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

Purpose: To identify genetic factors associated with risk of stroke among survivors of childhood cancer treated with cranial radiotherapy (CRT).

Experimental design: 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.

Results: We identified a genome-wide significant association between 5p15.33 locus and stroke [rs112896372: HR = 2.55; P = 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; P = 0.034). In CRT-exposed Europeans, rs112896372 significantly (P < 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 (P = 0.047). SNP rs112896372 was further evaluated in three independent datasets including 1,641 European (HR = 1.54; P = 0.055) and 316 African survivors (HR = 1.88; P = 0.283) not treated with CRT, and 166,988 males in the UK Biobank (OR = 1.0012; P = 0.042).

Conclusions: 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.

Figure 1 |

Cumulative incidence curves among survivors in the St. Jude Lifetime Cohort European-descent discovery sample are shown, stratified by cranial radiation therapy doses including survivors exposed to >0–20 Gy (top left panel), 20–25 Gy (top right panel), 25–50 Gy (bottom left panel) and ≥50 Gy (bottom right panel). Cumulative incidence of stroke among survivors carrying at least one copy of the rs112896372’s effect allele (TC+CC) is shown as red and among survivors without the effect allele (TT) is shown as blue.

Figure 2 |

Receiver operating characteristic (ROC) curves showing the probabilities of stroke among childhood cancer survivors at 30 years since childhood cancer diagnosis in the St. Jude Lifetime Cohort European-descent discovery sample (left) and St. Jude Lifetime Cohort African-descent replication sample (right) exposed to cranial radiation therapy. Probability of stroke based on the clinical model including non-genetic risk factors alone is shown in blue and the probability of stroke based on both non–genetic risk factors and the lead SNP rs112896372 at the 5p15.33 locus is shown in red. Random permutations (1000-times) of the rs112896372’s genotype within each sample were conducted to calculate p-value (P_perm) as the proportion of the 1000 permuted datasets that were greater than the area under the ROC curve difference with and without the rs112896372 genotype from the observed dataset.