Publications by authors named "Marta Jeison"

21 Publications

  • Page 1 of 1

Frequency and Prognostic Impact of Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1).

J Clin Oncol 2021 Jun 11:JCO2100086. Epub 2021 Jun 11.

Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.

Purpose: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact.

Materials And Methods: Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine amplification status (n = 330), mutational profile (n = 191), or both (n = 571).

Results: Genomic amplification (a) was detected in 4.5% of cases (41 out of 901), all except one with amplification (MNA). a was associated with a significantly poorer overall survival (OS) (5-year OS: a [n = 41] 28% [95% CI, 15 to 42]; no-a [n = 860] 51% [95% CI, 47 to 54], [ < .001]), particularly in cases with metastatic disease. mutations (m) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of m and MNA ( < .001). Among 571 cases with known a and m status, a statistically significant difference in OS was observed between cases with a or clonal m versus subclonal m or no alterations (5-year OS: a [n = 19], 26% [95% CI, 10 to 47], clonal m [n = 65] 33% [95% CI, 21 to 44], subclonal m (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively, = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; < .001), a (HR, 2.38; = .004), and clonal (HR, 1.77; = .001) were independent predictors of poor outcome.

Conclusion: Genetic alterations of (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with alterations.
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http://dx.doi.org/10.1200/JCO.21.00086DOI Listing
June 2021

Incorporation of somatic panels for the detection of haematopoietic transformation in children and young adults with leukaemia predisposition syndromes and with acquired cytopenias.

Br J Haematol 2021 May 27;193(3):570-580. Epub 2020 Dec 27.

Pediatric Hematology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel.

Detection of somatic mutations may help verify the diagnosis of myelodysplastic syndrome (MDS) in patients with persistent cytopenias or with MDS-predisposition syndromes, prior to the development of overt leukemia. However, the spectrum and consequences of acquired changes in paediatric patients have not been fully evaluated, and especially not in the context of an underlying syndrome. We incorporated a targeted next-generation-sequencing panel of 54 genes for the detection of somatic mutations in paediatric and young adult patients with inherited or acquired cytopenias. Sixty-five patients were included in this study, of whom 17 (26%) had somatic mutations. We detected somatic mutations in 20% of individuals with inherited MDS-predisposition syndromes, including in patients with severe congenital neutropenia and Fanconi anaemia, and with germline mutations in SAMD9L. Thirty-eight per cent of children with acquired cytopenias and suspected MDS had somatic changes, most commonly in genes related to signal transduction and transcription. Molecularly abnormal clones often preceded cytogenetic changes. Thus, routine performance of somatic panels can establish the diagnosis of MDS and determine the optimal timing of haematopoietic stem cell transplantation, prior to the development of leukaemia. In addition, performing somatic panels in patients with inherited MDS-predisposition syndromes may reveal their unique spectrum of acquired mutations.
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http://dx.doi.org/10.1111/bjh.17285DOI Listing
May 2021

Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable -Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group.

J Clin Oncol 2020 11 9;38(31):3685-3697. Epub 2020 Sep 9.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: For localized, resectable neuroblastoma without amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome.

Patients And Methods: Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children's Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group.

Results: Patients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD], 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients < 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in < 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; = .001). In < 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, = .038).

Conclusion: Genomic aberrations of resectable non-amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients < 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those > 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.
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http://dx.doi.org/10.1200/JCO.18.02132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605396PMC
November 2020

Validation of the United Kingdom copy-number alteration classifier in 3239 children with B-cell precursor ALL.

Blood Adv 2019 01;3(2):148-157

Hematology-Oncology Department, Hospital de Pediatría "Prof. Dr. J. P. Garrahan," Buenos Aires, Argentina.

Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymphoblastic leukemia (ALL) and are increasingly used to assign patients to risk groups. We recently proposed a novel classifier based on the copy-number alteration (CNA) profile of the 8 most commonly deleted genes in B-cell precursor ALL. This classifier defined 3 CNA subgroups in consecutive UK trials and was able to discriminate patients with intermediate-risk cytogenetics. In this study, we sought to validate the United Kingdom ALL (UKALL)-CNA classifier and reevaluate the interaction with cytogenetic risk groups using individual patient data from 3239 cases collected from 12 groups within the International BFM Study Group. The classifier was validated and defined 3 risk groups with distinct event-free survival (EFS) rates: good (88%), intermediate (76%), and poor (68%) ( < .001). There was no evidence of heterogeneity, even within trials that used minimal residual disease to guide therapy. By integrating CNA and cytogenetic data, we replicated our original key observation that patients with intermediate-risk cytogenetics can be stratified into 2 prognostic subgroups. Group A had an EFS rate of 86% (similar to patients with good-risk cytogenetics), while group B patients had a significantly inferior rate (73%, < .001). Finally, we revised the overall genetic classification by defining 4 risk groups with distinct EFS rates: very good (91%), good (81%), intermediate (73%), and poor (54%), < .001. In conclusion, the UKALL-CNA classifier is a robust prognostic tool that can be deployed in different trial settings and used to refine established cytogenetic risk groups.
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http://dx.doi.org/10.1182/bloodadvances.2018025718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341196PMC
January 2019

Circulating microRNA biomarkers for metastatic disease in neuroblastoma patients.

JCI Insight 2018 12 6;3(23). Epub 2018 Dec 6.

Center for Medical Genetics, Department of Biomolecular Medicine, and.

In this study, the circulating miRNome from diagnostic neuroblastoma serum was assessed for identification of noninvasive biomarkers with potential in monitoring metastatic disease. After determining the circulating neuroblastoma miRNome, 743 miRNAs were screened in 2 independent cohorts of 131 and 54 patients. Evaluation of serum miRNA variance in a model testing for tumor stage, MYCN status, age at diagnosis, and overall survival revealed tumor stage as the most significant factor impacting miRNA abundance in neuroblastoma serum. Differential abundance analysis between patients with metastatic and localized disease revealed 9 miRNAs strongly associated with metastatic stage 4 disease in both patient cohorts. Increasing levels of these miRNAs were also observed in serum from xenografted mice bearing human neuroblastoma tumors. Moreover, murine serum miRNA levels were strongly associated with tumor volume. These findings were validated in longitudinal serum samples from metastatic neuroblastoma patients, where the 9 miRNAs were associated with disease burden and treatment response.
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http://dx.doi.org/10.1172/jci.insight.97021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328024PMC
December 2018

Heterogeneous MYCN amplification in neuroblastoma: a SIOP Europe Neuroblastoma Study.

Br J Cancer 2018 05 14;118(11):1502-1512. Epub 2018 May 14.

Department of Tumour Biology CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, 1090, Vienna, Austria.

Background: In neuroblastoma (NB), the most powerful prognostic marker, the MYCN amplification (MNA), occasionally shows intratumoural heterogeneity (ITH), i.e. coexistence of MYCN-amplified and non-MYCN-amplified tumour cell clones, called heterogeneous MNA (hetMNA). Prognostication and therapy allocation are still unsolved issues.

Methods: The SIOPEN Biology group analysed 99 hetMNA NBs focussing on the prognostic significance of MYCN ITH.

Results: Patients <18 months (18 m) showed a better outcome in all stages as compared to older patients (5-year OS in localised stages: <18 m: 0.95 ± 0.04, >18 m: 0.67 ± 0.14, p = 0.011; metastatic: <18 m: 0.76 ± 0.15, >18 m: 0.28 ± 0.09, p = 0.084). The genomic 'background', but not MNA clone sizes, correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. Infiltrated bone marrows and relapse tumour cells mostly displayed no MNA. However, one stage 4s tumour with segmental chromosomal aberrations showed a homogeneous MNA in the relapse.

Conclusions: This study provides a rationale for the necessary distinction between heterogeneous and homogeneous MNA. HetMNA tumours have to be evaluated individually, taking age, stage and, most importantly, genomic background into account to avoid unnecessary upgrading of risk/overtreatment, especially in infants, as well as in order to identify tumours prone to developing homogeneous MNA.
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http://dx.doi.org/10.1038/s41416-018-0098-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988829PMC
May 2018

miR expression profiling at diagnosis predicts relapse in pediatric precursor B-cell acute lymphoblastic leukemia.

