| 1. |
- Gunnarsson, Rebeqa, et al.
(författare)
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Mutation, methylation, and gene expression profiles in dup(1q)-positive pediatric B-cell precursor acute lymphoblastic leukemia
- 2018
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 32:10, s. 2117-2125
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Tidskriftsartikel (refereegranskat)abstract
- High-throughput sequencing was applied to investigate the mutation/methylation patterns on 1q and gene expression profiles in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL) with/without (w/wo) dup(1q). Sequencing of the breakpoint regions and all exons on 1q in seven dup(1q)-positive cases revealed non-synonymous somatic single nucleotide variants (SNVs) in BLZF1, FMN2, KCNT2, LCE1C, NES, and PARP1. Deep sequencing of these in a validation cohort w (n = 17)/wo (n = 94) dup(1q) revealed similar SNV frequencies in the two groups (47% vs. 35%; P = 0.42). Only 0.6% of the 36,259 CpGs on 1q were differentially methylated between cases w (n = 14)/wo (n = 13) dup(1q). RNA sequencing of high hyperdiploid (HeH) and t(1;19)(q23;p13)-positive cases w (n = 14)/wo (n = 52) dup(1q) identified 252 and 424 differentially expressed genes, respectively; only seven overlapped. Of the overexpressed genes in the HeH and t(1;19) groups, 23 and 31%, respectively, mapped to 1q; 60-80% of these encode nucleic acid/protein binding factors or proteins with catalytic activity. We conclude that the pathogenetically important consequence of dup(1q) in BCP ALL is a gene-dosage effect, with the deregulated genes differing between genetic subtypes, but involving similar molecular functions, biological processes, and protein classes.
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| 2. |
- Castor, Anders, et al.
(författare)
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The ethics of palliative sedation in children
- 2016
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Konferensbidrag (refereegranskat)abstract
- At the end of life, when cure or meaningful prolongation of life is no longer available, relief of suffering is the overriding goal. In certain circumstances standard treatments may fall short of this goal, and palliative sedation (PS) to unconsciousness can be applied as a ultimum refugium.We cared for a 4-year old boy with a brain-stem tumor. In spite of all curative treatment efforts the tumor slowly but steadily progressed. All tumor-directed therapy was eventually abandoned, and together with the family efforts were focused on comfort. The child lost his ability to speak and communication became very difficult, he had difficulties swallowing, got a noisy breathing and was believed to have pain. The child was admitted for titration of pain medication and assessment of any breathing problems. In the course of a few days his condition deteriorated with noisier breathing and signs of continuing pain. The child seemed distressed and anxious, but the degree of symptoms was very difficult to assess with certainty. PS to unconsciousness is begun a week after admission, and continues for 2 weeks before he dies.The literature concerning PS for children is very sparse, and we want to explore the scope of indication and implementation, from an ethical point of view, for this small but vulnerable population. In what regard, and to which degree, does it matter that the child is not decision competent? Which symptoms, and how severe need they be, to allow PS? For how long can it be given? Can hydration and nutrition be foregone? How stringent need the indication be – or on which side would one prefer to err – in giving or withholding PS? How should the patient be monitored during PS, and why?
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| 3. |
- Karrman, Kristina, et al.
(författare)
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Deep sequencing and SNP array analyses of pediatric T-cell acute lymphoblastic leukemia reveal NOTCH1 mutations in minor subclones and a high incidence of uniparental isodisomies affecting CDKN2A
- 2015
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Ingår i: Journal of Hematology & Oncology. - : Springer Science and Business Media LLC. - 1756-8722. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease that arises in a multistep fashion through acquisition of several genetic aberrations, subsequently giving rise to a malignant, clonal expansion of T-lymphoblasts. The aim of the present study was to identify additional as well as cooperative genetic events in T-ALL.Methods: A population-based pediatric T-ALL series comprising 47 cases was investigated by SNP array and deep sequencing analyses of 75 genes, in order to ascertain pathogenetically pertinent aberrations and to identify cooperative events.Results: The majority (92%) of cases harbored copy number aberrations/uniparental isodisomies (UPIDs), with a median of three changes (range 0-11) per case. The genes recurrently deleted comprised CDKN2A, CDKN2B, LEF1, PTEN, RBI, and STIL. No case had a whole chromosome UPID; in fact, literature data show that this is a rare phenomenon in T-ALL. However, segmental UPIDs (sUPIDs) were seen in 42% of our cases, with most being sUPID9p that always were associated with homozygous CDKN2A deletions, with a heterozygous deletion occurring prior to the sUPID9p in all instances. Among the 75 genes sequenced, 14 (19%) were mutated in 28 (72%) of 39 analyzed cases. The genes targeted are involved in signaling transduction, epigenetic regulation, and transcription. In some cases, NOTCH1 mutations were seen in minor subclones and lost at relapse; thus, such mutations can be secondary events.Conclusions: Deep sequencing and SNP array analyses of T-ALL revealed lack of wUPIDs, a high proportion of sUPID9p targeting CDKN2A, NOTCH1 mutations in subclones, and recurrent mutations of genes involved in signaling transduction, epigenetic regulation, and transcription.
