Abstract 4909: Whole-genome sequencing of childhood cancer survivors treated with cranial radiation therapy identifies 5p15.33 locus for stroke: A report from the St. Jude Lifetime Cohort (SJLIFE) study

1516 Background: Survivors of childhood cancer are at increased risk of treatment-related cardiomyopathy, found to be modified by genetic factors. To further investigate genetic risks of cardiomyopathy, we utilized whole-genome sequencing (WGS) in a clinically phenotyped cohort of long-term survivors of pediatric cancer. Methods: Utilizing a novel 2-stage analytic approach, we first performed association analysis for ejection fraction (EF) using WGS data in European-descent childhood cancer survivors from the St. Jude Lifetime Cohort (SJLIFE). EF was analyzed as a continuous variable to increase statistical power for genetic discovery. Common variants (minor allele frequency (MAF) > 0.05) were analyzed using linear regression, adjusting for age at diagnosis, sex, age at follow-up, doses of anthracycline and average radiation dose to the heart, and eigenvectors. Rare/low-frequency variants were aggregated by different functional annotations and agnostic 4-kb sliding windows, testing jointly using Burden/SKAT test. In the second stage, only the variant showing genome-wide significance with EF was tested for its association with cardiomyopathy risk. Results: Among the 2,015 SJLIFE survivors with WGS data, a locus on 6p21.2 near KCNK17achieved genome-wide significance with EF (rs2815063; MAF = 0.13; per allele beta = -0.016; P = 2.10´10-8), which replicated in 320 SJLIFE African survivors (MAF = 0.48; beta = -0.015; P = 0.004). In SJLIFE Europeans, 282 had a CTCAE Grade 2-5 cardiomyopathy. rs2815063 was significantly associated with increased risk of cardiomyopathy [per allele odds ratio (OR) = 1.38; P = 0.02], which replicated in 3,957 European survivors from the Childhood Cancer Survivor Study (163 CTCAE Grade 3-5 self-reported cases; per allele OR = 1.39; P = 0.038). rs2815063 alters DNA binding motif of EWSR1-FLI1, whose expression was found to lead to cardiomyopathy and death due to chronic cardiac failure in mice. Conclusions: Using a 2-stage approach, we report a novel locus for cardiomyopathy in childhood cancer survivors, which warrants additional work to gain mechanistic insights.

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Abstract 9: Risk of Stroke and Stroke Recurrence in Pediatric Cancer Survivors treated with Cranial Radiation Therapy

Stroke ◽

10.1161/str.43.suppl_1.a9 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Sabine Mueller ◽

Katherine Sear ◽

Nancy K Hills ◽

Nassim Chettout ◽

Shervin Afghani ◽

...

Keyword(s):

Radiation Therapy ◽

Cancer Survivors ◽

Childhood Cancer ◽

Cumulative Incidence ◽

Recurrent Stroke ◽

Dose Range ◽

Childhood Cancer Survivors ◽

Dose Effect ◽

Stroke Recurrence ◽

Cranial Radiation

Background: Among childhood cancer survivors, cranial radiation therapy (CRT) increases risk of self-reported first-stroke; there are no published estimates of recurrent stroke. Objective: To assess rates and predictors of first and recurrent stroke in childhood cancer survivors treated with CRT. Methods: In a retrospective cohort study of all children who received CRT at one institution,1980-2009, we performed chart abstraction (n=321) and phone interviews (n=101) to measure first and recurrent stroke; we confirmed stroke through imaging review. Incidence of first-stroke was calculated as the number of first strokes per person-years of observation after radiation. We used survival analysis techniques to determine the cumulative incidence of first stroke after radiation, and recurrent stroke after first stroke; we used Cox proportional hazards models to examine potential predictors of first stroke. Results: Median age of children at the time of CRT treatment was 8 years (IQR 4-13 years). A total of 17 first-strokes (12 ischemic, 2 hemorrhagic, 3 unknown sub-type) were identified at a median age of 25 years (IQR 17-34 years): 6 from chart review, 8 from interview, 3 from both. Imaging was available in 12 cases and consistent with stroke in all. The overall rate of first-stroke was 594 (95% CI 346 - 949) per 100,000 person-years. The risk of stroke persists for decades after treatment (see Figure ). Males had a 4-fold hazard of first stroke compared to females (95% CI 1.1 - 14; P =0.034). Race and treatment with chemotherapy did not affect the stroke risk; dose effect of CRT could not be assessed due to a narrow dose range in our cohort. There were 5 recurrent strokes (2 ischemic, 2 hemorrhagic, 1 unknown) at a median of 6 months after first stroke (range 5.6 months to 8.9 years); brain imaging was available in 4 cases and consistent with stroke in all. The cumulative incidence of recurrent stroke was 21% (95% CI 7.5-53) at 1 year post first-stroke, 29% (95% CI 12-61) at 5 years, and 43% (95% CI 19-78) at 10 years. Conclusion: Survivors of childhood cancer who received CRT are at high risk for first and recurrent stroke. Larger studies are needed to identify predictors of recurrence to design secondary stroke prevention strategies.

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