are more likely to have a stroke as compared with their cancer-free siblings. Cranial radiation therapy, used to treat brain cancer or prevent brain metastasis, increases stroke risk in a dose-dependent manner.

St. Jude investigators established the SJLIFE retrospective cohort study to document long-term (≥5 years) outcomes of patients treated at the center. All long-term survivors have comprehensive evaluations of cardiac, reproductive, neurocognitive, neuromuscular, pulmonary, and psychological functioning. The database includes results of whole-genome sequencing for 4,500 SJLIFE participants.

Sapkota reported findings from a study involving 696 SJLIFE participants of European ancestry. The patients had a median age of 40.4, and 116 (17%) had a history of clinically diagnosed stroke.

Investigators performed an analysis of common genetic variants and identified an association between a variant on the gene 5p15.33 and cranial irradiation-associated stroke. Patients with the variant (rs112896372) had a risk for stroke 2.93 times greater than those patients without the variant (P=4.66 × 10^-8). Additional analyses showed that the variant had the strongest association with stroke in survivors who received cranial radiation doses of 25-50 Gy (OR 4.81, P=4.16 × 10^-4).

Briefing moderator William Nelson, MD, PhD, of Johns Hopkins University in Baltimore, said that to act on the study results, more information is needed about the mechanisms involved in the relationship between cranial irradiation and stroke. Beyond that, the field of radiation oncology has borrowed a page from diagnostic radiology and begun to examine radiomics, studies to determine exactly where the radiation dose was deposited. "As you begin to look at it that way, are there parts of the brain that are exquisitely vulnerable to this? In someone with this genetic defect you'd want to avoid or plan a different therapy approach."

Nelson also noted that multiple approaches have evolved in the use of radiation therapy in children, delivering more precisely targeted treatment to limit the potential for short- and long-term adverse effects.

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