Genes Chromosomes Cancer 2016 Apr 19;55(4):328-39. Epub 2015 Dec 19.

Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel.

Our aim was to identify miRNAs that can predict risk of relapse in pediatric patients with acute lymphoblastic leukemia (ALL). Following high-throughput miRNA expression analysis (48 samples), five miRs were selected for further confirmation performed by real time quantitative PCR on a cohort of precursor B-cell ALL patients (n = 138). The results were correlated with clinical parameters and outcome. Low expression of miR-151-5p, and miR-451, and high expression of miR-1290 or a combination of all three predicted inferior relapse free survival (P = 0.007, 0.042, 0.025, and <0.0001, respectively). Cox regression analysis identified aberrant expression of the three miRs as an independent prognostic marker with a 10.5-fold increased risk of relapse (P = 0.041) in PCR-MRD non-high risk patients. Furthermore, following exclusion of patients harboring IKZF1 deletion, the aberrant expression of all three miRs could identify patients with a 24.5-fold increased risk to relapse (P < 0.0001). The prognostic relevance of the three miRNAs was evaluated in a non-BFM treated precursor B-cell ALL cohort (n = 33). A significant correlation between an aberrant expression of at least one of the three miRs and poor outcome was maintained (P < 0.0001). Our results identify an expression profile of miR-151-5p, miR-451, and miR-1290 as a novel biomarker for outcome in pediatric precursor B-cell ALL patients, regardless of treatment protocol. The use of these markers may lead to improved risk stratification at diagnosis and allow early therapeutic interventions in an attempt to improve survival of high risk patients.
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http://dx.doi.org/10.1002/gcc.22334DOI Listing
April 2016

MiR-192 directly binds and regulates Dicer1 expression in neuroblastoma.

PLoS One 2013 1;8(11):e78713. Epub 2013 Nov 1.

Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel ; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Neuroblastoma (NB) arises from the embryonic neural crest and is the most common extracranial solid tumor in children under 5 years of age. Reduced expression of Dicer1 has recently been shown to be in correlation with poor prognosis in NB patients. This study aimed to investigate the mechanisms that could lead to the down-regulation of Dicer1 in neuroblastoma. We used computational prediction to identify potential miRs down-regulating Dicer1 in neuroblastoma. One of the miRs that were predicted to target Dicer1 was miR-192. We measured the levels of miR-192 in 43 primary tumors using real time PCR. Following the silencing of miR-192, the levels of dicer1 cell viability, cell proliferation and migration capability were analyzed. Multivariate analysis identified miR-192 as an independent prognostic marker for relapse in neuroblastoma patients (p=0.04). We were able to show through a dual luciferase assay and side-directed mutational analysis that miR-192 directly binds the 3' UTR of Dicer1 on positions 1232-1238 and 2282-2288. An increase in cell viability, proliferation and migration rates were evident in NB cells transfected with miR-192-mimic. Yet, there was a significant decrease in proliferation when NB cells were transfected with an miR-192-inhibitor We suggest that miR-192 might be a key player in NB by regulating Dicer1 expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078713PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815303PMC
August 2014

Novel SMARCAL1 bi-allelic mutations associated with a chromosomal breakage phenotype in a severe SIOD patient.

J Clin Immunol 2014 Jan 7;34(1):76-83. Epub 2013 Nov 7.

Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, 52621, Israel,

Purpose: Chromosomal instability syndromes include a group of rare diseases characterized by defective DNA-damage-response and increased risk of chromosomal breakage. Patients display defects in the recognition and/or repair of DNA damage, with a subsequent high rate of malignancies and abnormal gene rearrangements. Other clinical manifestations, such as immunodeficiency, neurodevelopmental delay and skeletal abnormalities, are present in some of these syndromes. We studied a patient with profound T-lymphocyte defect, neurodevelopmental delay, facial dysmorphism, nephrotic syndrome and spondyloepiphyseal bone dysplasia typical of SIOD.

