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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).

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.

Five-year survival rates of pediatric acute lymphoblastic leukemia (ALL) have reached 90% in the developed countries. However, toxicity because of methotrexate (MTX) occurs frequently. Variety in the occurrence of toxicity is partly determined by single nucleotide polymorphisms (SNPs) in coding regions. Recently, five SNPs in non-coding pre-microRNAs and microRNA processing (miRNA) genes were identified in association with MTX-induced oral mucositis. This study aimed to replicate the association of these miRNA variants in relation to MTX-induced oral mucositis in a prospective childhood ALL cohort. Three out of five SNPs with a minor allele frequency more than 0.15 [CCR4-NOT transcription complex (CNOT4) rs3812265, miR-1206 rs2114358, miR-2053 rs10505168] were analyzed in 117 pediatric ALL patients treated with 5 g/m 2 MTX (DCOG ALL-10). Oral mucositis was defined as grade more than or equal to 3 according to the National Cancer Institute criteria. rs2114358 in miR-1206 was associated with oral mucositis [odds ratio (OR): 3.6; 95% confidence interval (CI): 1.1-11.5], whereas we did not confirm the association of CNOT4 rs3812265 (OR: 0.69; 95% CI: 0.27-1.80) and miR-2053 rs10505168 (OR: 2.50; 95% CI: 0.76-8.24). Our results replicate the association between rs2114358 in miR-1206 and MTX-induced oral mucositis in childhood ALL. Genetic variation in miR-1206 has potential as a novel biomarker to predict MTX-induced toxicity.

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of invasive non-Hodgkin's lymphoma (NHL). DLBCL presents with variable backgrounds, which results in heterogeneous outcomes among patients. Although new tools have been developed for the classification and management of patients, 40% of them still have primary refractory disease or relapse. In addition, multiple factors regarding the pathogenesis of this disease remain unclear and identification of novel biomarkers is needed. In this context, recent investigations point to microRNAs as useful biomarkers in cancer. The aim of this systematic review was to provide new insight into the role of miRNAs in the diagnosis, classification, treatment response and prognosis of DLBCL patients. We used the following terms in PubMed" (('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 search for studies evaluating miRNAs as a diagnosis, subtype, treatment response or prognosis biomarkers in primary DLBCL in human patient populations. As a result, the analysis was restricted to the role of miRNAs in tumor tissue and we did not consider circulating miRNAs. A total of thirty-six studies met the inclusion criteria. Among them, twenty-one were classified in the diagnosis category, twenty in classification, five in treatment response and nineteen in prognosis. In this review, we have identified miR-155-5p and miR-21-5p as miRNAs of potential utility for diagnosis, while miR-155-5p and miR-221-3p could be useful for classification. Further studies are needed to exploit the potential of this field. This study was funded by the Basque Government (IT989-16), and Bioef-EiTB maratoia (BIO15/CA/022). The funding source did not have any role in the study design, collection, analysis and interpretation of data, writing of the report, or decision to submit the article for publication.

Chromosome translocations are especially frequent in human lymphomas and leukemias but are insufficient to drive carcinogenesis. Indeed, several of the so-called tumor specific translocations have been detected in peripheral blood of healthy individuals, finding a higher frequency of some of them with aging. The inappropriate repair of DNA double strand breaks by the nonhomologous end joining (NHEJ) pathway is one of the reasons for a translocation to occur. Moreover, fidelity of this pathway has been shown to decline with age. Although the mechanism underlying this inefficacy is unknown, other repair pathways are inactivated by methylation with aging. In this study, we analyzed the implication of NHEJ genes methylation in the increase of translocations with the age. To this aim, we determined the relationship between translocations and aging in 565 Spanish healthy individuals and correlated these data with the methylation status of 11 NHEJ genes. We found higher frequency of BCL2-JH and BCR-ABL (major) translocations with aging. In addition, we detected that two NHEJ genes (LIG4 and XRCC6) presented age-dependent promoter methylation changes. However, we did not observe a correlation between the increase of translocations and methylation, indicating that other molecular mechanisms are involved in the loss of NHEJ fidelity with aging. Fil: Martin Guerrero, Idoia. Universidad del Pais Vasco; España Fil: de Prado, Elena. Universidad del Pais Vasco; España Fil: López López, Elixabet. Universidad del Pais Vasco; España Fil: Ardanaz, Maite. Hospital Txagorritxu; España Fil: Vitoria, Juan Carlos. Hospital de Cruces; España Fil: Parada, Luis Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Salta. Instituto de Patología Experimental; Argentina. Universidad Nacional de Salta; Argentina Fil: García Orad, Cristina. Hospital General Valencia; España Fil: García Orad, Africa. BioCruces Health Research Institute; España. Universidad del Pais Vasco; España

Genome wide association studies (GWAS) have identified several low-penetrance susceptibility alleles in chronic lymphocytic leukemia (CLL). Nevertheless, these studies scarcely study regions that are implicated in non-coding molecules such as microRNAs (miRNAs). Abnormalities in miRNAs, as altered expression patterns and mutations, have been described in CLL, suggesting their implication in the development of the disease. Genetic variations in miRNAs can affect levels of miRNA expression if present in pre-miRNAs and in miRNA biogenesis genes or alter miRNA function if present in both target mRNA and miRNA sequences. Therefore, the present study aimed to evaluate whether polymorphisms in pre-miRNAs, and/or miRNA processing genes contribute to predisposition for CLL. A total of 91 SNPs in 107 CLL patients and 350 cancer-free controls were successfully analyzed using TaqMan Open Array technology. We found nine statistically significant associations with CLL risk after FDR correction, seven in miRNA processing genes (rs3805500 and rs6877842 in DROSHA, rs1057035 in DICER1, rs17676986 in SND1, rs9611280 in TNRC6B, rs784567 in TRBP and rs11866002 in CNOT1) and two in pre-miRNAs (rs11614913 in miR196a2 and rs2114358 in miR1206). These findings suggest that polymorphisms in genes involved in miRNAs biogenesis pathway as well as in pre-miRNAs contribute to the risk of CLL. Large-scale studies are needed to validate the current findings. This work was supported by the Basque Government (IT661-13), UPV/EHU (UFI11/35), Saiotek (S-PE13UN079) and RTICC (RD12/0036/0060, RD12/0036/0036). AGC was supported by a predoctoral grant from the Basque Government through the grant "Programa de Formacion de Personal Investigador no doctor del Departamento de Educacion, Politica Linguistica y Cultura del Gobierno Vasco". ELL was supported by a postdoctoral grant from the Basque Government through the grant "Programa Posdoctoral, de Perfeccionamiento de Personal Investigador Doctor del Departamento de Educacion, Politica Linguistica y Cultura del Gobierno Vasco". The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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. 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.