| 1. |
- Abrahamsson, Hasse, 1943, et al.
(author)
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Familial intestinal degenerative neuropathy with chronic intestinal pseudo-obstruction linked to a gene locus with duplication in chromosome 9
- 2019
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In: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 54:12, s. 1441-1447
-
Journal article (peer-reviewed)abstract
- Background: Intestinal degenerative neuropathy without extra-intestinal involvement occurs as familial forms (FIDN) but the genetics behind is unknown. We studied a Swedish family with autosomal dominant disease and several cases of chronic intestinal pseudo-obstruction (CIP). Methods: We included 33 members of a family sharing a male ancestor. Chronic intestinal symptoms including diarrhoea occurred in 11, four had severe CIP. DNA was analysed with SNP-microarray (Affymetrix), linkage (Allegro Software) and gene dosage (CNAG 3.0). Results: Genetic linkage was found to the short arm of Ch9 to a 9.7 Mb region with 45 protein-coding genes, 22 of which were duplicated (1.2 Mb duplication) (dup(9)(p21.3) with breaking point in the FOCAD-gene. Lod score for the region was 3.4. Fourteen subjects were duplication carriers including all 11 subjects having severe chronic symptoms/CIP. Nineteen subjects had no duplication. The occurrence of gastrointestinal symptoms in the family was strongly linked to duplication carrier-ship (p = .0005). The two branches of the family had separate maternal ancestors (A and B). Including the previous generation, severe disease (overt CIP and/or death from intestinal failure) was assessed to occur in 100% (5/5) of duplication carriers in branch A and in 21% (3/14) in branch B (p = .005). In branch B the onset of symptoms was later (median 38 vs. 24 yrs) and three duplication carriers were symptom-free. Conclusions: In this family with autosomal dominant hereditary intestinal neuropathy, the disorder is linked to a 9.7 Mb region in Ch9 including a 1.2 Mb duplication. There is a significant difference in disease expressivity between family branches, seemingly related to separate maternal ancestors.
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| 2. |
- Fransson, Susanne, 1975, et al.
(author)
-
Intragenic anaplastic lymphoma kinase (ALK) rearrangements: Translocations as a novel mechanism of ALK activation in neuroblastoma tumors.
- 2015
-
In: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 54:2, s. 99-109
-
Journal article (peer-reviewed)abstract
- Anaplastic lymphoma kinase (ALK) has been demonstrated to be deregulated in sporadic as well as in familiar cases of neuroblastoma (NB). Whereas ALK-fusion proteins are common in lymphoma and lung cancer, there are few reports of ALK rearrangements in NB indicating that ALK mainly exerts its oncogenic capacity via activating mutations and/or overexpression in this tumor type. In this study, 332 NB tumors and 13 cell lines were screened by high resolution single nucleotide polymorphism microarray. Gain of 2p was detected in 23% (60/332) of primary tumors and 46% (6/13) of cell lines, while breakpoints at the ALK locus were detected in four primary tumors and two cell lines. These were further analyzed by next generation sequencing and a targeted enrichment approach. Samples with both ALK and MYCN amplification displayed complex genomic rearrangements with multiple breakpoints within the amplicon. None of the translocations characterized in primary NB tumors are likely to result in a chimeric protein. However, immunohistochemical analysis reveals high levels of phosphorylated ALK in these samples despite lack of initial exons, possibly due to alternative transcription initiation sites. Both ALK proteins predicted to arise from such alterations and from the abnormal ALK exon 4-11 deletion observed in the CLB-BAR cell line show strong activation of downstream targets STAT3 and extracellular signal-regulated kinase (ERK) when expressed in PC12 cells. Taken together, our data indicate a novel, although rare, mechanism of ALK activation with implications for NB tumorigenesis.
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| 3. |
- Guan, Jikui, et al.
(author)
-
Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib.
- 2018
-
In: Cold Spring Harbor molecular case studies. - : Cold Spring Harbor Laboratory. - 2373-2873. ; 4:4
-
Journal article (peer-reviewed)abstract
- Tumors with Anaplastic Lymphoma Kinase (ALK) fusion rearrangements, including non-small cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. While mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, due to lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germ-line FANCA mutations as well as a novel ALK-I1171T variant. ALK-I1171T generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Mono-therapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 months treatment, residual primary tumor was surgically removed and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 months treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma.
