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
Authors: Sapkota Yadav , Cheung Yin Ting , Moon Wonjong , Shelton Kyla , Wilson Carmen L. , Wang Zhaoming , Mulrooney Daniel A. , Zhang Jinghui , Armstrong Gregory T. , Hudson Melissa M. , Robison Leslie L. , Krull Kevin R. , Yasui Yutaka 
Published: August 2019

Abstract
Long-term survivors of childhood cancer are at increased risk of stroke, which is attributed to the well-established dose-response association with cranial radiation therapy (CRT) dose and risk. While radiation-induced vasculopathy is believed to be the likely mechanism underlying CRT-associated stroke, there is a variation in the dose-risk association, suggesting a potential contribution of genetic factors. We performed analyses of deep-coverage (36.8X) whole-genome sequencing data of 696 childhood cancer survivors of European descent [median (range): 40.4 (12.4-64.7) years old; 54% male] from the SJLIFE cohort treated with CRT, of whom 116 (17%) developed clinically-diagnosed stroke. Analyses of common variants [minor allele frequency (MAF)&gt;0.05] were performed using logistic regression, adjusting for age at cancer diagnosis, sex, age at follow-up, CRT dose and top principal components derived from genotypes. Rare/low-frequency variants (MAF≤0.05) were aggregated by different functional annotations and agnostic 4-kb sliding windows and tested jointly using Burden and SKAT Tests, adjusted for the same covariates. Results identified a genome-wide significant association between a common variant on 5p15.33 locus and CRT-associated stroke [rs112896372: MAFaffected=0.27; odds ratio (OR)=2.93; P=4.66×10-8]. Stratified analyses showed that rs112896372 had the strongest association (OR=4.81; P=4.16×10-4) among survivors treated with CRT dose 25-50 Gray (Gy); survivors treated with CRT dose &lt;25 Gy and those treated with CRT dose &gt;50 Gy had the weaker associations (OR=2.41; P=1.01×10-3, OR=3.01; P=4.91×10-3, respectively). We replicated the association between rs112896372 and stroke in two independent SJLIFE samples: (1) 20 with and 70 without stroke of African ancestry treated with CRT (MAFaffected=0.23; OR=6.47; P=8.99×10-3) and (2) 60 with and 1581 without stroke of European ancestry not treated with CRT (MAFaffected=0.25; OR=1.58; P=0.04). SNP rs112896372 maps to an intergenic region located approximately 155 kb downstream of IRX1 (iroquois homeobox 1), a member of IRX family of transcription factors with established roles in ventricular chamber, conducting system development and heterogeneity of ventricular repolarization. Overall, we identified and independently replicated a novel locus for CRT-associated stroke among survivors of childhood cancer, with a possible CRT dose-specific effect. Considering the large effect size and the relatively high MAF, the 5p15.33 locus may have potential clinical utility for identifying high-risk CRT exposed cancer survivors and guide intervention strategies.
Citation Format: 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. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4909.