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Simple Summary: B-cell acute lymphoblastic leukemia is genetically diverse, with one of the most commonly altered genes being PAX5. Recently, alterations in PAX5 have been identified not merely as secondary events, but also as the oncogenic drivers, with newly defined genetic subtypes like PAX5alt and PAX5 P80R. Studying a consecutive cohort of 99 B-ALL patients, we found PAX5 alterations in over a third of patients, mostly involving copy number variations. Seven of our patients exhibited the PAX5alt genetic profile and one carried the P80R variant, and these patients showed intermediate outcomes. We also discovered that patients within the hyperdiploid group that carried extra copies of PAX5 did not respond as well to the treatment. Overall, our study highlights widespread PAX5 alterations affecting treatment response, particularly in specific genetic subtypes, underlining the need to identify these alterations for improved treatment strategies. In this study, we aimed to identify patients within our B-ALL cohort with altered PAX5. Our objective was to use a comprehensive analysis approach to characterize the types of genetic changes, determine their origin (somatic/germline), and analyze the clinical outcomes associated with them. A consecutive cohort of 99 patients with B-ALL treated at the Children's Hospital of the UMC Ljubljana according to the ALL IC-BFM 2009 protocol was included in our study. We used RNA sequencing data for gene expression analysis, fusion gene detection and single nucleotide variant identification, multiplex-ligation dependent probe amplification for copy number variation assessment, and Sanger sequencing for germline variant detection. PAX5 was impacted in 33.3% of our patients, with the genetic alterations ranging from CNVs and rearrangements to SNVs. The most common were CNVs, which were found in more than a third of patients, followed by point mutations in 5.2%, and gene rearrangements in 4.1%. We identified eight patients with a PAX5-associated genetic subtype that were previously classified as "B-other", and they showed intermediate outcomes. We showed higher minimal residual disease values at the end of induction and poorer event-free survival in hyperdiploid cases carrying duplications in PAX5 compared to other hyperdiploid cases. We also report an interesting case of a patient with PAX5::FKBP15 and a pathogenic variant in PTPN11 who underwent an early relapse with a monocytic switch. In conclusion, this study provides valuable insights into the presence, frequency, and prognostic significance of diverse PAX5 alterations in B-ALL patients, highlighting the complexity of genetic factors and their impact on patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: The Wilms tumor is the most common kidney cancer in children. This study characterized complete miRNA and mRNA profiles using a comprehensive NGS sequencing approach to identify miRNAs as transcriptome regulators involved in the Wilms tumor. By analyzing two independent groups of kidney samples with matched controls, we identified 43 miRNAs that are independently differentially expressed in the Wilms tumor irrespective of tumor histological type. Our results provide new insights into the role of transcriptomics in the Wilms tumor and identify universal miRNAs as potential biomarkers for early detection and targets for prevention and treatment of the Wilms tumor. Our study aimed to identify relevant transcriptomic biomarkers for the Wilms tumor, the most common pediatric kidney cancer, independent of the histological type and stage. Using next-generation sequencing, we analyzed the miRNA profiles of 74 kidney samples, which were divided into two independent groups: fresh frozen tissue and formalin-fixed paraffin-embedded tissue samples. Subsequent mRNA expression profiling and pathway analysis were performed to establish the interplay and potential involvement of miRNAs and mRNA in the Wilms tumor. Comparative analysis, irrespective of post-dissection tissue processing, revealed 41 differentially expressed miRNAs, with 27 miRNAs having decreased expression and 14 miRNAs having increased expression in the Wilms tumor tissue compared to healthy kidney tissue. Among global mRNA transcriptomic profile differences, cross-sectional analysis suggested a limited list of genes potentially regulated by differentially expressed miRNAs in the Wilms tumor. This study identified the comprehensive miRNA and mRNA profile of the Wilms tumor using next-generation sequencing and bioinformatics approach, providing better insights into the pathogenesis of the Wilms tumor. The identified Wilms tumor miRNAs have potential as biomarkers for the diagnosis and treatment of the Wilms tumor, regardless of histological subtype and disease stage. [ABSTRACT FROM AUTHOR]

Background Insulin resistance ( IR) is one of the major metabolic complications of obesity in children and adolescents. DEP domain-containing mammalian target of rapamycin interacting protein ( DEPTOR) is involved in downstream insulin signaling and DEPTOR's effects are regulated by its level of expression. Objectives To analyze promoter region of DEPTOR for genetic variants associated with altered IR in obese children and adolescents. Subjects and methods IR was determined in 322 normoglycemic obese subjects [173 females, 149 males; mean age 13.3 ± 3.5 yr, mean BMI-SDS 2.85 ± 0.83, HbA1C 5.2 ± 0.2% (33 ± 2.5 mmol/mol)] using homeostatic model assessment - insulin resistance [ HOMA-IR (>2 prepubertal and >3 pubertal)] and whole body insulin sensitivity index [ WBISI (<6.5 prepubertal and <4.5 pubertal)]. Genetic variants, determined by high resolution melting analysis, were confirmed by Sanger sequencing, whereas population allele distribution was determined by TaqMan genotyping probes. Results Genetic variant c.- 143T>C (rs7840156) was associated with a significant 2-fold decreased risk to present with IR, determined by HOMA-IR [odds ratio ( OR) = 0.614, 95% confidence interval ( CI) = 0.435-0.867, p = 0.0057) and WBISI ( OR = 0.582, 95% CI = 0.414-0.817, p = 0.0018). The CC genotype had lower mean HOMA-IR value (2.47 ± 0.44 vs. 3.04 ± 0.14, p = 0.0177) and higher mean WBISI value (7.00 ± 0.71 vs. 5.27 ± 0.33, p = 0.0235) than TT genotype. Variant c.- 143T>C was located in evolutionary highly conserved region in DEPTOR promoter region. Conclusion Presented results on association between insulin sensitivity and genetic variants in DEPTOR gene suggest DEPTOR and mammalian target of rapamycin signaling pathway to be potential target for future research and pharmacological interventions. [ABSTRACT FROM AUTHOR]

The prevalence of the autism spectrum disorder (ASD) was recently estimated to 1 in 88 children by the CDC MMWR. In up to 25 % of the cases, the genetic cause can be identified. Past studies identified increased level of advanced glycation end products (AGE) in the brain samples of ASD patients. The methylglyoxal (MG) is one of the main precursors for AGE formation. Humans developed effective mechanism of the MG metabolism involving two enzymes glyoxalase 1 ( GLO1) and hydroxyacylglutathione hydrolase ( HAGH). Our aim was to analyse genetic variants of GLO1 and HAGH in population of 143 paediatric participants with ASD. We detected 7 genetic variants in GLO1 and 16 variants in HAGH using high-resolution melting (HRM) analysis. A novel association between variant rs1049346 and ASD [OR ] = 1.5; 95 % CI = 1.1-2.2 and p < 0.05) was identified, and weak association between ASD and variant rs2736654 [OR ] = 2.2; 95 % CI = 0.99-4.9; p = 0.045) was confirmed. Additionally, a novel genetic variant ( GLO1 c.484G > A, p.Ala161Thr) with predicted potentially damaging effect on the activity of the glyoxalase 1 that may contribute to the aetiology of ASD was identified in one participant with ASD. No association between genetic variants of the HAGH gene and ASD was found. Increased level of MG and, consequently, AGEs can induce oxidative stress, mitochondrial dysfunction and inflammation all of which have been implicated to act in the aetiology of the ASD. Our results indicate potential importance of MG metabolism in ASD. However, these results must be interpreted with caution until a causative relation is demonstrated. [ABSTRACT FROM AUTHOR]