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

Pharmacogenomics. 2018 Oct;19(15):1181-1193. doi: 10.2217/pgs-2018-0093. Epub 2018 Sep 7.

Abstract

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.

Keywords: acute lymphoblastic leukemia; adverse drug reactions; association study; cancer; genetics; pharmacogenetics; polymorphism; vincristine-induced peripheral neuropathy; whole-exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Child
  • Exome
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation / genetics*
  • Genotype
  • Humans
  • Male
  • Peripheral Nervous System Diseases / chemically induced*
  • Peripheral Nervous System Diseases / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Risk Factors
  • Vincristine / adverse effects*
  • Whole Exome Sequencing / methods

Substances

  • Vincristine

Grant support