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Common Variant May Increase Stroke Risk Among Cranial Radiation-Treated Childhood Cancer Survivors

ATLANTA (GenomeWeb) – Childhood cancer survivors with a certain common genetic variant who were treated with cranial radiation therapy are at an increased risk of developing stroke, according to data presented at the American Association for Cancer Research annual meeting here.

In the US, cancer is a leading cause of disease-linked death among children who are 14 years old or younger, leading to about 1,190 deaths a year. But due to advances in treatment, there is an increasing number of childhood cancer survivors. According to Yadav Sapkota from St. Jude Children's Research Hospital, the current five-year survival rate of childhood cancer is now greater than 85 percent, as compared to the 20 percent to 30 percent survival rates observed in the 1960s.

"However, the cure comes with a cost," Sapkota said during a press briefing. "Because the cancer therapies can cause health problems."

While some of these health issues are short-term, as childhood cancer survivors age, most experience late effects of their earlier cancer treatments, such as secondary cancers, infertility, and stroke.

As part of the St. Jude Lifetime Cohort (SJLIFE) study, Sapkota and his colleagues are conducting a retrospective cohort study with prospective clinical follow up of childhood cancer survivors to tease out risk factors for these later effects of cancer treatment. These survivors are undergoing comprehensive clinical evaluations as well as whole-genome sequencing, with data currently available for 4,500 patients.

Long-term childhood cancer survivors have a roughly eightfold increased risk of stroke as compared to their siblings, Sapkota noted, adding that having undergone cranial radiation therapy (CRT) is a known risk factor. While there is a known dose-response relationship between CRT and stroke risk, variation in that association has further suggested risk could be influenced by genetic factors.

Through the SJLIFE cohort, the St. Jude team analyzed whole genomes of 686 childhood cancer survivors of European ancestry. The patients were a median 40.4 years old and all had been treated with CRT as children, mostly for leukemia or brain cancer. Additionally, 116, or 17 percent, of these patients developed clinically diagnosed stroke.

Sapkota and his colleagues uncovered a genome-wide significant association between a common variant at the 5p15.33 locus and CRT-associated stroke. This variant, located on chromosome 5 near the IRX1, LINC01019, and LINC01017 genes is common. Sapkota said it is present in about 18 percent of the general population.

Childhood cancer survivors with this allele had a nearly threefold increased risk of stroke compared to survivors who did not have the risk allele. Additionally, nearly half the survivors with stroke carried at least one copy of the risk allele.

They confirmed the association between this allele and stroke risk in a separate cohort of childhood cancer survivors treated with CRT of African ancestry.

Within the European ancestry cohort, the strength of the genetic association varied among the patients based on the dose of radiation they had received as children, he noted. Patients with the risk allele who received an intermediate dose of radiation — between 25 Grays and 50 Grays — exhibited strongest risk of stroke. These patients had a nearly fivefold increased risk of stroke.

At the same time, patients with the risk allele who received a low dose of less than 25 Gy had a 2.4-fold increase in stroke risk, while patients with the risk allele who received a high dose of radiation, more than 50 Gy, had a threefold increased risk of stroke, suggesting that at higher doses, radiation might have a greater influence n risk than genetics. Patients with the genetic variant, but not exposed to cranial radiation with the genetic variant, meanwhile, have a 1.5-fold increased risk of stroke.

This, Sapkota said, could help identify childhood cancer survivors at increased risk of stroke and help devise approaches to minimize their later risk.

He noted, though, that the study was small and that functional experiments are needed to tease out the link between the variant and stroke risk.

"I can imagine with the tools that the radiation oncologists have that this kind of information might drive them to do a different treatment plan," said William Nelson, the director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, who was not part of the work, during the briefing.

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