| 1. |
- Anh, Nhi, et al.
(författare)
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High-resolution detection of chromosomal rearrangements in leukemias through mate pair whole genome sequencing
- 2018
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- The detection of recurrent somatic chromosomal rearrangements is standard of care for most leukemia types. Even though karyotype analysis-a low-resolution genome-wide chromosome analysis-is still the gold standard, it often needs to be complemented with other methods to increase resolution. To evaluate the feasibility and applicability of mate pair whole genome sequencing (MP-WGS) to detect structural chromosomal rearrangements in the diagnostic setting, we sequenced ten bone marrow samples from leukemia patients with recurrent rearrangements. Samples were selected based on cytogenetic and FISH results at leukemia diagnosis to include common rearrangements of prognostic relevance. Using MP-WGS and in-house bioinformatic analysis all sought rearrangements were successfully detected. In addition, unexpected complexity or additional, previously undetected rearrangements was unraveled in three samples. Finally, the MP-WGS analysis pinpointed the location of chromosome junctions at high resolution and we were able to identify the exact exons involved in the resulting fusion genes in all samples and the specific junction at the nucleotide level in half of the samples. The results show that our approach combines the screening character from karyotype analysis with the specificity and resolution of cytogenetic and molecular methods. As a result of the straightforward analysis and high-resolution detection of clinically relevant rearrangements, we conclude that MP-WGS is a feasible method for routine leukemia diagnostics of structural chromosomal rearrangements.
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| 2. |
- Ivanov Öfverholm, Ingegerd, et al.
(författare)
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Detailed gene dose analysis reveals recurrent focal gene deletions in pediatric B-cell precursor acute lymphoblastic leukemia
- 2016
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Ingår i: Leukemia & Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 57:9, s. 2161-2170
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Tidskriftsartikel (refereegranskat)abstract
- To identify copy number alterations (CNAs) in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL), array comparative genomic hybridization was performed on 50 cases; detected CNAs were validated in a cohort of 191 cases analyzed by single nucleotide polymorphism arrays. Apart from CNAs involving leukemia-associated genes, recurrent deletions targeting genes not previously implicated in BCP ALL, e.g. INIP, IRF1 and PDE4B, were identified. Deletions of the DNA repair gene INIP were exclusively found in cases with t(12;21), and deletions of SH2B3 were associated with intrachromosomal amplification of chromosome 21 (p
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| 3. |
- Ivanov Öfverholm, Ingegerd
(författare)
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Identification and evaluation of novel prognostic genetic markers for childhood acute lymphoblastic leukemia
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Childhood acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer today. Due to advances in risk stratification and treatment, survival rates have increased drastically the last decades. Currently, children with acute leukemia in the Nordic countries are diagnosed and treated according to the NOPHO-2008 treatment protocol. In this protocol, a number of cytogenetic markers are used for risk stratification and guidance of treatment intensity. However, genetic markers associated with high risk are infrequent and relapses occur across all genetic subtypes, including those associated with a favorable outcome. Importantly, over 25% of childhood ALL cases harbor none of the currently used genetic risk markers in their bone marrow cells at diagnosis. The aim of this thesis was to generate a greater understanding of the genetic landscape in ALL, as well as to identify novel genetic markers of prognostic relevance, with special focus on the group of patients lacking risk-stratifying markers. In paper I, we investigated the frequency and prognostic impact of IKZF1 deletions in patients diagnosed with B-cell precursor (BCP) ALL in the Stockholm region; IKZF1 deletions were present in 15% of cases and significantly associated with inferior outcome. These results led to paper II, where the cohort was extended to include BCP ALL cases with available IKZF1 data from other centers in Sweden. This study verified that IKZF1 deletion was an independent risk factor for decreased survival, and could confirm that the frequency and prognostic effect was most pronounced in patients without risk-stratifying markers. A high frequency of IKZF1 deletions could also be detected in paper III, where we investigated the genetic copy number landscape of BCP ALL across the different cytogenetic subtypes. This study showed that a majority of cases without risk-stratifying markers harbor deletions with potential prognostic significance, suggesting that a large proportion of this group could be assigned to distinct genetic subtypes. Intrachromosomal amplification of chromosome 21 (iAMP21) is an intermediate/high-risk subtype for which the biological cause of the high relapse risk is unknown. In paper IV, we used an integrated molecular approach to investigate the iAMP21 subtype, and identified significant overexpression of tree potential candidate genes, i.e. DYRK1A, SON and CHAF1B, with leukemia-relevant functions that could represent future targets for therapy. Together, these studies have identified a number of potential novel prognostic genetic markers that may contribute to the clinical risk-evaluation of children diagnosed with BCP ALL, and to our understanding of the biology behind relapse and poor outcome in this disease.
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| 4. |
- Krali, Olga, et al.
(författare)
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Multimodal classification of molecular subtypes in pediatric acute lymphoblastic leukemia
- 2023
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Ingår i: npj Precision Oncology. - : Springer Nature. - 2397-768X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Genomic analyses have redefined the molecular subgrouping of pediatric acute lymphoblastic leukemia (ALL). Molecular subgroups guide risk-stratification and targeted therapies, but outcomes of recently identified subtypes are often unclear, owing to limited cases with comprehensive profiling and cross-protocol studies. We developed a machine learning tool (ALLIUM) for the molecular subclassification of ALL in retrospective cohorts as well as for up-front diagnostics. ALLIUM uses DNA methylation and gene expression data from 1131 Nordic ALL patients to predict 17 ALL subtypes with high accuracy. ALLIUM was used to revise and verify the molecular subtype of 281 B-cell precursor ALL (BCP-ALL) cases with previously undefined molecular phenotype, resulting in a single revised subtype for 81.5% of these cases. Our study shows the power of combining DNA methylation and gene expression data for resolving ALL subtypes and provides a comprehensive population-based retrospective cohort study of molecular subtype frequencies in the Nordic countries.
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| 5. |
- Öfverholm, Ingegerd, et al.
(författare)
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The prognostic impact of IKZF1 deletions and UKALL genetic classifiers in paediatric B-cell precursor acute lymphoblastic leukaemia treated according to NOPHO 2008 protocols
- 2023
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Ingår i: British Journal of Haematology. - : Wiley-Blackwell. - 0007-1048 .- 1365-2141. ; 202:2, s. 384-392
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Tidskriftsartikel (refereegranskat)abstract
- We investigated 390 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) patients treated according to NOPHO ALL 2008, regarding copy number alterations (CNA) of eight loci associated with adverse prognosis, including IKZF1. The impact on outcome was investigated for each locus individually, combined as CNA profiles and together with cytogenetic information. The presence of IKZF1 deletion or a poor-risk CNA profile was associated with poor outcome in the whole cohort. In the standard-risk group, IKZF1-deleted cases had an inferior probability of relapse-free survival (pRFS) (p <= 0.001) and overall survival (pOS) (p <= 0.001). Additionally, among B-other patients, IKZF1 deletion correlated with poor pRFS (60% vs. 90%) and pOS (65% vs. 89%). Both IKZF1 deletion and a poor-risk CNA profile were independent factors for relapse and death in multivariable analyses adjusting for known risk factors including measurable residual disease. Our data indicate that BCP-ALL patients with high-risk CNA or IKZF1 deletion have worse prognosis despite otherwise low-risk features. Conversely, patients with both a good CNA and cytogenetic profile had a superior relapse-free (p <= 0.001) and overall survival (p <= 0.001) in the cohort, across all risk groups. Taken together, our findings highlight the potential of CNA assessment to refine stratification in ALL.
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