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| 2. |
- Chen, Dongfeng, et al.
(författare)
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CD99 expression is strongly associated with clinical outcome in children with B-cell precursor acute lymphoblastic leukaemia
- 2019
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 184:3, s. 418-423
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Tidskriftsartikel (refereegranskat)abstract
- Our study aimed to determine the expression pattern and clinical relevance of CD99 in paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Our findings demonstrate that high expression levels of CD99 are mainly found in high-risk BCP-ALL, e.g. BCR-ABL1 and CRLF2 Re/Hi, and that high CD99 mRNA levels are strongly associated with a high frequency of relapse, high proportion of positive for minimal residual disease at day 29 and poor overall survival in paediatric cohorts, which indicate that CD99 is a potential biomarker for BCP-ALL.
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| 3. |
- Chen, Dongfeng, et al.
(författare)
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The Expression Pattern of the Pre-B Cell Receptor Components Correlates with Cellular Stage and Clinical Outcome in Acute Lymphoblastic Leukemia.
- 2016
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- Precursor-B cell receptor (pre-BCR) signaling represents a crucial checkpoint at the pre-B cell stage. Aberrant pre-BCR signaling is considered as a key factor for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) development. BCP-ALL are believed to be arrested at the pre-BCR checkpoint independent of pre-BCR expression. However, the cellular stage at which BCP-ALL are arrested and whether this relates to expression of the pre-BCR components (IGHM, IGLL1 and VPREB1) is still unclear. Here, we show differential protein expression and copy number variation (CNV) patterns of the pre-BCR components in pediatric BCP-ALL. Moreover, analyzing six BCP-ALL data sets (n = 733), we demonstrate that TCF3-PBX1 ALL express high levels of IGHM, IGLL1 and VPREB1, and are arrested at the pre-B stage. By contrast, ETV6-RUNX1 ALL express low levels of IGHM or VPREB1, and are arrested at the pro-B stage. Irrespective of subtype, ALL with high levels of IGHM, IGLL1 and VPREB1 are arrested at the pre-B stage and correlate with good prognosis in high-risk pediatric BCP-ALL (n = 207). Our findings suggest that BCP-ALL are arrested at different cellular stages, which relates to the expression pattern of the pre-BCR components that could serve as prognostic markers for high-risk pediatric BCP-ALL patients.
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| 4. |
- Deland, Lily, et al.
(författare)
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Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib
- 2021
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Ingår i: Cancer Biology & Therapy. - : Taylor & Francis. - 1538-4047 .- 1555-8576. ; 22:3, s. 184-195
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Tidskriftsartikel (refereegranskat)abstract
- Here we report a case of an 11-year-old girl with an inoperable tumor in the optic chiasm/hypothalamus, who experienced several tumor progressions despite three lines of chemotherapy treatment. Routine clinical examination classified the tumor as a BRAF-negative pilocytic astrocytoma. Copy-number variation profiling of fresh frozen tumor material identified two duplications in 9q21.32–33 leading to breakpoints within the GKAP1 and NTRK2 genes. RT-PCR Sanger sequencing revealed a GKAP1-NTRK2 exon 10–16 in-frame fusion, generating a putative fusion protein of 658 amino acids with a retained tyrosine kinase (TK) domain. Functional analysis by transient transfection of HEK293 cells showed the GKAP1-NTRK2 fusion protein to be activated through phosphorylation of the TK domain (Tyr705). Subsequently, downstream mediators of the MAPK- and PI3K-signaling pathways were upregulated in GKAP1-NTRK2 cells compared to NTRK2 wild-type; phosphorylated (p)ERK (3.6-fold), pAKT (1.8- fold), and pS6 ribosomal protein (1.4-fold). Following these findings, the patient was enrolled in a clinical trial and treated with the specific TRK-inhibitor larotrectinib, resulting in the arrest of tumor growth. The patient’s condition is currently stable and the quality of life has improved significantly. Our findings highlight the value of comprehensive clinical molecular screening of BRAF-negative pediatric low-grade gliomas, to reveal rare fusions serving as targets for precision therapy.
