Genetic risk factors for VIPN in childhood acute lymphoblastic leukemia patients identified using whole-exome sequencing.

Aim: To identify genetic markers associated with vincristine-induced peripheral neuropathy (VIPN) in childhood acute lymphoblastic leukemia. Patients & methods: Whole-exome sequencing data were combined with exome-wide association study to identify predicted-functional germline variants associated with high-grade VIPN. Genotyping was then performed for top-ranked signals (n =237), followed by validation in independent replication group (n =405). Results: Minor alleles of rs2781377/SYNE2 (p=0.01) and rs10513762/MRPL47 (p=0.01) showed increased risk, whereas that of rs3803357/BAHD1 had a protective effect (p=0.007). Using a genetic model based on weighted genetic risk scores, an additive effect of combining these loci was observed (p=0.003). The addition of rs1135989/ACTG1 further enhanced model performance (p=0.0001). Conclusion: Variants in SYNE2, MRPL47 and BAHD1 genes are putative new risk factors for VIPN in childhood acute lymphoblastic leukemia.