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| 4. |
- Lan, Bui Ngoc, et al.
(författare)
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Adherence to childhood cancer treatment : A prospective cohort study from Northern Vietnam
- 2019
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 9:8, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Global incidence and attention to childhood cancer is increasing and treatment abandonment is a major cause of treatment failure in low-and middle-income countries. The purpose of this study was to gain an understanding of factors contributing to non-adherence to treatment. Design A prospective cohort study with 2 year follow-up of incidence, family-reported motives and risk factors. Setting The largest tertiary paediatric oncology centre in Northern Vietnam. Participants All children offered curative cancer treatment, from January 2008 to December 2009. Primary and secondary outcome measures Family decision to start treatment was analysed with multivariable logistic regression, and family decision to continue treatment was analysed with a multivariable Cox model. This assessment of non-adherence is thereby methodologically consistent with the accepted definitions and recommended practices for evaluation of treatment abandonment. Results Among 731 consecutively admitted patients, 677 were eligible for treatment and were followed for a maximum 2 years. Almost half the parents chose to decline curative care (45.5%), either before (35.2%) or during (10.3%) the course of treatment. Most parents reported perceived poor prognosis as the main reason for non-adherence, followed by financial constraints and traditional medicine preference. The odds of starting treatment increased throughout the study-period (OR 1.04 per month (1.01 to 1.07), p=0.002), and were independently associated with prognosis (OR 0.51 (0.41 to 0.64), p=<0.0001) and travel distance to hospital (OR 0.998 per km (0.996 to 0.999), p=0.004). The results also suggest that adherence to initiated treatment was significantly higher among boys than girls (HR 1.69 (1.05 to 2.73), p=0.03). Conclusions Non-adherence influenced the prognosis of childhood cancer, and was associated with cultural and local perceptions of cancer and the economic power of the affected families. Prevention of abandonment is a prerequisite for successful cancer care, and a crucial early step in quality improvements to care for all children with cancer.
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| 5. |
- Lilljebjörn, Henrik, et al.
(författare)
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Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia
- 2016
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11790
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Tidskriftsartikel (refereegranskat)abstract
- Fusion genes are potent driver mutations in cancer. In this study, we delineate the fusion gene landscape in a consecutive series of 195 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL). Using RNA sequencing, we find in-frame fusion genes in 127 (65%) cases, including 27 novel fusions. We describe a subtype characterized by recurrent IGH-DUX4 or ERG-DUX4 fusions, representing 4% of cases, leading to overexpression of DUX4 and frequently co-occurring with intragenic ERG deletions. Furthermore, we identify a subtype characterized by an ETV6-RUNX1-like gene-expression profile and coexisting ETV6 and IKZF1 alterations. Thus, this study provides a detailed overview of fusion genes in paediatric BCP ALL and adds new pathogenetic insights, which may improve risk stratification and provide therapeutic options for this disease.
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| 6. |
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| 7. |
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| 8. |
- Olsson, Linda, et al.
(författare)
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Cooperative Genetic Changes in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia with Deletions or Mutations of IKZF1
- 2015
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley: 12 months. - 1045-2257 .- 1098-2264. ; 54:5, s. 315-325
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Tidskriftsartikel (refereegranskat)abstract
- In contrast to IKZF1 deletions (IKZF1), IKZF1 sequence mutations (mutIKZF1) have been reported to be rare in B-cell precursor acute lymphoblastic leukemia and their clinical implications are unknown. We performed targeted deep sequencing of all exons of IKZF1 in 140 pediatric cases, eight (5.7%) of which harbored a mutIKZF1. The probabilities of relapse (pRel) and event-free survival (pEFS) did not differ between cases with or without mutIKZF1, whereas pEFS was decreased and pRel increased in IKZF1-positive case. Coexisting microdeletions, mutations (FLT3, JAK2, SH2B3, and SPRED1), and rearrangements (ABL1, CRLF2, JAK2, and PDGFRB) in 35 IKZF1 and/or mutIKZF1-positive cases were ascertained using fluorescence in situ hybridization, single nucleotide polymorphism array, Sanger, and targeted deep sequencing analyses. The overall frequencies of copy number alterations did not differ between cases with our without IKZF1/mutIKZF1. Deletions of HIST1, SH2B3, and the pseudoautosomal region (PAR1), associated with deregulation of CRLF2, were more common in IKZF1-positive cases, whereas PAR1 deletions and JAK2 mutations were overrepresented in the combined IKZF1/mutIKZF1 group. There was no significant impact on pRel of the deletions in IKZF1-positive cases or of JAK2 mutations in cases with IKZF1/mutIKZF1. In contrast, the pRel was higher (P=0.005) in IKZF1/mutIKZF1-positive cases with PAR1 deletions. (c) 2015 Wiley Periodicals, Inc.
