| Title: | 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 |
| Journal: | Clinical Cancer Research |
| Published: | 15 Nov 2019 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/31462438/ |
| DOI: | https://doi.org/10.1158/1078-0432.ccr-19-1231 |
| URL: | https://clincancerres.aacrjournals.org/content/clincanres/25/22/6700.full.pdf |
| Citations: | 20 (5 in last 2 years) as of 8 Aug 2024 |
Publication 6013
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Abstract
PURPOSE: To identify genetic factors associated with risk of stroke among survivors of childhood cancer treated with cranial radiotherapy (CRT).</p>
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.</p>
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).</p>
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.</p>
24 Keywords
- Adolescent
- Adult
- Alleles
- Cancer Survivors
- Child
- Chromosomes, Human, Pair 5
- Cranial Irradiation
- Disease Susceptibility
- Female
- Gene Frequency
- Genome-Wide Association Study
- Genotype
- Humans
- Male
- Middle Aged
- Neoplasms
- Polymorphism, Single Nucleotide
- Public Health Surveillance
- Quantitative Trait Loci
- ROC Curve
- Retrospective Studies
- Stroke
- Whole Genome Sequencing
- Young Adult
13 Authors
- Yadav Sapkota
- Yin Ting Cheung
- Wonjong Moon
- Kyla Shelton
- Carmen L. Wilson
- Zhaoming Wang
- Daniel A. Mulrooney
- Jinghui Zhang
- Gregory T. Armstrong
- Melissa M. Hudson
- Leslie L. Robison
- Kevin R. Krull
- Yutaka Yasui
Enabling scientific discoveries that improve human health