In this study, we aimed to identify patients within our B-ALL cohort with altered
. 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.
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
-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
compared to other hyperdiploid cases. We also report an interesting case of a patient with
and a pathogenic variant in
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
alterations in B-ALL patients, highlighting the complexity of genetic factors and their impact on patient outcomes.
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.
Akutna limfoblastna levkemija (ALL) je genetsko zelo hete-rogena bolezen in tudi ena najbolje raziskanih. Kljub temu je naše razumevanje, kako genetske spremembe sodelujejo pri nastanku levkemije ali ...odpornosti na zdravljenje, še vedno pomanjkljivo. Še vedno ostajajo določeni podtipi z izjemno slabimi izidi zdravljenja, saj se bolezen pri kar 20 % bolnikov ponovi in večina ne preživi. Novi pristopi v diagnosticiranju ALL, ki temeljijo na uporabi metod sekvenciranja naslednje generacije, prinašajo nove možnosti za boljše razumevanje razvoja bolezni, opredelitev novih podtipov bolezni in boljše ocenjevanje tveganja. Omogočajo tudi spremljanje klonalne dinamike med zdravljenjem in ob relapsu, kar odpira nove možnosti za boljšo obravnavo bolnikov z relapsom ALL. Prav tako lahko s temi metodami natančneje spremljamo odziv na zdravljenje in prepoznavamo nove potencialne tarče za bolj usmerjeno zdravljenje.
Genetically, acute lymphoblastic leukaemia (ALL) is a very heterogeneous disease, but it has also been one of the most thoroughly researched diseases. Nevertheless, our knowledge of how genetic ...changes are interrelated in the development of leukaemia and treatment resistance is still lacking. Certain ALL subtypes still have extremely poor treatment outcomes, with up to 20% of patients experiencing a relapse, the majority of whom do not survive. New approaches in the diagnostic work-up for ALL, based on the use of next-generation sequencing methods, have provided new possibilities for expanding our understanding of the development of the disease biology, identification of new genetic subtypes, and better risk assessment. They also enable monitoring of clonal dynamics during treatment and at relapse, which opens up new prospects for better management of patients with ALL relapses. There are also attempts to use these methods for more accurate monitoring of treatment response and identification of new potential targets for more focused treatment.
gene deletions have been identified as a poor prognostic factor in pediatric B-cell acute lymphoblastic leukemia (B-ALL), especially in the presence of co-occurring deletions (
profile). This study ...aimed to determine the frequency of
deletions and deletions in other B-cell differentiation and cell cycle control genes, and their prognostic impact in Slovenian pediatric B-ALL patients.
We studied a cohort of 99 patients diagnosed with B-ALL from January 2012 to December 2020 and treated according to the ALL IC-BFM 2009 protocol. Eighty-eight bone marrow or peripheral blood samples were analysed for copy number variations (CNVs) using the SALSA MLPA P335 ALL-IKZF1 probemix.
At least one CNV was detected in more than 65% of analysed samples. The most frequently altered genes were
and
(30.7%, 26.1%, and 25.0%, respectively). Deletions in
were present in 18.2% of analysed samples and were associated with an inferior 5-year event-free survival (EFS; 54.8%
. 85.9%, p = 0.016). The
profile was identified in 12.5% of the analysed samples, and these patients had an inferior 5-year EFS than those with deletions in
only and those without deletions (50.8%
. 75.0%
. 85.9%, respectively, p = 0.049). Overall survival (OS) was also worse in patients with the
profile than those with deletions in
only and those without deletions (5-year OS 76.2%
. 100%
. 93.0%, respectively). However, the difference between the groups was not statistically significant.
Our results are in concordance with the results obtained in larger cooperative clinical trials. Copy number variations analysis using the SALSA MLPA kit is a reliable tool for initial diagnostic approach in children with B-ALL, even in smaller institutions in low- and middle-income countries.
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.
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