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Despite remarkable improvements in survival of childhood acute lymphoblastic leukemia (ALL), nonresponding or relapsing patients still represent one of the most frequent causes of death by disease in children. Accurate patient risk stratification based on genetic markers could increases survival rates. miRNAs can represent novel candidates with diagnostic, predictive and prognostic potential; however, many groups investigated their involvement with contradictory results. Aim: To clarify the role of miRNAs as biomarkers through a systematic review. Results: From a revision of 45 manuscripts, we found that miR-128 and miR-181 overexpression could represent markers for ALL diagnosis and underexpression of miR-708 and miR-99a could be markers for bad prognosis. Conclusion: These signatures could refine classification and risk stratification of patients and improve ALL outcome.

Late-onset Alzheimer's disease (LOAD) is a high-occurrence neurological disorder but the difficulty in identifying precise and early biomarkers has complicated the understanding of the disease and the development of new treatments. In this sense, important knowledge is emerging regarding novel molecular and biological candidates with diagnostic potential, including microRNAs (miRNAs), which have a key role in gene repression. The aim of this systematic review was to define the role of miRNAs' expression as biomarkers for LOAD both in brain tissues, which could help understand the biology of the disease, and circulating tissues, which could serve as non-invasive markers of the pathology. A systematic search was performed in Web of Science and PubMed using the keywords ((Alzheimer or Alzheimer's) and (microRNA or microRNAs or miRNA or miRNAs or miR)) until August 2018 to retrieve all articles that presented independent original data evaluating the impact of miRNA expression on the development of LOAD in human population. A total of 90 studies investigating the role of miRNAs' expression in the development of LOAD were identified. While other widely studied miRNAs such as hsa-miR-146a presented contradictory results among studies, deregulation in brain tissue of seven miRNAs, hsa-miR-16-5p, hsa-miR-34a-5p, hsa-miR-107, hsa-miR-125-5p, hsa-miR-132-3p, hsa-miR-181-3p, and hsa-miR-212-3p, was consistently identified in LOAD patients. Their role in the disease could be mediated through the regulation of key pathways, such as axon guidance, longevity, insulin, and MAPK signaling pathway. However, regarding their role as non-invasive biomarkers of LOAD in fluids, although the limited results available are promising, further studies are required.

Vincristine is an important drug of acute lymphoblastic leukemia (ALL) treatment protocols that can cause neurotoxicity. Patients treated with LAL/SHOP protocols often suffer from vincristine-related neurotoxicity in early phases of treatment. A genetic variant in CEP72, a gene involved in vincristine pharmacodynamics, was recently associated with neurotoxicity after prolonged vincristine treatment. This association was not replicated in our Spanish population during induction phase. To test the possibility that other variants in genes involved in vincristine pharmacodynamics were associated with vincristine neuropathy in early phases of the treatment, we evaluated the correlation with toxicity of 24 polymorphisms in 9 key genes in a large cohort of 152 Spanish children with B-ALL homogeneously treated. Results showed no association between any genetic variant in the TUBB1, TUBB2A, TUBB2B, TUBB3, TUBB4, MAPT, MIR146a, MIR202, and MIR411 genes and vincristine-related neurotoxicity. These results are in line with the hypothesis that there are different mechanisms causing pheripheral neurotoxicity after prolonged and short-term vincristine treatments.

Aim: Mucositis, linked to methotrexate, daunorubicin or cyclophosphamide, is a frequent childhood acute lymphoblastic leukemia (ALL) therapy side effect. miRNAs regulate the expression of pharmacokinetic/pharmacodynamic pathway genes. SNPs in miRNAs could affect their levels or function, and affect their pharmacokinetic/pharmacodynamic pathway target genes. Our aim was to determine the association between miRNA genetic variants targeting mucositis-related genes and mucositis-developing risk. Patients & methods: We analyzed 160 SNPs in 179 Spanish children with B-cell precursor ALL homogeneously treated with LAL/SHOP protocols. Results: We identified three SNPs in miR-4268, miR-4751 and miR-3117 associated with mucositis, diarrhea and vomiting, respectively. Conclusion: The effect of these SNPs on genes related to drug pharmacokinetics/pharmacodynamics could explain mucositis, diarrhea and vomiting development during ALL therapy.

