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 Study.

Abstract

To identify genetic factors associated with risk of stroke among survivors of childhood cancer treated with cranial radiotherapy (CRT). We analyzed whole-genome sequencing (36.8-fold) data of 686 childhood cancer survivors of European ancestry [median (range), 40.4 (12.4-64.7) years old; 54% male] from the St. Jude Lifetime Cohort study treated with CRT, of whom 116 (17%) had clinically diagnosed stroke. Association analyses (single-variant and Burden/SKAT tests) were performed, adjusting for demographic characteristics and childhood cancer treatment exposures. We identified a genome-wide significant association between 5p15.33 locus and stroke [rs112896372: HR = 2.55; <i>P</i> = 1.42 × 10^-8], with a stronger association (HR = 3.68) among survivors treated with CRT dose 25-50 Gray (Gy) and weaker associations among those treated with CRT doses <20 or 20-25 or >50 Gy (HRs = 2.14, 2.40, and 2.28). The association was replicated in 90 CRT-exposed African survivors (HR = 3.05; <i>P</i> = 0.034). In CRT-exposed Europeans, rs112896372 significantly (<i>P</i> < 0.001) improved predictive ability (AUC = 0.717) for determining stroke risk than nongenetic factors alone (AUC = 0.663) at 30 years since diagnosis, with significant improvement among African survivors (<i>P</i> = 0.047). SNP rs112896372 was further evaluated in three independent datasets including 1,641 European (HR = 1.54; <i>P</i> = 0.055) and 316 African survivors (HR = 1.88; <i>P</i> = 0.283) not treated with CRT, and 166,988 males in the UK Biobank (OR = 1.0012; <i>P</i> = 0.042). A novel locus 5p15.33 is associated with stroke risk among childhood cancer survivors, with a possible CRT dose-specific effect. The locus is of potential clinical utility in characterizing individuals who may benefit from surveillance and intervention strategies.