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| 5. |
- Fogelstrand, Linda, 1974, et al.
(författare)
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Prognostic Implications of Mutations in NOTCH1 and FBXW7 in Childhood T-ALL Treated According to the NOPHO ALL-1992 and ALL-2000 Protocols
- 2014
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Ingår i: Pediatric Blood & Cancer. - : Wiley-Blackwell. - 1545-5009 .- 1545-5017. ; 61:3, s. 424-430
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Tidskriftsartikel (refereegranskat)abstract
- Background In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis.Procedure We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes.Results Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P=0.14) or event-free survival (EFS) (P=0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.21.9 (mean +/- SEM), MYB 8.7 +/- 0.8 (mean +/- SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 +/- 0.7, MYB 5.1 +/- 1.2, P=0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P=0.02) and EFS (P=0.028) was seen.Conclusions Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated. Pediatr Blood Cancer 2014;61:424-430. (c) 2013 Wiley Periodicals, Inc.
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| 6. |
- Olsson, Linda, et al.
(författare)
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The clinical impact of IKZF1 deletions in paediatric B-cell precursor acute lymphoblastic leukaemia is independent of minimal residual disease stratification in Nordic Society for Paediatric Haematology and Oncology treatment protocols used between 1992 and 2013
- 2015
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 170:6, s. 847-858
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Tidskriftsartikel (refereegranskat)abstract
- Paediatric B-cell precursor acute lymphoblastic leukaemias (BCP ALL) with IKZF1 deletions (IKZF1) are associated with a poor outcome. However, there are conflicting data as to whether IKZF1 is an independent risk factor if minimal residual disease (MRD) and other copy number alterations also are taken into account. We investigated 334 paediatric BCP ALL, diagnosed 1992-2013 and treated according to Nordic Society for Paediatric Haematology and Oncology ALL protocols, with known IKZF1 status based on either single nucleotide polymorphism array (N=218) or multiplex ligation-dependent probe amplification (N=116) analyses. IKZF1, found in 15%, was associated with inferior 10-year probabilities of event-free (60% vs. 83%; P<0001) and overall survival (pOS; 73% vs. 89%; P=0001). Adjusting for known risk factors, including white blood cell (WBC) count and MRD, IKZF1 was the strongest independent factor for relapse and death. IKZF1 was present in 27% of cases with non-informative cytogenetics (BCP-other') and a poor 10-year pOS was particularly pronounced in this group (58% vs. 90%; P<0001). Importantly, neither MRD nor WBC count predicted events in the IKZF1-positive cases. Co-occurrence of pseudoautosomal region 1 (PAR1) deletions in Xp22.33/Yp11.32 (P2RY8-CRLF2) and IKZF1 increased the risk of relapse (75% vs. 30% for cases with only IKZF1; P=0045), indicating that BCP-other ALL with both P2RY8-CRLF2 and IKZF1 constitutes a particularly high-risk group.
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| 7. |
- Paulsson, Kajsa, et al.
(författare)
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The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 47:6, s. 672-676
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Tidskriftsartikel (refereegranskat)abstract
- High hyperdiploid (51-67 chromosomes) acute lymphoblastic leukemia (ALL) is one of the most common childhood malignancies, comprising 30% of all pediatric B cell-precursor ALL. Its characteristic genetic feature is the nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18 and 21, with individual trisomies or tetrasomies being seen in over 75% of cases, but the pathogenesis remains poorly understood. We performed whole-genome sequencing (WGS) (n = 16) and/or whole-exome sequencing (WES) (n = 39) of diagnostic and remission samples from 51 cases of high hyperdiploid ALL to further define the genomic landscape of this malignancy. The majority of cases showed involvement of the RTK-RAS pathway and of histone modifiers. No recurrent fusion gene-forming rearrangement was found, and an analysis of mutations on trisomic chromosomes indicated that the chromosomal gains were early events, strengthening the notion that the high hyperdiploid pattern is the main driver event in this common pediatric malignancy.