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| 9. |
- Olsson, Linda, et al.
(författare)
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Improved cytogenetic characterization and risk stratification of pediatric acute lymphoblastic leukemia using single nucleotide polymorphism array analysis : A single center experience of 296 cases
- 2018
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Ingår i: Genes Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 57:11, s. 604-607
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Tidskriftsartikel (refereegranskat)abstract
- Single nucleotide polymorphism array (SNP-A) analyses are increasingly being introduced in routine genetic diagnostics of acute lymphoblastic leukemia (ALL). Despite this, only few studies that have compared the diagnostic value of SNP-A with conventional chromosome banding have been published. We here report such a comparison of 296 ALL cases, the largest series to date. Only genomic imbalances >5 Mb and microdeletions targeting the BTG1, CDKN2A/B, EBF1, ERG, ETV6, IKZF1, PAX5, and RB1 genes and the pseudoautosomal region 1 (PAR1) were ascertained, in agreement with recent guidelines. Of 36 T-cell ALL cases, the karyotypes of 24 cases (67%) were revised by SNP-A analyses that either revealed additional imbalances >5 Mb or better characterized the changes found by G-banding. Of 260 B-cell precursor (BCP) ALL cases, SNP-A analyses identified additional copy number alterations, including the above-mentioned microdeletions, or better characterized the imbalances found by G-banding in 236 (91%) cases. Furthermore, the cytogenetic subtype classification of 41/260 (16%) BCP ALL cases was revised based on the SNP-A findings. Of the subtype revisions, 12/41 (29%) had clinical implications as regards risk stratifying cytogenetic groups or genotype-specific minimal residual disease stratification. We conclude that SNP-A analyses dramatically improve the cytogenetic characterization of both T-cell and BCP ALL and also provide important information pertinent to risk stratification of BCP ALL.
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| 10. |
- Olsson, Linda, et al.
(författare)
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The genetic landscape of paediatric de novo acute myeloid leukaemia as defined by single nucleotide polymorphism array and exon sequencing of 100 candidate genes
- 2016
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Ingår i: British Journal of Haematology. - Chichester : Wiley-Blackwell. - 0007-1048 .- 1365-2141. ; 174:2, s. 292-301
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Tidskriftsartikel (refereegranskat)abstract
- Cytogenetic analyses of a consecutive series of 67 paediatric (median age 8 years; range 0-17) de novo acute myeloid leukaemia (AML) patients revealed aberrations in 55 (82%) cases. The most common subgroups were KMT2A rearrangement (29%), normal karyotype (15%), RUNX1-RUNX1T1 (10%), deletions of 5q, 7q and/or 17p (9%), myeloid leukaemia associated with Down syndrome (7%), PML-RARA (7%) and CBFBMYH11 (5%). Single nucleotide polymorphism array (SNP-A) analysis and exon sequencing of 100 genes, performed in 52 and 40 cases, respectively (39 overlapping), revealed >= 1 aberration in 89%; when adding cytogenetic data, this frequency increased to 98%. Uniparental isodisomies (UPIDs) were detected in 13% and copy number aberrations (CNAs) in 63% (median 2/case); three UPIDs and 22 CNAs were recurrent. Twenty-two genes were targeted by focal CNAs, including AEBP2 and PHF6 deletions and genes involved in AML-associated gene fusions. Deep sequencing identified mutations in 65% of cases (median 1/case). In total, 60 mutations were found in 30 genes, primarily those encoding signalling proteins (47%), transcription factors (25%), or epigenetic modifiers (13%). Twelve genes (BCOR, CEBPA, FLT3, GATA1, KIT, KRAS, NOTCH1, NPM1, NRAS, PTPN11, SMC3 and TP53) were recurrently mutated. We conclude that SNP-A and deep sequencing analyses complement the cytogenetic diagnosis of paediatric AML.
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