Methods: Karyotype and chromosome fragility assays on patients' peripheral blood mononuclear cells showed an abnormal rate of spontaneous breaks. Cell cycle analysis of patient's fibroblasts following replication stress induced by hydroxyhurea revealed a delay in their release from S-phase to G2. When using higher concentrations of hydroxyhurea no patient fibroblast colonies could survive, compared with control fibroblasts. Whole-exome sequencing revealed novel compound heterozygote mutations in SMARCAL1 gene, resulting in putative frame shifts of encoded SMARCAL1 from each allele and no detected protein in patient's cells. The patient's youngest brother was found to have similar manifestations of SIOD but of less severity, including short stature, facial dysmorphism and typical osseous dysplasia, but no clinical findings suggestive of immunodeficiency and no chromosomal fragility. Similar to his sister, the brother carries both bi-allelic mutations in SMARCAL1 gene.

Conclusions: We present here the first evidence of intrinsic chromosomal instability in a severe SMARCAL1-deficient patient with a clinical picture of SIOD. Our results are consistent with the recently outlined role of SMARCAL1 protein in DNA damage response.
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http://dx.doi.org/10.1007/s10875-013-9957-3DOI Listing
January 2014

Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: a collaborative study by the International-Berlin-Frankfurt-Munster AML-study group.

Blood 2013 Oct 23;122(15):2704-13. Epub 2013 Aug 23.

Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands;

In pediatric acute myeloid leukemia (AML), cytogenetic abnormalities are strong indicators of prognosis. Some recurrent cytogenetic abnormalities, such as t(8;16)(p11;p13), are so rare that collaborative studies are required to define their prognostic impact. We collected the clinical characteristics, morphology, and immunophenotypes of 62 pediatric AML patients with t(8;16)(p11;p13) from 18 countries participating in the International Berlin-Frankfurt-Münster (I-BFM) AML study group. We used the AML-BFM cohort diagnosed from 1995-2005 (n = 543) as a reference cohort. Median age of the pediatric t(8;16)(p11;p13) AML patients was significantly lower (1.2 years). The majority (97%) had M4-M5 French-American-British type, significantly different from the reference cohort. Erythrophagocytosis (70%), leukemia cutis (58%), and disseminated intravascular coagulation (39%) occurred frequently. Strikingly, spontaneous remissions occurred in 7 neonates with t(8;16)(p11;p13), of whom 3 remain in continuous remission. The 5-year overall survival of patients diagnosed after 1993 was 59%, similar to the reference cohort (P = .14). Gene expression profiles of t(8;16)(p11;p13) pediatric AML cases clustered close to, but distinct from, MLL-rearranged AML. Highly expressed genes included HOXA11, HOXA10, RET, PERP, and GGA2. In conclusion, pediatric t(8;16)(p11;p13) AML is a rare entity defined by a unique gene expression signature and distinct clinical features in whom spontaneous remissions occur in a subset of neonatal cases.
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http://dx.doi.org/10.1182/blood-2013-02-485524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314534PMC
October 2013

Genetic stratification of neuroblastoma for treatment tailoring.

Future Oncol 2011 Sep;7(9):1087-99

Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.

Neuroblastoma is the most common extracranial tumor of childhood. The clinical behavior is variable, ranging from spontaneous regression to fatal progression despite aggressive therapy. The most highly statistically significant and clinically relevant factors that are currently used for classification include stage, age, histopathologic category, MYCN oncogene status, chromosome 11q status and DNA ploidy. These genetic markers were analyzed separately by classical methods until recently: mainly fluorescence in situ hybridization or loss of heterozygosity. The development of genome-wide techniques such as comparative genomic hybridization, array comparative genomic hybridization and single nucleotide polymorphism allows the analysis of copy number variations through the whole genome in one step. This enabled the investigators to refine different genetic subtypes for the better comprehension of neuroblastoma tumor behavior and reach the conclusion that these data together with a genomic profile based on gene expression should be included in future treatment stratification.
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http://dx.doi.org/10.2217/fon.11.87DOI Listing
September 2011

EVI1-mediated down regulation of MIR449A is essential for the survival of EVI1 positive leukaemic cells.

Br J Haematol 2011 Aug 14;154(3):337-48. Epub 2011 May 14.

Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

Chromosomal rearrangements involving the MECOM (MDS1 and EVI1 complex) locus are recurrent genetic events in myeloid leukaemia and are associated with poor prognosis. In this study, we assessed the role of MECOM locus protein EVI1 in the transcriptional regulation of microRNAs (miRNAs) involved in the leukaemic phenotype. For this, we profiled expression of 366 miRNAs in 38 MECOM-rearranged patient samples, normal bone marrow controls and MECOM (EVI1) knock down/re-expression models. Cross-comparison of these miRNA expression profiling data showed that MECOM rearranged leukaemias are characterized by down regulation of MIR449A. Reconstitution of MIR449A expression in MECOM-rearranged cell line models induced apoptosis resulting in a strong decrease in cell viability. These effects might be mediated in part by MIR449A regulation of NOTCH1 and BCL2, which are shown here to be bona fide MIR449A targets. Finally, we confirmed that MIR449A repression is mediated through direct promoter occupation of the EVI1 transcriptional repressor. In conclusion, this study reveals MIR449A as a crucial direct target of the MECOM locus protein EVI1 involved in the pathogenesis of MECOM-rearranged leukaemias and unravels NOTCH1 and BCL2 as important novel targets of MIR449A. This EVI1-MIR449A-NOTCH1/BCL2 regulatory axis might open new possibilities for the development of therapeutic strategies in this poor prognostic leukaemia subgroup.
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http://dx.doi.org/10.1111/j.1365-2141.2011.08737.xDOI Listing
August 2011

A multilocus technique for risk evaluation of patients with neuroblastoma.

Clin Cancer Res 2011 Feb;17(4):792-804

CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.

Purpose: Precise and comprehensive analysis of neuroblastoma genetics is essential for accurate risk evaluation and only pangenomic/multilocus approaches fulfill the present-day requirements. We present the establishment and validation of the PCR-based multiplex ligation-dependent probe amplification (MLPA) technique for neuroblastoma.

Experimental Design: A neuroblastoma-specific MLPA kit was designed by the SIOP Europe Neuroblastoma Biology Committee in cooperation with MRC-Holland. The contained target sequences cover 19 chromosomal arms and reference loci. Validation was performed by single locus and pangenomic techniques (n = 174). Dilution experiments for determination of minimal tumor cell percentage were performed and testing of reproducibility was checked by interlaboratory testing (n = 15). Further 156 neuroblastomas were used for establishing the amplification cutoff level.

Results: The MLPA technique was tested in 310 neuroblastomas and 8 neuroblastoma cell lines (including validation and amplification cutoff level testing). Intertechnique validation showed a high concordance rate (99.5%). Interlaboratory MLPA testing (κ = 0.95, P < 0.01) revealed 7 discrepant of 1,490 results (0.5%). Validation by pangenomic techniques showed a single discordance of 190 consensus results (0.5%). The test results led to formulation of interpretation standards and to a kit revision. The minimal tumor cell percentage was fixed at 60%.

Conclusions: The recently designed neuroblastoma-specific MLPA kit covers all chromosomal regions demanded by the International Neuroblastoma Risk Group for therapy stratification and includes all hitherto described genetic loci of prognostic interest for future studies and can be modified or extended at any time. Moreover, the technique is cost effective, reliable, and robust with a high interlaboratory and intertechnique concordance.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-0830DOI Listing
February 2011

2p24 Gain region harboring MYCN gene compared with MYCN amplified and nonamplified neuroblastoma: biological and clinical characteristics.

Am J Pathol 2010 Jun 15;176(6):2616-25. Epub 2010 Apr 15.

Ca-Cytogenetic Lab, Schneider Children's Medical Center of Israel, Kaplan St. 14, 49202 Petah Tikva, Israel.

