Pharmacogenetics of microRNAs and microRNAs biogenesis machinery in pediatric acute lymphoblastic leukemia

PLoS One. 2014 Mar 10;9(3):e91261. doi: 10.1371/journal.pone.0091261. eCollection 2014.

Abstract

Despite the clinical success of acute lymphoblastic leukemia (ALL) therapy, toxicity is frequent. Therefore, it would be useful to identify predictors of adverse effects. In the last years, several studies have investigated the relationship between genetic variation and treatment-related toxicity. However, most of these studies are focused in coding regions. Nowadays, it is known that regions that do not codify proteins, such as microRNAs (miRNAs), may have an important regulatory function. MiRNAs can regulate the expression of genes affecting drug response. In fact, the expression of some of those miRNAs has been associated with drug response. Genetic variations affecting miRNAs can modify their function, which may lead to drug sensitivity. The aim of this study was to detect new toxicity markers in pediatric B-ALL, studying miRNA-related polymorphisms, which can affect miRNA levels and function. We analyzed 118 SNPs in pre-miRNAs and miRNA processing genes in association with toxicity in 152 pediatric B-ALL patients all treated with the same protocol (LAL/SHOP). Among the results found, we detected for the first time an association between rs639174 in DROSHA and vomits that remained statistically significant after FDR correction. DROSHA had been associated with alterations in miRNAs expression, which could affect genes involved in drug transport. This suggests that miRNA-related SNPs could be a useful tool for toxicity prediction in pediatric B-ALL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Child
  • Female
  • Genotyping Techniques
  • Humans
  • Linkage Disequilibrium / genetics
  • Male
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Pharmacogenetics
  • Polymorphism, Single Nucleotide / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • RNA Processing, Post-Transcriptional / genetics

Substances

  • MicroRNAs

Grants and funding

This project was supported by the Spanish Thematic Network for Cooperative Investigation in Cancer RTICC (RD/06/0020/0048), Basque Government (GIC10/71, SAI11/75), and University of the Basque Country UPV/EHU (UFI11/35 and GIU10/24). ELL was supported by a predoctoral grant from the Basque Government and by a “Fellowship for recent doctors until their integration in postdoctoral programs” by the Investigation Vice-rector's office of the University of the Basque Country UPV/EHU. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.