Methotrexate (MTX) is an effective and toxic chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia(ALL). In this prospective study, we aimed to identify metabolic and genetic determinants of MTX toxicity. One hundred and thirty-four Dutch pediatric ALL patients were treated with four high infusions MTX (HD-MTX: 5 g m(-2)) every other week according to the DCOG-ALL-10 protocol. Mucositis (National Cancer Institute grade ⩾ 3) was the most frequent occurring toxicity during the HD-MTX phase (20%) and occurred especially after the first MTX course. Mucositis was not associated with plasma MTX, plasma folate or plasma homocysteine levels. Patients with mucositis had higher erythrocyte folate levels at the start of protocol M than patients without mucositis (median 1.4 vs 1.2 μmol l(-1), P<0.008), this could reflect an increased MTX uptake in mucosal cells of patients with mucositis. From 17 single-nucleotide polymorphisms in the MTX pathway, only patients with the wild-type variant of rs7317112 SNP in the ABCC4 gene had more mucositis (AA (39%) vs AG/GG (15%), P=0.016). We found no evidence that erythrocyte folate levels mediate in the association between the rs7317112 and mucositis.

Polymorphisms in ABCC2 could be novel markers for vincristine-related neurotoxicity in pediatric ALL in early phases.

Vincristine is a component of acute lymphoblastic leukemia (ALL) treatment with the potential to induce peripheral neuropathy. Recently, the CEP72 rs924607 TT genotype was found to be associated with vincristine-induced toxicity during the continuation phase in pediatric ALL patients treated on the Total XIIIB and COG AALL0433 protocols at St Jude Children's Research Hospital and Children's Oncology Group. This finding could provide a base for safer dosing of vincristine. Nevertheless, there are variations in vincristine regimens among ALL treatment protocols and phases in different populations. Therefore, the aim of this study was to determine whether the CEP72 rs924607 TT genotype is a useful marker of vincristine neuropathy during induction therapy among Spanish children with B-ALL treated on the LAL-SHOP protocols. No association was found between neurotoxicity during the induction phase and the rs924607 TT genotype. This lack of association could be because of population differences and/or differences in neurotoxicity etiology between induction and continuation phases of treatment.

Background: Evidence for an inherited genetic risk for pediatric acute lymphoblastic leukemia has been provided in several studies. Most of them focused on coding regions. However, those regions represent only 1.5% of the entire genome. In acute lymphoblastic leukemia (ALL), it has been suggested that the expression of microRNAs (miRNAs) is dysregulated, which suggests that they may have a role in ALL risk. Changes in miRNA function may occur through single-nucleotide polymorphisms (SNPs). Therefore, the aim of this study was to evaluate whether polymorphisms in premiRNAs, and/or miRNA-processing genes, contribute to a predisposition for childhood ALL. Methods: In this study, we analyzed 118 SNPs in pre-miRNAs and miRNA-processing genes in 213 B-cell ALL patients and 387 controls. results: We found 11 SNPs significantly associated with ALL susceptibility. These included three SNPs present in miRNA genes (miR-612, miR-499, and miR-449b) and eight SNPs present in six miRNA biogenesis pathway genes (TNRC6B, DROSHA, DGCR8, EIF2C1, CNOT1, and CNOT6). Among the 118 SNPs analyzed, rs12803915 in mir-612 and rs3746444 in mir-499 exhibited a more significant association, with a P value <0.01. conclusion: The results of this study indicate that SNP rs12803915 located in pre-mir-612, and SNP rs3746444 located in pre-mir-499, may represent novel markers of B-cell ALL susceptibility. a cute lymphoblastic leukemia (ALL) is the most common pediatric hematological malignancy in developed countries. Its etiology is believed to be multifactorial, with both environmental and genetic risk factors being relevant (1). Recently, several studies have provided evidence for an inherited genetic risk for pediatric ALL (2,3). Most of these studies focused on the coding regions of these genetic components. However, this represents only ~1.5% of the entire genome, and noncoding regions of the genome have also been shown to mediate regulatory functions. For example, microRNAs (miRNAs) are a class of small noncoding RNA molecules that regulate gene expression at the posttranscriptional level by binding to the 3′ untranslated region of a target gene (4). This can lead to an inhibition of translation or enhanced degradation of a target mRNA (Figure 1). Primary double-stranded miRNA transcripts (pri-miRNA) are processed in the nucleus by microprocessor machinery, which includes DROSHA RNase and the double-stranded RNA-binding protein, DGCR8. A hairpin precursor miRNA molecule of 70-100 nucleotides (pre-miRNA) is then produced, and its translocation into the cytoplasm is facilitated by RAN GTPase and Exportin 5 (XPO5). In the cytoplasm, pre-miRNAs are further processed by a protein complex that includes DICER1, TRBP, EIF2C1, EIF2C2, GEMIN3, and GEMIN4, resulting in the production of mature miRNAs (4). It has been predicted that there are more than 1,000 miRNA genes in the human genome (5), and ~30% of human genes are regulated by miRNAs.In the past few years, it was suggested that miRNAs in ALL are dysregulated. For example, in the study of Zhang ...

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.

Methotrexate (MTX) is an important component in the therapy used to treat childhood acute lymphoblastic leukemia (ALL). Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme for MTX pharmacokinetics. Two single-nucleotide polymorphisms in MTHFR gene, C677T and A1298C, affecting MTHFR activity, have been widely studied as potential markers of MTX toxicity and/or outcome in pediatric ALL. In this review, we show that the majority of published reports do not find association or present opposite effect. Therefore, MTHFR C677T and A1298C polymorphisms do not seem to be good markers of MTX-related toxicity and/or outcome in pediatric ALL. The efforts should be focused on other genes, such as transporter genes or microRNA-related genes.

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.

Acute lymphoblastic leukemia (ALL) is the major pediatric cancer in developed countries. Although treatment outcome has improved owing to advances in chemotherapy, there is still a group of patients for which therapy fails while some patients experience severe toxicity. In the last few years, several pharmacogenetic studies have been performed to search for markers of outcome and toxicity in pediatric ALL. However, to date, TPMT is the only pharmacogenetic marker in ALL with clinical guidelines for drug dosing. In this article, we will provide an overview of the most important findings carried out in pharmacogenetics for pediatric ALL, such as the interest drawn by methotrexate transporters in the context of methotrexate treatment. Even if most of the studies are centered on coding genes, we will also point to new approaches focusing on noncoding regions and epigenetic variation that could be interesting for consideration in the near future.