The development of the human brain starts in the first weeks of embryo differentiation. However, there are many relevant neurodevelopmental processes that take place after birth and during lifespan. Such a fine and changing scenario requires the coordinated expression of thousands of genes to achieve the proper specialization and inter-connectivity. In this context, microRNAs (miRNAs), which can modulate mRNA stability and translation, are gaining recognition for their involvement in both brain development and neurodevelopmental disorders. Therefore, cerebrospinal fluid (CSF) miRNAs should be perfectly differentiated in relevant age periods. In this study, we aimed to highlight the biological variability of miRNA expression in the CSF throughout life, which is also crucial for biomarker discovery in CNS pathologies, especially in children, where they are desperately needed. We analyzed the CSF microRNAome of 14 healthy children (aged 0-7.4 years) by smallRNA-Seq and compared it with previously published data in adults (N = 7) and elders (N = 11). miR-423-5p and miR-22-3p were overexpressed in the 1 and 3 years groups, respectively. Additionally, we detected 18 miRNAs that reached their highest peak of expression at different time-points during the lifespan and sets of miRNAs that were exclusively expressed in a specific age group. On the contrary, miR-191-5p showed stable expression in CSF from the first year of life. Our results remark the complex differential miRNA expression profile that can be observed through life, which underlines the need for including appropriate age-matched controls when the expression of CSF miRNAs is analyzed in different pathological contexts. Graphical abstract.

Association studies in osteosarcoma risk found significant results in intergenic regions, suggesting that regions which do not codify for proteins could play an important role. The deregulation of microRNAs (miRNAs) has been already associated with osteosarcoma. Consequently, genetic variants affecting miRNA function could be associated with risk. This study aimed to evaluate the involvement of all genetic variants in pre-miRNAs described so far in relationship to the risk of osteosarcoma. We analyzed a total of 213 genetic variants in 206 pre-miRNAs in two cohorts of osteosarcoma patients (n = 100) and their corresponding controls (n = 256) from Spanish and Slovenian populations, using Goldengate Veracode technology (Illumina). Four polymorphisms in pre-miRNAs at 14q32 miRNA cluster were associated with osteosarcoma risk in the Spanish population (rs12894467, rs61992671, rs58834075 and rs12879262). Pathway enrichment analysis including target genes of these miRNAs pointed out the WNT signaling pathways overrepresented. Moreover, different single nucleotide polymorphism (SNP) effects between the two populations included were observed, suggesting the existence of population differences. In conclusion, 14q32 miRNA cluster seems to be a hotspot for osteosarcoma susceptibility in the Spanish population, but not in the Slovenian, which supports the idea of the existence of population differences in developing this disease. Special thanks to Slovenian Osteosarcoma Study Group for their collaboration in sample collection. The "Slovenian Osteosarcoma Study Group" is conformed by Katja Goricar from the Institute of Biochemistry, Faculty of Medicine of Ljubljana, Viljem Kovac from the Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine of University of Ljubljana, Janez Jazbec from the Institute of Oncology Ljubljana, Janez Lamovec from the Oncology and Hematology Unit, University Children's Hospital, University Medical Centre of Ljubljana and Prof. Vita Dolzan included in the authorship of this article. The authors would like to thank Leire Iparraguirre for her technical assistance with figures. This study was funded by the Basque Government (IT661-13, IT989-16), UPV/EHU (UFI11/35).

