Gutierrez-Camino Ángela, Umerez Maitane, Martin-Guerrero Idoia, García de Andoin Nagore, Santos Borja, Sastre Ana, Echebarria-Barona Aizpea, Astigarraga Itziar, Navajas Aurora, Garcia-Orad Africa
Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, UPV/EHU, Leioa, Spain.
Department of Pediatrics, University Hospital Donostia, San Sebastian, Spain.
Pharmacogenomics J. 2018 Dec;18(6):704-712. doi: 10.1038/s41397-017-0003-3. Epub 2017 Dec 27.
Vincristine (VCR), an important component of childhood acute lymphoblastic leukemia (ALL) therapy, can cause sensory and motor neurotoxicity. This neurotoxicity could lead to dose reduction or treatment discontinuation, which could in turn reduce survival. In this line, several studies associated peripheral neurotoxicity and polymorphisms in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) of VCR. Nowadays, it is well known that these genes are regulated by microRNAs (miRNAs) and SNPs in miRNAs could modify their levels or function. Therefore, the aim of this study was to determine whether SNPs in miRNAs could be associated with VCR-induced neurotoxicity. To achieve this aim, we analyzed all the SNPs in miRNAs (minor allele frequency (MAF) ≥ 0.01) which could regulate VCR-related genes in a large cohort of Spanish children with B-cell precursor ALL (B-ALL) homogeneously treated with LAL/SHOP protocols. We identified the A allele of rs12402181 in the seed region of miR-3117-3p, that could affect the binding with ABCC1 and RALBP1 gene, and C allele of rs7896283 in pre-mature sequence of miR-4481, which could be involved in peripheral nerve regeneration, significantly associated with VCR-induced neurotoxicity. These findings point out the possible involvement of two SNPs in miRNA associated with VCR-related neurotoxicity.
长春新碱（VCR）是儿童急性淋巴细胞白血病（ALL）治疗的重要组成部分，可导致感觉和运动神经毒性。这种神经毒性可能导致剂量减少或治疗中断，进而降低生存率。在这方面，多项研究将外周神经毒性与VCR药代动力学（PK）和药效学（PD）相关基因的多态性联系起来。如今，众所周知，这些基因受微小RNA（miRNA）调控，miRNA中的单核苷酸多态性（SNP）可能会改变其水平或功能。因此，本研究的目的是确定miRNA中的SNP是否与VCR诱导的神经毒性相关。为实现这一目标，我们分析了miRNA中所有可能调控VCR相关基因的SNP（次要等位基因频率（MAF）≥0.01），这些SNP来自一大群接受LAL/SHOP方案均匀治疗的西班牙B细胞前体ALL（B-ALL）儿童。我们在miR-3117-3p的种子区域中鉴定出rs12402181的A等位基因，其可能影响与ABCC1和RALBP1基因的结合，以及在miR-4481的前体序列中的rs7896283的C等位基因，其可能参与周围神经再生，与VCR诱导的神经毒性显著相关。这些发现指出了两个与VCR相关神经毒性相关的miRNA中的SNP可能参与其中。
