Mutation, methylation, and gene expression profiles in dup(1q)-positive pediatric B-cell precursor acute lymphoblastic leukemia

Gunnarsson, R; DiLorenzo, Sebastian; Lundin-Ström, Kristina B.; Olsson, Linda; Biloglav, Andrea; Lilljebjörn, Henrik; Rissler, Marianne; Wahlberg, Per; Lundmark, Anders; Castor, Anders; Behrendtz, Mikael; Fioretos, Thoas; Paulsson, Kajsa; Isaksson, Anders; Johansson, Bertil

doi:10.1038/s41375-018-0092-2

Cited by 5 publications

(6 citation statements)

References 48 publications

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“…In the present study, unlike the numerical abnormalities, the structural tended to be random which goes in agreement with that previously reported 2,7,19 . We detected dup(1q) in 15% of c‐HeH patients, and this goes in concordance with previous studies 20‐22 that reported dup (1q) to be present in about 10‐15% of HeH cases.…”

Section: Discussionsupporting

confidence: 93%

Duplication 1q is highly correlated with poor prognosis in high hyperdiploid pediatric B‐acute lymphoblastic leukemia

Ashry

El-Sayed

Madney

et al. 2020

Int J Lab Hematology

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Background The role of structural abnormalities in high hyperdiploidy (HeH) has been debatable, with few studies that addressed recurrent translocations with concurrent HeH (t‐HeH). We aimed at the characterization of HeH cases in pediatric B‐acute lymphoblastic leukemia (B‐ALL) patients with special emphasis on the structural abnormalities including t‐HeH. Patients and methods Our study included all patients diagnosed with HeH over the period from January 2016 to April 2019 presenting to the Pediatric Oncology Department, National Cancer Institute, Cairo University. Results Among 480 de novo B‐ALL pediatric patients, HeH was detected in eighty (16.7%) cases with a median age of 5 years. t‐HeH was identified in 17/480 (3.5%) cases: 9(1.9%) with t(12;21), 7(1.5%) with t(9;22), and 1(0.2%) with t(4;11). Duplication (1q) was the most prevalent structural abnormality in c‐HeH (hyperdiploidy without recurrent translocations) (n = 12,15%). Children ≥10 years or presenting with white blood cells (WBC) ≥50 × 109/L) had an inferior 3 year‐overall survival as compared to younger children (P = .003), and to lower WBC (P = .02). Duplication (1q) was an independent adverse parameter on the disease‐free survival (DFS) of c‐HeH patients (P = .004). Conclusions Older age and WBC ≥ 50 × 109/L were adverse prognostic factors. Duplication (1q) is correlated with lower DFS in c‐HeH patients. t‐HeH has distinct patterns of chromosomal gain.

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Section: Discussionsupporting

confidence: 93%

Duplication 1q is highly correlated with poor prognosis in high hyperdiploid pediatric B‐acute lymphoblastic leukemia

Ashry

El-Sayed

Madney

et al. 2020

Int J Lab Hematology

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“…There is sporadic data on the expression of GAS5 in hematological malignancies. It was found that GAS5 was overexpressed in pediatric B-cell precursor acute lymphoblastic leukemia, specifically in high hyperdiploid (HeH) and t(1;19)(q23;p13)-positive cases (23). However, it is essential to underline that GAS5 gene is located on chromosome 1q and that its increased expression level could be a consequence of a gene dosage effect in subtypes of childhood ALL characterised by a gain of 1q through duplication or an unbalanced translocation.…”

Section: Discussionmentioning

confidence: 99%

Expression pattern of long non-coding RNA growth arrest-specific 5 in the remission induction therapy in childhood acute lymphoblastic leukemia

