Adolescents with acute lymphoblastic leukemia (ALL) who experienced thromboembolism (TE) had a genetic predisposition for TE, according to the results of a study published in Thrombosis Research.
Given that TE is a common side effect of ALL treatment, a team of investigators assessed whether TE in ALL and TE in the general adult population have a shared genetic basis. They prospectively documented TE events and collected DNA from patients in the Nordic Society of Pediatric Hematology and Oncology ALL2008 study, which took place between July 2008 and July 2016. Genetic variant profiling of DNA from this cohort was conducted on coding regions of the genome using exome arrays.
They then obtained summary statistics from 2 genome-wide association studies (GWAS) on venous TE (VTE) in adults: the International Network of Venous Thromboembolism Clinical Research Networks (INVENT) consortium GWAS and the UK Biobank GWAS. They initially used only genetic variants that were significantly associated with VTE to build a polygenic risk score (PRS) based on either GWAS and then relaxed the significance threshold to include additional genetic loci that may contribute to smaller genetic effects.
Of 1252 patients with ALL (age range, 1.0-45.9 years), 89 developed TE; the 2.5-year cumulative incidence was 7.2%. Analyses of the whole cohort revealed that the polygenic risk scores, comprising genome-wide significant single nucleotide polymorphisms (SNPs) from either GWAS, were not significantly associated with TE. Similarly, when the significance threshold for SNP inclusion in the polygenic risk scores was relaxed, the scores were not significantly associated with TE in this cohort.
However, subgroup analysis of the 231 adolescents (age range, 10.0–17.9 years) found a significant association between the polygenic risk score using data from the INVENT GWAS and TE, indicating polygenic overlap. The best fit polygenic risk score that was associated with TE included 16,144 SNPs from the INVENT GWAS (hazard ratio, 1.76; 95% CI, 1.23-2.52; empirical P =.02).
Limitations of the study included a limited number of SNPs rendering the study underpowered to test the polygenic risk scores with significance thresholds up to 1.0 or to test for a polygenic risk score-age interaction. The authors also noted that consent to participate in the genetic portion of the study was delayed in some cases, and some early deaths may not have been included.
“We found evidence of polygenic overlap in subgroup analysis of adolescents aged 10.0–17.9 years with ALL, and we believe the genetics of TE in this group should be further explored in future risk prediction models for identification of those who might benefit from thromboprophylaxis,” the authors concluded.
Jarvis KB, Nielsen RL, Gupta R, et al. Polygenic risk score-analysis of thromboembolism in patients with acute lymphoblastic leukemia. Thromb Res. 2020;196:140244. doi:10.1016/j.thromres.2020.08.015