Most significant associations between polymorphisms in biogenesis machinery and toxicity parameters.

<p>Ind: induction. Cons: consolidation.</p><p>p-corrected =  p-value after FDR correction.</p><p>N.S.: non-significant, p-value>0.05 after FDR correction.</p

Pharmacogenetics of MicroRNAs and MicroRNAs Biogenesis Machinery in Pediatric Acute Lymphoblastic Leukemia

<div><p>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 <i>DROSHA</i> and vomits that remained statistically significant after FDR correction. <i>DROSHA</i> 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.</p></div

Linkage disequilibrium plot of the SNPs analyzed in DROSHA.

<p>White: r2 = 0, shades of grey: 0</p

Genes involved in miRNA biogenesis and processing.

<p>Genes involved in miRNA biogenesis and processing.</p

Characteristics of the study population.

a<p>MTX levels were considered high if the concentration was over 0.2 µM at 72 h.</p

Most significant associations between polymorphisms in pre-miRNAs and toxicity parameters.

<p>Ind: induction. Cons: consolidation.</p><p>p-corrected = p-value after FDR correction.</p><p>N.S.: non-significant, p-value>0.05 after FDR correction.</p

Novel constitutive CNV detected in Wilms Tumor.

<p>Schematic representation of CNVs detected in both blood and tissue by aCGH. Duplications (blue bars): 2p21 including <i>SIX3</i>, 3p22.1 with <i>CTNNB1</i>, 4p16.3 with <i>FGFR3</i>, and 20q13.3 with <i>SALL4</i>. Deletion (red bar): 19q13.31 including <i>ZNF227</i>, <i>ZNF233</i> and <i>ZNF235</i>. All the alterations were also detected in matched tumor samples.</p