Gašić¹,

Stanković²,

Zukić³

et al. 2019

Journal of Medical Biochemistry

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Summary Background Long non-coding RNA growth arrest-specific 5 (GAS5) is deregulated in many cancers because of its role in cell growth arrest and apoptosis. Additionally, GAS5 interacts with glucocorticoid receptor, making it a potential pharmacotranscription marker of glucocorticoid (GC) therapy. In this study, we aimed at analysing GAS5 expression in the remission induction therapy phase of childhood acute lymphoblastic leukemia (ALL), in which GCs are mandatorily used, and to correlate it with therapy response. Methods GAS5 expression was measured in peripheral blood mononuclear cells taken from 29 childhood ALL patients at diagnosis, on day 15 and day 33 of remission induction therapy using RT-qPCR methodology. Results Our results have shown interindividual differences in GAS5 expression at all time points. For each ALL patient, GAS5 expression was higher on day 15 in comparison to its level at diagnosis (p<0.0005). On day 33, the level of GAS5 expression decreased in comparison with day 15 (p<0.0005), but it was still significantly higher than at diagnosis for the majority of patients (p=0.001). Patients whose number of blasts on day 8 was below 100 per μL of peripheral blood had a higher GAS5 expression at diagnosis (p=0.016), and lower ratio day 15/diagnosis (p=0.009). Conclusions Our results suggest that the expression level of GAS5 could be a potential marker of therapy response in remission induction therapy of childhood ALL.

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“…S9). Gain of the q arm of chromosome 1, a common genomic aneuploidy in ALL 24 was observed in the linked-read data from patient ALL_689, but not in the diagnostic karyotype.…”

Section: Translocations T(12;21) and T(9;22) The T(12;21)[etv6-runx1mentioning

confidence: 90%

Refined detection and phasing of structural aberrations in pediatric acute lymphoblastic leukemia by linked-read whole-genome sequencing

Nordlund

Marincevic-Zuniga

Cavelier

et al. 2020

Sci Rep

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Structural chromosomal rearrangements that can lead to in-frame gene-fusions are a leading source of information for diagnosis, risk stratification, and prognosis in pediatric acute lymphoblastic leukemia (ALL). Traditional methods such as karyotyping and FISH struggle to accurately identify and phase such large-scale chromosomal aberrations in ALL genomes. We therefore evaluated linked-read WGS for detecting chromosomal rearrangements in primary samples of from 12 patients diagnosed with ALL. We assessed the effect of input DNA quality on phased haplotype block size and the detectability of copy number aberrations and structural variants in the ALL genomes. We found that biobanked DNA isolated by standard column-based extraction methods was sufficient to detect chromosomal rearrangements even at low 10x sequencing coverage. Linked-read WGS enabled precise, allelespecific, digital karyotyping at a base-pair resolution for a wide range of structural variants including complex rearrangements and aneuploidy assessment. With use of haplotype information from the linked-reads, we also identified previously unknown structural variants, such as a compound heterozygous deletion of ERG in a patient with the DUX4-IGH fusion gene. We conclude that linked-read WGS allows detection of important pathogenic variants in ALL genomes at a resolution beyond that of traditional karyotyping and FISH. Sequencing of complete human genomes has become feasible owing to next generation sequencing (NGS) technologies, but detection of the whole spectrum of somatic single nucleotide variants (SNVs), copy number alterations (CNAs), and structural variations (SVs) in cancer cells remains challenging 1. The human genome is diploid, and molecular haplotyping of the two alleles across large genomic regions is beyond the resolution of standard short-read NGS technologies 2. "Linked-read" technology, by which single DNA molecules are massively barcoded in a microfluidic format and subsequently sequenced using short-read NGS technology, allows determination of molecular haplotypes across mega-base regions of the genome 3-5. An advantage of linked-read whole genome sequencing (WGS) is its enhanced ability to detect the breakpoints of SVs and to provide long-range haplotype information for phasing SNVs and SVs. Linked-read WGS has the potential to provide an ordered view of the structure of all genetic variants in a genome, shown by assignment of complex SVs, chromosomal rearrangements, and CNAs to individual chromosomes in germline and cancer genomes 3,5,6. Structural chromosomal rearrangements that may lead to aberrant gene-fusions are used for diagnosis, risk stratification and prognosis in pediatric acute lymphoblastic leukemia (ALL) 7. Several recurrent chromosomal

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Mutation, methylation, and gene expression profiles in dup(1q)-positive pediatric B-cell precursor acute lymphoblastic leukemia

Cited by 5 publications

References 48 publications

Duplication 1q is highly correlated with poor prognosis in high hyperdiploid pediatric B‐acute lymphoblastic leukemia

Duplication 1q is highly correlated with poor prognosis in high hyperdiploid pediatric B‐acute lymphoblastic leukemia

Expression pattern of long non-coding RNA growth arrest-specific 5 in the remission induction therapy in childhood acute lymphoblastic leukemia

Refined detection and phasing of structural aberrations in pediatric acute lymphoblastic leukemia by linked-read whole-genome sequencing

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