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| 4. |
- Guan, Jikui, et al.
(author)
-
The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN
- 2016
-
In: DMM Disease Models and Mechanisms. - : The Company of Biologists. - 1754-8403 .- 1754-8411. ; 9:9, s. 941-952
-
Journal article (peer-reviewed)abstract
- The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predictedto exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo. In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse modelof high-risk neuroblastoma driven by Th-ALKF1174L/MYCN. Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients. © 2016. Published by The Company of Biologists Ltd.
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| 5. |
- Javanmardi, Niloufar, et al.
(author)
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Low Frequency ALK Hotspots Mutations In Neuroblastoma Tumours Detected By Ultra-deep Sequencing: Implications For ALK Inhibitor Treatment
- 2019
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
-
Journal article (peer-reviewed)abstract
- The ALK tyrosine kinase receptor is oncogenically activated in neuroblastoma. Whereas numerous ALK fusion genes have been reported in different malignancies, in neuroblastoma ALK is mainly activated through point mutations. Three hotspot residues (F1174, F1245, and R1275) account for 85% of mutant ALK seen in neuroblastoma. In a cohort of 105 Swedish neuroblastoma cases of all stages, these hotspot regions were re-sequenced (> 5000X). ALK mutations were detected in 16 of 105 patients (range of variant allele fraction: 2.7-60%). Mutations at the F1174 and F1245 hotspot were observed in eleven and three cases respectively. ALK mutations were also detected at the I1171 and L1240 codons in one tumor each. No mutations were detected at R1275. Sanger sequencing could confirm ALK status for all mutated samples with variant allele fraction above 15%. Four of the samples with subclonal ALK mutation fraction below this would have gone undetected relying on Sanger sequencing only. No distinct mutation spectrum in relation to neuroblastoma tumours genomic subtypes could be detected although there was a paucity of ALK mutations among 11q-deleted tumors. As ALK mutations status opens up an excellent opportunity for application of small molecule inhibitors targeting ALK, early and sensitive detection of ALK alterations is clinically important considering its potential role in tumour progression.
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| 6. |
- Umapathy, Ganesh, et al.
(author)
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MEK inhibitor trametinib does not prevent the growth of anaplastic lymphoma kinase (ALK)-addicted neuroblastomas.
- 2017
-
In: Science signaling. - : American Association for the Advancement of Science (AAAS). - 1937-9145 .- 1945-0877. ; 10:507
-
Journal article (peer-reviewed)abstract
- Activation of the RAS-RAF-MEK-ERK signaling pathway is implicated in driving the initiation and progression of multiple cancers. Several inhibitors targeting the RAS-MAPK pathway are clinically approved as single- or polyagent therapies for patients with specific types of cancer. One example is the MEK inhibitor trametinib, which is included as a rational polytherapy strategy for treating EML4-ALK-positive, EGFR-activated, or KRAS-mutant lung cancers and neuroblastomas that also contain activating mutations in the RAS-MAPK pathway. In addition, in neuroblastoma, a heterogeneous disease, relapse cases display an increased rate of mutations in ALK, NRAS, and NF1, leading to increased activation of RAS-MAPK signaling. Co-targeting ALK and the RAS-MAPK pathway is an attractive option, because monotherapies have not yet produced effective results in ALK-addicted neuroblastoma patients. We evaluated the response of neuroblastoma cell lines to MEK-ERK pathway inhibition by trametinib. In contrast to RAS-MAPK pathway-mutated neuroblastoma cell lines, ALK-addicted neuroblastoma cells treated with trametinib showed increased activation (inferred by phosphorylation) of the kinases AKT and ERK5. This feedback response was mediated by the mammalian target of rapamycin complex 2-associated protein SIN1, resulting in increased survival and proliferation that depended on AKT signaling. In xenografts in mice, trametinib inhibited the growth of EML4-ALK-positive non-small cell lung cancer and RAS-mutant neuroblastoma but not ALK-addicted neuroblastoma. Thus, our results advise against the seemingly rational option of using MEK inhibitors to treat ALK-addicted neuroblastoma.
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| 7. |
- Berbegall, A. P., et al.