Although the role of MYCN amplification in neuroblastoma is well established, the biological and clinical characteristics of the 2p gain region harboring the MYCN gene remain unclear. The aim of this study was to compare the biological and clinical characteristics of these tumors with MYCN amplified and nonamplified neuroblastoma and to determine their impact on disease outcome. Samples from 177 patients were analyzed by fluorescence in situ hybridization, including MYCN, 1p, 17q, and 11q regions; 2p gain was identified in 25 patients, MYCN amplification in 31, and no amplification in 121 patients. Patients with 2p gain had a significantly worse 5-year event-free survival rate than patients with no MYCN amplified (P < 0.001), and an intermediate 5-year overall survival rate difference existed between the MYCN amplified tumors (P = 0.025) and nonamplified (P = 0.003) groups. All of the 2p gain samples were associated with segmental and/or numerical alterations in the other tested regions. The presence of segmental alterations with or without MYCN amplification was recently found to be the strongest predictor of relapse in a multivariate analysis. The results of the present study suggest that the determination of MYCN gene copy number relative to chromosome 2, when evaluating MYCN status at diagnosis, may help to reveal the underlying genetic pattern of these tumors and better understand their clinical behavior.
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http://dx.doi.org/10.2353/ajpath.2010.090624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877825PMC
June 2010

Reduced levels of miR-34a in neuroblastoma are not caused by mutations in the TP53 binding site.

Genes Chromosomes Cancer 2009 Jul;48(7):539-43

Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel.

Neuroblastoma (NB) is the most common extracranial solid tumor in children below the age of 5 years. miR-34a, located in chromosome band 1p36, has been recently implicated as a tumor suppressor gene in NB. In addition, it has been shown that miR-34a is activated by TP53 by binding to a TP53 binding site upstream to the mature miR-34a. We studied NB tumors from 57 patients for miR-34a expression levels, 1p status, mutations in the TP53 coding region and mutations of the TP53 binding site. Reduced expression levels of miR-34a were identified in tumors harboring 1p36.3 Loss (P = 0.028). No mutations were identified in the coding region of TP53, or in the TP53 binding site. Thus, mutations in the binding site are not an additional mechanism for the inactivation of miR-34a in NB. Other regulatory mechanisms controlling miR-34a expression and its relationship to TP53 should be further explored.
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http://dx.doi.org/10.1002/gcc.20662DOI Listing
July 2009

Minimal residual disease in peripheral blood stem cell harvests from high-risk neuroblastoma patients.

J Pediatr Hematol Oncol 2009 Jan;31(1):22-6

Molecular Oncology, Felsenstein Medical Research Center, Tel Aviv University, Tel Aviv, Israel.

Purpose: We investigated whether detection of minimal residual disease (MRD) in peripheral blood stem cells (PBSC) by using tyrosine hydroxylase (TH) expression could predict outcome of patients with advanced neuroblastoma.

Patients And Methods: Quantitative real time polymerase chain reaction was performed for the detection of tumor contamination using TH messenger ribonucleic acid (mRNA) and correlated to clinical parameters and outcome in 45 high-risk neuroblastoma patients.

Results: High TH expression was detected in PBSC harvests obtained from 26 out of 45 (58%) patients. We did not find a significant correlation between MYCN status, DNA index or primary tumor site, and the TH mRNA level. Patients harboring high TH expression had reduced progression-free survival (PFS) (23%) versus those with low/negative TH expression (43%), although these results were not statistically significant. No significant correlation was observed between TH expression and overall survival.

Conclusions: The correlation between an unfavorable outcome and high TH expression in patients' PBSC harvests was not significant. This indicates a need to increase sample size in a long-term clinical outcome study to clarify the importance of TH mRNA contamination in PBSC.
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http://dx.doi.org/10.1097/MPH.0b013e31818e532cDOI Listing
January 2009

Short telomeres: a novel potential predictor of relapse in Ewing sarcoma.

Clin Cancer Res 2007 Oct;13(19):5777-83

Molecular Oncology, Felsenstein Medical Research Center, Petach Tikva, Israel.

Purpose: Despite advances in therapy, >50% of patients with Ewing sarcoma will relapse. The current prognostic factors are not optimal for risk prediction. Studies have shown that telomere length could predict outcome in different malignancies. Our aim was to evaluate whether telomere length could be a better prognostic factor in Ewing sarcoma and correlate the results with clinical variables, outcome, and chromosomal instability.

Experimental Design: Telomere length was determined in the primary tumor and peripheral blood of 32 patients with Ewing sarcoma. Chromosomal instability was evaluated by combining classical cytogenetics, comparative genomic hybridization and random aneuploidy. Telomere length was correlated to clinical variables, chromosomal instability, and outcome.

