Research identifies genomic risk factor associated with stroke in childhood cancer survivors

Research at St. Jude Children's Research Hospital has identified a genomic risk factor associated with stroke in childhood cancer survivors. The findings were announced today at a press conference as part of the American Association for Cancer Research annual meeting in Atlanta.

This investigation draws on whole genome sequencing and other data gathered longitudinally through the St. Jude Lifetime Cohort (SJLIFE) study. The purpose of SJLIFE is to learn about the health of adult survivors of childhood cancer and to reduce the late effects of childhood cancer treatments.

"Long-term survivors of childhood cancer are known to be at an increased risk of stroke, which is often attributed to their prior cancer treatment," said first author Yadav Sapkota, Ph.D., of the St. Jude Department of Epidemiology and Cancer Control. "But we observed variation in risk that suggested there may be an underlying genetic component."

To study the risk of stroke, Sapkota and his colleagues focused on 686 childhood cancer survivors in the cohort treated with cranial radiation therapy. Higher doses of radiation have been previously correlated with risk of stroke. However, the researchers wanted to understand why some patients treated with high doses do not experience a stroke, while other patients do even when they are treated at lower doses.

"This is one of the first studies to evaluate the genomic underpinnings of stroke in such a robust cohort," Sapkota said. "Ultimately our findings help determine who is at a greater risk so we can intervene on modifiable lifestyle and other factors that are known to affect the risk of stroke."

The genomic data generated through this research is freely available to researchers on the St. Jude Cloud platform, a data-sharing resource pioneered by St. Jude and available to the global research community. St. Jude Cloud is one of the world's largest repositories of pediatric genomics data and offers a suite of unique analysis tools and visualizations.

Key findings from the study include:

• In addition to the dose level of cranial radiation therapy that increases stroke risk up to 11 fold, variants on a chromosomal region called 5p15.33 increase risk approximately three-fold overall. This result suggests that testing for variants of 5p15.33 may be useful for identifying patients who, when treated with cranial radiation therapy, will be at a high risk of stroke as adults.
• This is the first study to link the chromosomal region with an increased risk of stroke. These variants in 5p15.33 are found to elevate stroke risk approximately five-fold among childhood cancer survivors treated with intermediate dose (25-50 Gray) of cranial radiation therapy. This suggests that among those treated with cranial radiation therapy, 5p15.33 may modify the effect of the treatment on stroke risk.
• The researchers replicated the finding in two independent groups of survivors from SJLIFE, consisting of survivors of African ancestry who received cranial radiation therapy and survivors of European descent who did not receive cranial radiation therapy. Results of the replication analysis suggest that a combination of cranial radiation therapy and genetic factors can greatly increase childhood cancer survivors' risk for developing stroke.

This research is included in a poster session to be held Wednesday, April 3, 2019, as part of the AACR meeting. Additionally, SJLIFE is one of the projects for which the St. Jude Survivorship Research Team was awarded the 2019 AACR Team Science Award. To date, through SJLIFE, more than 4,300 survivors and 580 control cases have undergone comprehensive evaluations of cardiac, reproductive, neuromuscular, neurocognitive and psychosocial functions.