(author)
-
Comparative genetic study of intratumoral heterogenous MYCN amplified neuroblastoma versus aggressive genetic profile neuroblastic tumors
- 2016
-
In: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 35:11, s. 1423-1432
-
Journal article (peer-reviewed)abstract
- Intratumoral heterogeneous MYCN amplification (hetMNA) is an unusual event in neuroblastoma with unascertained biological and clinical implications. Diagnosis is based on the detection of MYCN amplification surrounded by non-amplified tumor cells by fluorescence in situ hybridization (FISH). To better define the genetic features of hetMNA tumors, we studied the Spanish cohort of neuroblastic tumors by FISH and single nucleotide polymorphism arrays. We compared hetMNA tumors with homogeneous MNA (homMNA) and nonMNA tumors with 11q deletion (nonMNA w11q-). Of 1091 primary tumors, 28 were hetMNA by FISH. Intratumoral heterogeneity of 1p, 2p, 11q and 17q was closely associated with hetMNA tumors when analyzing different pieces for each case. For chromosome 2, 16 cases showed 2p intact, 4 focal gain at 2p24.3 and 8 MNA. The lengths of the smallest regions of overlap (SROs) for 2p gains and 1p deletions were between the SRO lengths observed in homMNA and nonMNA w11q- tumors. Co-occurrence of 11q- and +17q was frequently found with the largest SROs for both aberrations. The evidence for and frequency of different genetic subpopulations representing a hallmark of the hetMNA subgroup of NB indicates, on one hand, the presence of a considerable genetic instability with different SRO of either gains and losses compared with those of the other NB groups and highlights and, on the other hand, the need for multiple sampling from distant and macroscopically and microscopically distinct tumor areas. Narrowing down the different SRO for both deletions and gains in NB groups would be crucial to pinpointing the candidate gene(s) and the critical gene dosage with prognostic and therapeutic significance. This complexity of segmental chromosomal aberration patterns reinforces the necessity for a larger cohort study using FISH and pangenomic techniques to develop a suitable therapeutic strategy for these patients.
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| 8. |
- Biswas, S., et al.
(author)
-
Exome sequencing of an adult pituitary atypical teratoid rhabdoid tumor
- 2015
-
In: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 5:Article 236
-
Journal article (peer-reviewed)abstract
- Atypical teratoid rhabdoid tumors (AT/RTs) are rare pediatric brain tumors characterized by bialleic loss of the SMARCB1 tumor suppressor gene. In contrast to pediatric AT/RT that has a simple genome, very little is known about the adult AT/RT genomic landscape. Using a combination of whole-exome sequencing and high-resolution SNP array in a single adult pituitary AT/RT, we identified a total of 47 non-synonymous mutations, of which 20 were predicted to cause non-conservative amino acid substitutions, in addition to a subclone of cells with trisomy 8. We suggest that adult AT/RT may not be markedly dissimilar to other adult brain tumors where mutations in a range of genes, reflecting the functional specialization of different brain regions, but including SMARCB1 inactivation, may be required for its pathogenesis. © 2015 Biswas, Wood, Joshi, Bown, Strain, Martinsson, Campbell, Ashworth and Swain.
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| 9. |
- Bogen, D., et al.
(author)
-
The genetic tumor background is an important determinant for heterogeneous MYCN-amplified neuroblastoma
- 2016
-
In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 139:1, s. 153-163
-
Journal article (peer-reviewed)abstract
- Amplification of MYCN is the signature genetic aberration of 20-25% of neuroblastoma and a stratifying marker associated with aggressive tumor behavior. The detection of heterogeneous MYCN amplification (hetMNA) poses a diagnostic dilemma due to the uncertainty of its relevance to tumor behavior. Here, we aimed to shed light on the genomic background which permits hetMNA in neuroblastoma and tied the occurrence to other stratifying markers and disease outcome. We performed SNP analysis using Affymetrix Cytoscan HD arrays on 63 samples including constitutional DNA, tumor, bone marrow and relapse samples of 26 patients with confirmed hetMNA by MYCN-FISH. Tumors of patients 18m were mostly aneuploid with numeric chromosomal aberrations (NCAs), presented a prominent MNA subclone and carried none or a few segmental chromosomal aberrations (SCAs). In older patients, tumors were mostly di- or tetraploid, contained a lower number of MNA cells and displayed a multitude of SCAs including concomitant 11q deletions. These patients often suffered disease progression, tumor dissemination and relapse. Restricted to aneuploid tumors, we detected chromosomes with uniparental di- or trisomy (UPD/UPT) in almost every sample. UPD11 was exclusive to tumors of younger patients whereas older patients featured UPD14. In this study, the MNA subclone appears to be constraint by the tumor environment and thus less relevant for tumor behavior in aggressive tumors with a high genomic instability and many segmental aberrations. A more benign tumor background and lower tumor stage may favor an outgrowth of the MNA clone but tumors generally responded better to treatment. What's new?MYCN amplification (MNA) in neuroblastoma (NB) generally associates with an aggressive tumor behavior and detection of MNA leads to an automatic upstaging of the tumor in non-stage 1 tumors. But what if only a fraction of the tumor cells is MYCN-amplified? To investigate the diagnostic importance of heterogeneous MNA, the authors conducted a genetic analysis of samples from 26 NB patients with a particular focus on accompanying genetic aberrations. They concluded that tumor behavior is largely dependent on patient age and other chromosomal alterations in the genetic tumor background rather than the mere presence of the MNA clone.