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| 8. |
- Persson, Fredrik, 1973, et al.
(författare)
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Characterization of the 12q amplicons by high-resolution, oligonucleotide array CGH and expression analyses of a novel liposarcoma cell line
- 2008
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Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835. ; 260:1-2, s. 37-47
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Tidskriftsartikel (refereegranskat)abstract
- The cytogenetic hallmark of well-differentiated liposarcoma (WDLS) is a giant marker chromosomes containing amplified genes from chromosome 12q13-q15. Here, we have employed SKY and high-resolution 244K oligonucleotide array CGH to characterize rearrangements and amplifications in a new WDLS cell line (GOT3) with a giant marker chromosome derived from chromosomes 12, 1, and X. The most prominent amplifications included 144 genes in 12q11-q21.2, 201 genes in 1q23.3-q44, and six genes in 13q32.1-q32.2. In the 12q amplicons, MDM2 showed the highest level of amplification followed by LYZ, HMGA2 (5'-part), TSPAN8, CNOT2, YEATS4, CDK4, GNS, HELB, and TSFM. Expression analysis of genes from the three major amplicons revealed that several highly amplified potential target genes, including HMGA2, MDM2, YEATS4, CDK4, PKP1, IPO9, and SOX21, were strongly overexpressed. Studies of cell cycle controlling proteins that interact with CDK4 and MDM2 revealed an abnormally strong expression of cyclins D1 and E. The selective high-level amplification of the 5'-part of HMGA2, including the DNA-binding domains, suggests that this gene is a major target of amplifications in WDLS. Our results also identify several novel candidate genes of potential pathogenetic and therapeutic importance for WDLS.
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| 9. |
- Persson, Fredrik, 1973, et al.
(författare)
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High-resolution genomic profiling of adenomas and carcinomas of the salivary glands reveals amplification, rearrangement, and fusion of HMGA2
- 2009
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Ingår i: Genes Chromosomes Cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 48:1, s. 69-82
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Tidskriftsartikel (refereegranskat)abstract
- Carcinoma ex pleomorphic adenoma (Ca-ex-PA) is an epithelial malignancy developing within a benign salivary gland pleomorphic adenoma (PA). Here we have used genome-wide, high-resolution array-CGH, and fluorescence in situ hybridization to identify genes amplified in double min chromosomes and homogeneously staining regions in PA and Ca-ex-PA and to identify additional genomic imbalances characteristic of these tumor types. Ten of the 16 tumors analyzed showed amplification/gain of a 30-kb minimal common region, consisting of the 5'-part of HMGA2 (encoding the three DNA-binding domains). Coamplification of MDM2 was found in nine tumors. Five tumors had cryptic HMGA2-WIF1 gene fusions with amplification of the fusion oncogene in four tumors. Expression analysis of eight amplified candidate genes in 12q revealed that tumors with amplification/rearrangement of HMGA2 and MDM2 had significantly higher expression levels when compared with tumors without amplification. Analysis of individual HMGA2 exons showed that the expression of exons 3-5 were substantially reduced when compared with exons 1-2 in 9 of 10 tumors with HMGA2 activation, indicating that gene fusions and rearrangements of HMGA2 are common in tumors with amplification. In addition, recurrent amplifications/gains of 1q11-q32.1, 2p16.1-p12, 8q12.1, 8q22-24.1, and 20, and losses of 1p21.3-p21.1, 5q23.2-q31.2, 8p, 10q21.3, and 15q11.2 were identified. Collectively, our results identify HMGA2 and MDM2 as amplification targets in PA and Ca-ex-PA and suggest that amplification of 12q genes (in particular MDM2), deletions of 5q23.2-q31.2, gains of 8q12.1 (PLAG1) and 8q22.1-q24.1 (MYC), and amplification of ERBB2 may be of importance for malignant transformation of benign PA.
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