Late-onset Alzheimer's disease (LOAD) is a neurodegenerative disorder of growing relevance in an aging society for which predictive biomarkers are needed. Many genes involved in LOAD are tightly controlled by microRNAs (miRNAs), which can be modulated by single-nucleotide polymorphisms (SNPs). Our aim was to determine the association between SNPs in miRNAs and LOAD. We selected all SNPs in pre-miRNAs with a minor allele frequency (MAF) > 1% and genotyped them in a cohort of 229 individuals diagnosed with LOAD and 237 unrelated healthy controls. In silico analyses were performed to predict the effect of SNPs on miRNA stability and detect downstream pathways. Four SNPs were associated with LOAD risk with a p value < 0.01 (rs74704964 in hsa-miR-518d, rs71363366 in hsa-miR-1283-2, rs11983381 in hsa-miR-4653, and rs10934682 in hsa-miR-544b). In silico analyses support a possible functional effect of those SNPs in miRNA levels and in the regulation of pathways of relevance for the development of LOAD. Although the results are promising, additional studies are needed to validate the association between SNPs in miRNAs and the risk of developing LOAD. Graphical abstract.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Numerous studies have shown that microRNAs (miRNAs) could play a role in this disease. Nowadays, more than 2500 miRNAs have been described, that regulate more than 50% of genes, including those involved in B-cell maturation, differentiation and proliferation. Genetic variants in miRNAs can alter their own levels or function, affecting their target gene expression, and then, may affect ALL risk. Therefore, the aim of this study was to determine the role of miRNA genetic variants in B-ALL susceptibility. We analyzed all variants in pre-miRNAs (MAF > 1%) in two independent cohorts from Spain and Slovenia and inferred their functional effect by in silico analysis. SNPs rs12402181 in miR-3117 and rs62571442 in miR-3689d2 were associated with ALL risk in both cohorts, possibly through their effect on MAPK signalling pathway. These SNPs could be novel markers for ALL susceptibility.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous malignancy, with highly variable outcomes among patients. Although classification and prognostic tools have been developed, standard therapy still fails in 30-40% of patients. Hence, identification of novel biomarkers is needed. Recently, circulating microRNAs (miRNAs) have been suggested as non-invasive biomarkers in cancer. Our aim was to review the potential role of circulating miRNAs as biomarkers for diagnosis, classification, prognosis, and treatment response in DLBCL. We performed a search in PubMed using the terms [(('Non-coding RNA') OR ('microRNA' OR 'miRNA' OR 'miR') OR ('exosome') OR ('extracellular vesicle') OR ('secretome')) AND ('Diffuse large B cell lymphoma' OR 'DLBCL')] to identify articles that evaluated the impact of circulating miRNAs as diagnosis, subtype, treatment response or prognosis biomarkers in DLBCL in human population. Among the twelve articles that met the inclusion criteria, eleven considered circulating miRNAs as biomarkers for diagnosis, two for classification, and five for prognosis or treatment response. The limited number of studies performed and lack of consistency in results make it difficult to draw conclusions about the role of circulating miRNAs as non-invasive biomarkers in DLBCL. Although the preliminary associations observed seem promising, the only consistent result is the upregulation of mir-21 in DLBCL patients, which could be a biomarker for diagnosis. Further studies are needed.

Aim: Hepatotoxicity is one of the most common drug-related toxicities during the treatment of childhood acute lymphoblastic leukemia (ALL). Many genes involved in liver-specific signaling pathways are tightly controlled by miRNAs, and miRNA function could be modulated by SNPs. As a consequence, we hypothesized that variants in miRNAs could be associated with drug-induced hepatotoxicity. Methods: We analyzed 213 SNPs in 206 miRNAs in a cohort of 179 children with ALL homogeneously treated. Results: rs2648841 in miR-1208 was the most significant SNP during consolidation phase after false discovery rate correction, probably through an effect on its target genes DHFR, MTR and MTHFR. Conclusion: These results point out the possible involvement of SNPs in miRNAs in toxicity to chemotherapy in children with ALL.

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.