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Gene variant linked to stroke risk in survivors of childhood cancer
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ATLANTA — A research team at St. Jude Children’s Research Hospital has identified a single nucleotide polymorphism that may increase risk for stroke among childhood cancer survivors treated with cranial radiation therapy, according to a report from the St. Jude Cohort Lifetime study presented at the American Association for Cancer Research Annual Meeting.
“Cancer is a leading cause of death by disease in children under the age of 14 [years] in the U.S.; in 2019 alone, there are an estimated 11,000 new cancer cases, and roughly 1,200 of these children will die of the disease,” Yadav Sapkota, PhD, clinical research scientist at St. Jude, said during a press conference. “Thanks to advances in treatment over the past few decades, more than 85% of children now survive 5 years or longer. However, the cure comes at a cost, because cancer therapies can cause health problems that may not resolve by themselves or may not even appear for years or several months after the cancer therapies.”
Survivors who undergo 30 Gy to 50 Gy of cranial radiation therapy have a six-fold increased risk for stroke, and those who received more than 50 Gy have an eleven-fold increased risk for stroke compared with survivors who do not undergo cranial radiation therapy.
“However, the stroke risk seems to vary within the same cranial radiation therapy dose group, even after accounting for other clinical and demographic factors,” Sapkota said in a press release. “This indicated to us that there may be genetic predisposition that influences a cranial radiation therapy-exposed survivor’s risk for developing stroke.”
To better understand whether there is an inherited genetic predisposition may contribute to this variation in risk, Sapkota and colleagues evaluated data from 686 long-term survivors (median age, 40.4 years; range, 12.4-64.7; 54% male) of the St. Jude Lifetime Cohort (SJLIFE) who underwent cranial radiation therapy. All long-term survivors in the cohort undergo thorough evaluations for cardiac, reproductive, neurocognitive, neuromuscular, pulmonary and psychological functions. Researchers have conducted whole-genome sequencing on 4,500 patients from SJLIFE, data from which are available publicly through the St. Jude Cloud.
In the retrospective study with prospective clinical follow-up, Sapkota and colleagues evaluated deep-coverage (36.8x) whole-genome sequencing data from the 686 survivors, 116 (17%) of whom experienced stroke.
The investigators identified a genome-wide significant association between a common variant on 5p15.44 locus and cranial radiation therapy-related stroke (rs11289632; minor allele frequency [MAF]affected = 0.27; OR = 2.93; P = 4.66 x 10-8).
Compared with survivors without the risk allele, those who carried it had an approximately three-fold increased risk for stroke, and 48% (n = 56) survivors with subsequent stroke had at least one copy of the risk allele.
A stratified analyses showed that rs112896371 had the strongest correlation in survivors who received a cranial radiation therapy dose of 25 Gy to 50 Gy (OR = 4.81; P = 4.16 x 10-4), whereas the association appeared weaker among patients whose treatment dose was less than 25 Gy (OR = 2.41; P = 1.01 x 10-3) or more than 50 Gy (OR =3.01; P = 4.91 x 10-3).
This correlation between rs112896372 and stroke was replicated in two other SJLIFE samples: patients of African ancestry treated with cranial radiation therapy, of whom 20 experienced stroke and 70 did not (MAFaffected = 0.23; OR =6.47; P = 8.99 x 10-3); and patients of European ancestry who were not treated with cranial radiation therapy, 60 of whom had a stroke and 1,581 of whom did not (MAFaffected = 0.25; OR = 1.58; P = .04).
“Results of the replication analysis suggest that a combination of cranial radiation therapy treatment and genetic factors can greatly increase childhood cancer survivors’ risk for developing stroke,” Sapkota said. “Survivors treated with cranial radiation therapy who carry this genetic variant can benefit from being monitored and counseled to minimize their modifiable cardiovascular risk factors.”
The authors acknowledged the study’s small sample size as a limitation.
“Given the small sample size of this study, we are looking forward to evaluating this association in additional cohorts of survivors of childhood cancer,” Sapkota said during the press conference. “We would also like to perform functional experiments to gain mechanistic insights underlying the association between this common variant and stroke risk.”– by Jennifer Byrne
Reference:
Sapkota Y, et al. Abstract 4909. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.
Disclosures: The study was sponsored by the NCI and American Lebanese Syrian Associated Charities, the fundraising and awareness organization of St. Jude Children’s Research Hospital. Sapkota and the other authors report no relevant disclosures.