Results: In 75% of the tumors, changes in telomere length, when compared with the corresponding peripheral blood lymphocytes, were noted. The majority of changes consisted of a reduction in telomere length. Patients harboring shorter telomeres had a significantly adverse outcome (P = 0.015). Chromosomal instability was identified in 65% of tumors, significantly correlating with short telomeres (P = 0.0094). Using multivariate analysis, telomere length remained the only significant prognostic variable (P = 0.034). Patients with short telomeres had a 5.3-fold risk of relapse as compared to those with unchanged or longer telomeres.

Conclusion: We have shown that tumors with telomere length reduction result in genomic instability. In addition, telomere length reduction was the only significant predictor of outcome. We suggest that reduction of telomere length in tumor cells at diagnosis could serve as a prognostic marker in Ewing sarcoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-0308DOI Listing
October 2007

Classical and molecular cytogenetic abnormalities and outcome of childhood acute myeloid leukaemia: report from a referral centre in Israel.

Br J Haematol 2004 Aug;126(3):320-37

Centre of Pediatric Hematology/Oncology, Schneider Children's Medical Centre of Israel, Petah Tiqva, Israel.

The incidence of cytogenetic abnormalities in childhood de novo acute myeloid leukaemia (AML) and its prognostic significance was assessed in an Israeli paediatric referral centre. Cytogenetic analysis was successful in 86 of 97 children (< 20 years of age) diagnosed between 1988 and 2002 with de novo AML. Fluorescence in situ hybridization analysis detected new information in 11 of them, leading to reassignment in cytogenetic group classification. The incidence of the various cytogenetic subgroups was as follows: normal - 9%; t(11q23) - 22%; t(8;21) - 13%; t(15;17) - 8%; inv(16) - 3.4%; abn(3q) - 4.6%; 7/7q-(sole or main) - 5.8%; del(9q)(sole) and +21(sole) - 4.6% each; t(8;16) - 2.3%; t(6;9), t(1;22), +8(sole) - 1.1% each; and miscellaneous - 18%. The overall survival (OS) and event-free survival (EFS) (4 years) for 94 patients treated with the modified Berlin-Frankfürt-Münster (BFM) AML protocols (non-irradiated) were 59.9% (SE = 5%) and 55.7% (SE = 5%), respectively, and for the favourable t(8;21), t(15;17) and inv(16), OS was 60% (SE = 15%), 83% (SE = 15%) and 100% respectively. For the normal group it was 62% (SE = 17%), miscellaneous 64% (SE = 12%), t(11q23) 44.6% (SE = 11%) and of the -7/7q-, del(9q)(sole) or t(6;9), none had survived at 4 years. The incidence of cytogenetic subgroups in the Israeli childhood AML population and their outcome were similar to other recently reported paediatric series. Cytogenetic abnormalities still carry clinical relevance for treatment stratification in the context of modern chemotherapy.
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http://dx.doi.org/10.1111/j.1365-2141.2004.05038.xDOI Listing
August 2004

der(11)t(11;17): a distinct cytogenetic pathway of advanced stage neuroblastoma (NBL) - detected by spectral karyotyping (SKY).

Cancer Lett 2003 Jul;197(1-2):75-9

Schneider Children's Medical Center of Israel, Tel Aviv University, Tel Aviv, Israel.

