Unraveling Novel Genetic Determinants of Thiopurine Response Via TWAS.

Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Thiopurines such as 6-mercaptopurine (6MP) are essential in ALL maintenance therapy. However, dose-limiting toxicities can significantly disrupt treatment. While genetic variants in TPMT and NUDT15 are known to affect thiopurine response, many patients with normal function genotypes in these genes still experience adverse effects, suggesting that additional genes might be involved. We analyzed 663 pediatric ALL patients enrolled in the AALL03N1 trial to identify novel genetic determinants of 6MP sensitivity, focusing on individuals with normal function TPMT and NUDT15 genotypes. A transcriptome-wide association study (TWAS) was conducted to focus on expression quantitative trait loci (eQTLs). Findings were validated in two independent cohorts: St. Jude Total Therapy XV (n = 390) and XVI (n = 552). TWAS identified 31 genes associated with 6MP dose intensity (q-value < 0.90). Of these, the imputed GNAQ expression was positively correlated with 6MP dose intensity and passed multiple testing thresholds in the validation cohorts. The rs60561071 variant, the eQTL in the GNAQ TWAS model, was associated with reduced gene expression and lower 6MP dose intensity. This study identifies GNAQ as a novel gene associated with thiopurine tolerance in ALL patients lacking known risk alleles in TPMT and NUDT15. Moreover, this research highlighted the innovative use of TWAS, providing deeper insights into the molecular mechanisms that explain drug response variability.