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.

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.

Two polymorphisms in the murine double minute 2 (MDM2) gene (rs1690916 and rs2279744) have been associated with the risk of osteosarcoma (OS). When we analyzed these two polymorphisms in two new independents cohorts (Spanish and Slovenian), we found no association. In order to clarify this, we conducted a meta-analysis including six populations, with a total of 246 OS patients and 1,760 controls for rs1690916; and 433 OS patients and 1,959 controls for rs2279744. Pooled odds ratio risks and corresponding 95% CI were estimated to assess the possible associations. Our results showed that these two polymorphisms were not associated with the susceptibility of OS under any genetic model studied. In conclusion, the present meta-analysis indicates that MDM2 rs1690916 and rs2279744 cannot be considered as genetic risk factors for OS susceptibility in the different populations. Therefore, the influence of these two polymorphisms on the risk of OS may be less important than previously suggested. Future studies are needed to confirm these results.O steosarcoma (OS) is the most common primary malignant tumor of bone, mainly occurring in the second decade of life. The precise etiology of the disease remains partially unknown (1). Nevertheless, genetic factors might play a key role in its pathogenesis (2). To date diverse studies have reported associations of common genetic variants in biologically plausible pathways with OS risk (3-6). Among the analyzed variants, rs1690916 and rs2279744 in the murine double minute 2 gene (MDM2) are two of the most recurrently studied and associated with the susceptibility of OS (5,7-9). The MDM2 gene is especially interesting because it functions as an E3 ubiquitin ligase promoting p53 degradation (10,11).MDM2 rs1690916, located at the 3′ untranslated region of the gene, was significantly associated with the risk of OS in a large North-American population including 96 patients and 1,416 controls (7). They found that rs1690916 AA genotype decreased the risk of the disease. rs1690916 A allele was also found to be associated with a decreased risk of bone tumors in Russian population including 68 patients and 86 controls (9). However, this study only included 26 OS patients out of 68 analyzed. MDM2 rs2279744, situated in the promoter region, was related to an increased risk of OS (GG vs. TT) in Italian population (211 OS patients and 250 controls) (5), being this association stronger in females. Moreover, a robust correlation between rs2279744 G allele enrichment and MDM2 amplification was found, suggesting the contribution of this polymorphism to OS tumorigenesis (12). However, this single nucleotide polymorphism (SNP) did not show any association in the North-American population (7). A meta-analysis evaluating the association between these two polymorphisms and the risk of OS was performed, concluding that both SNPs influence the risk of OS (13). Nevertheless, some inaccuracies were detected in the study. Among others, the lack of information in the methods used to select the studies and extr...

Systematic reviews on osteosarcoma have concluded that CTLA4 rs231775 AA genotype influences risk for the disease in the Chinese population. Remarkably, rs231775 shows different frequencies in different human populations. Therefore, it would be interesting to know whether this SNP is related to the risk of osteosarcoma in other populations. The present study aimed to evaluate the association between rs231775 and the susceptibility of osteosarcoma in the Spanish population. We performed an updated meta-analysis including a total of 538 cases and 623 controls. The genotypic association analyses showed that the CTLA4 rs231755 was associated with osteosarcoma susceptibility in the Spanish population. When meta-analysis was performed, the results displayed that CTLA4 rs231775 AA genotype was associated with the risk of developing osteosarcoma in all analyzed populations (OR=2.07; 95% CI: 1.48-2.89).The rs231775 AA genotype could be considered as a susceptibility marker in osteosarcoma Keywords: CTLA4, rs231775, +49A/G and osteogenic sarcoma.

This study suggests that SNPs in RISC complex genes may be involved in osteosarcoma susceptibility, especially rs11866002 in CNOT1.

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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.

We have read with interest the article by Wang et al. [1] in a recent issue of Tumor Biology. In this study, the authors conducted a systematic review and meta-analysis to assess the effects of two murine double minute 2 (MDM2) polymorphisms, rs2274799 and rs160916, on the risk and survival of osteosarcoma. The authors concluded that MDM2 polymorphisms had effects on the risk but had no effect on the survival of patients with osteosarcoma. In a recent letter to the editor, Liu et al. [2] detected several weaknesses in the meta-analysis. Firstly, they criticize the small number of papers included in the analyses, which could lead to false significant associations. They also point out the lack of information in the methods used to select the studies. Moreover, they comment the absence of Hardy-Weinberg equilibrium analysis in the control population. Finally, they question the quality of the selected studies. In the present letter, we would like to add some other inaccuracies found in the Wang et al.[1] meta-analysis.According to our analyses, there is no association between MDM2 rs2279744 and osteosarcoma risk in the population used by Ito et al. [3]. This contradicts the result shown by Wang et al. [1] in their study. When we calculate the odds ratio (OR) value of Ito et al. [3] samples, using the total of benign tumors (n=37) as controls, we obtain a different OR value. This contradictory result has been observed in all hereditary models (allele model, OR=1.46, codominant model, OR=1.50, recessive model, OR 1.11, dominant model, OR=1.88,