Conventional cytogenetic, molecular cytogenic and genetic methods disclosed a broad spectrum of genetic abnormalities leading to gain and loss of chromosomal segments in advanced stage neuroblastoma (NBL). Specific correlation between the genetic findings could delineate distinct genetic pathways, of which the biology and prognostic significance is as yet undetermined. Using spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) on metaphases from 16 patients with advanced stage NBL, it was possible to explore the whole spectrum of rearrangement within complex karyotypes and to detect hidden recurrent translocations. All translocations were unbalanced. The most prevalent recurrent unbalanced translocations resulted in 17q gain in 12 patients (75%), 11q loss in nine patients (56%), and 1p deletion/imbalance in eight patients (50%). The most frequent recurrent translocation was der(11)t(11;17) in six patients. Three cytogenetic pathways could be delineated. The first, with six patients, was characterized by the unbalanced translocation der(11)t(11;17), detected only by SKY, resulting in the concomitant 17q gain and 11q loss. No MYCN amplification or 1p deletion (except one patient with 1p imbalance) were found, while 3p deletion, and complex karyotypes were common. The second subgroup, with four patients, had 17q gain and 1p deletion, and in two patients 11q loss, that was apparent only by FISH. 1p deletion occurred through der(1)t(1;17) or del(1p). The third subgroup of four patients was characterized by MYCN amplification with 17q gain and 1p deletion, very rarely with 11q loss (one patient) through a translocation with a non-17q partner. The SKY subclassifications were in accordance with the findings reported by molecular genetic techniques, and may indicate that distinct oncogenes and suppressor genes are involved in the der(11)t(11;17) pathway of advanced stage NBL.
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http://dx.doi.org/10.1016/s0304-3835(03)00083-1DOI Listing
July 2003

Acquired trisomy 21 and distinct clonal evolution in acute megakaryoblastic leukaemia in young monozygotic twins.

Br J Haematol 2002 Sep;118(4):1082-6

Cancer Cytogenetic Laboratory and Centre of Paediatric Haematology/Oncology, Schneider Children's Medical Centre of Israel, Petah Tiqva, Israel.

An intrauterine origin of childhood acute lymphoblastic leukaemia (ALL) was proven by the identical clonotypic gene rearrangement in the concordant leukaemias of monozygotic twins, arising from a single clonogenic progeny. The monozygotic twins, presented at the age of 22 months with acute megakaryoblastic leukaemia (AML-M7) in one and myelodysplasia transformed to AML-M7 in the other. Leukaemic cells in both twins carried trisomy 21 and additional different clonal evolution changes of del(20q) in the first twin and trisomy 8 in the second. AML-M7 of late infancy with trisomy 21 may be included in the leukaemias of intrauterine origin, possibly a result of genotoxic insult.
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http://dx.doi.org/10.1046/j.1365-2141.2002.03756.xDOI Listing
September 2002

Distinct cytogenetic pathways of advanced-stage neuroblastoma tumors, detected by spectral karyotyping.

Genes Chromosomes Cancer 2002 Jul;34(3):313-24

Cancer Cytogenetic Laboratory, Schneider Children's Medical Center of Israel, Petah Tiqva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Molecular studies of advanced-stage neuroblastoma (NBL) have revealed a marked genetic heterogeneity. In addition to MYCN amplification and chromosome 1 short-arm deletions/translocations detected by conventional cytogenetics, application of fluorescence in situ hybridization has disclosed a high prevalence of 17q gain, whereas allelotyping and comparative genomic hybridization techniques also have revealed loss of 11q and of other chromosomal material. Using the recently developed technique of spectral karyotyping (SKY), we sought to refine the cytogenetic information, identify hidden recurrent structural chromosomal abnormalities, and compare them to the molecular findings. Thirteen samples of metaphase spreads from 11 patients with advanced-stage NBL were analyzed by SKY. Most of them were found to have complex karyotypes (more than three changes per metaphase) and complex unbalanced rearrangements. Recurrent aberrations leading to 17q gain, deletion of 1p, MYCN amplification, and loss of 11q appeared in 7, 4, 4, and 5 patients, respectively, in simple and complex karyotypes. Chromosome 3 changes and gain of 1q and 7q appeared in 6, 5, and 4 patients, respectively, in complex karyotypes only, reflecting later changes. A strikingly high prevalence of the unbalanced translocation der(11)t(11;17), leading to concomitant 11q loss and 17q gain in 4 patients, delineated a distinct cytogenetic group, none having 1p deletion and/or MYCN amplification. der(11)t(11;17) was associated with complex karyotypes with changes in chromosomes 3 and 7q. The 17q translocations with partners other than 11q were associated with 1p deletion and/or MYCN amplification. The distinct cytogenetic subgroups identified by SKY confirm and extend the recent molecular observations, and suggest that different genes may interact in the der(11)t(11;17) pathway of NBL development and progression.
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http://dx.doi.org/10.1002/gcc.10082DOI Listing
July 2002
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