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| 10. |
- Braekeveldt, N., et al.
(author)
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Patient-Derived Xenograft Models Reveal Intratumor Heterogeneity and Temporal Stability in Neuroblastoma
- 2018
-
In: Cancer Research. - 0008-5472. ; 78:20, s. 5958-5969
-
Journal article (peer-reviewed)abstract
- Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain under-explored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phosphoproteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in patients with high-risk neuroblastoma. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX-Avatar studies into preclinical cancer research. Significance: These findings underpin the complexity of PDX modeling as a means to advance translational applications against neuroblastoma. (C) 2018 AACR.
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| 11. |
- Defferrari, R., et al.
(author)
-
Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification
- 2015
-
In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 112:2, s. 290-295
-
Journal article (peer-reviewed)abstract
- Background: The prognostic impact of segmental chromosome alterations (SCAs) in children older than 1 year, diagnosed with localised unresectable neuroblastoma (NB) without MYCN amplification enrolled in the European Unresectable Neuroblastoma (EUNB) protocol is still to be clarified, while, for other group of patients, the presence of SCAs is associated with poor prognosis. Methods: To understand the role of SCAs we performed multilocus/pangenomic analysis of 98 tumour samples from patients enrolled in the EUNB protocol. Results: Age at diagnosis was categorised into two groups using 18 months as the age cutoff. Significant difference in the presence of SCAs was seen in tumours of patients between 12 and 18 months and over 18 months of age at diagnosis, respectively (P = 0.04). A significant correlation (P = 0.03) was observed between number of SCAs per tumour and age. Event-free (EFS) and overall survival (OS) were calculated in both age groups, according to both the presence and number of SCAs. In older patients, a poorer survival was associated with the presence of SCAs (EFS = 46% vs 75%, P = 0.023; OS = 66.8% vs 100%, P = 0.003). Moreover, OS of older patients inversely correlated with number of SCAs (P = 0.002). Finally, SCAs provided additional prognostic information beyond histoprognosis, as their presence was associated with poorer OS in patients over 18 months with unfavourable International Neuroblastoma Pathology Classification (INPC) histopathology (P = 0.018). Conclusions: The presence of SCAs is a negative prognostic marker that impairs outcome of patients over the age of 18 months with localised unresectable NB without MYCN amplification, especially when more than one SCA is present. Moreover, in older patients with unfavourable INPC tumour histoprognosis, the presence of SCAs significantly affects OS.
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| 12. |
- Dyberg, C., et al.
(author)
-
Rho-associated kinase is a therapeutic target in neuroblastoma
- 2017
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 114:32
-
Journal article (peer-reviewed)abstract
- Neuroblastoma is a peripheral neural system tumor that originates from the neural crest and is the most common and deadly tumor of infancy. Here we show that neuroblastoma harbors frequent mutations of genes controlling the Rac/Rho signaling cascade important for proper migration and differentiation of neural crest cells during neuritogenesis. RhoA is activated in tumors from neuroblastoma patients, and elevated expression of Rho-associated kinase (ROCK) 2 is associated with poor patient survival. Pharmacological or genetic inhibition of ROCK1 and 2, key molecules in Rho signaling, resulted in neuroblastoma cell differentiation and inhibition of neuroblastoma cell growth, migration, and invasion. Molecularly, ROCK inhibition induced glycogen synthase kinase 3 beta-dependent phosphorylation and degradation of MYCN protein. Small-molecule inhibition of ROCK suppressed MYCN-driven neuroblastoma growth in TH-MYCN homozygous transgenic mice and MYCN gene-amplified neuroblastoma xenograft growth in nude mice. Interference with Rho/Rac signaling might offer therapeutic perspectives for high-risk neuroblastoma.
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| 13. |
- Fransson, Susanne, 1975, et al.
(author)
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Estimation of copy number aberrations: Comparison of exome sequencing data with SNP microarrays identifies homozygous deletions of 19q13.2 and iin neuroblastoma
- 2016
-
In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 48:3, s. 1103-1116
-
Journal article (peer-reviewed)abstract
- In the pediatric cancer neuroblastoma, analysis of recurrent chromosomal aberrations such as loss of chromosome 1p, 11q, gain of 17q and MYCN amplification are used for patient stratification and subsequent therapy decision making. Different analysis techniques have been used for detection of segmental abnormalities, including fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH)-microarrays and multiplex ligation-dependent probe amplification (MLPA). However, as next-generation sequencing becomes available for clinical use, this technique could also be used for assessment of copy number alterations simultaneously with mutational analysis. In this study we compare genomic profiles generated through exome sequencing data with profiles generated from high resolution Affymetrix single nucleotide polymorphism (SNP) microarrays on 30 neuroblastoma tumors of different stages. Normalized coverage reads for tumors were calculated using Control-FREEC software and visualized through a web based Shiny application, prior to comparison with corresponding SNP-microarray data. The two methods show high-level agreement for breakpoints and copy number of larger segmental aberrations and numerical aneuploidies. However, several smaller gene containing deletions that could not readily be detected through the SNP-microarray analyses were identified through exome profiling, most likely due to difference between spatial distribution of microarray probes and targeted regions of the exome capture. These smaller aberrations included focal ATRX deletion in two tumors and three cases of novel deletions in chromosomal region 19q13.2 causing homozygous loss of multiple genes including the CIC (Capicua) gene. In conclusion, genomic profiles generated from normalized coverage of exome sequencing show concordance with SNP microarray generated genomic profiles. Exome sequencing is therefore a useful diagnostic tool for copy number variant (CNV) detection in neuroblastoma tumors, especially considering the combination with mutational screening. This enables detection of theranostic targets such as ALK and ATRX together with detection of significant segmental aneuploidies, such as 2p-gain, 17q-gain, 11q-deletion as well as MYCN amplification.
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| 14. |
- Larsson, K., et al.
(author)
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COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset
- 2015
-
In: Proceedings of the National Academy of Science of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:26, s. 8070-8075
-
Journal article (peer-reviewed)abstract
- The majority of solid tumors are presented with an inflammatory microenvironment. Proinflammatory lipid mediators including prostaglandin E2 (PGE2) contribute to the establishment of inflammation and have been linked to tumor growth and aggressiveness. Here we show that high-risk neuroblastoma with deletion of chromosome 11q represents an inflammatory subset of neuroblastomas. Analysis of enzymes involved in the production of proinflammatory lipid mediators showed that 11q-deleted neuroblastoma tumors express high levels of microsomal prostaglandin E synthase-1 (mPGES-1) and elevated levels of PGE2. High mPGES-1 expression also corresponded to poor survival of neuroblastoma patients. Investigation of the tumor microenvironment showed high infiltration of tumor-promoting macrophages with high expression of the M2-polarization markers CD163 and CD206. mPGES-1-expressing cells in tumors from different subtypes of neuroblastoma showed differential expression of one or several cancer-associated fibroblast markers such as vimentin, fibroblast activation protein alpha, alpha smooth muscle actin, and PDGF receptor beta. Importantly, inhibition of PGE2 production with diclofenac, a nonselective COX inhibitor, resulted in reduced tumor growth in an in vivo model of 11q-deleted neuroblastoma. Collectively, these results suggest that PGE2 is involved in the tumor microenvironment of specific neuroblastoma subgroups and indicate that therapeutic strategies using existing anti-inflammatory drugs in combination with current treatment should be considered for certain neuroblastomas.
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| 15. |
- Li, S. J., et al.
(author)
-
The 1p36 Tumor Suppressor KIF 1B beta Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis
- 2016
-
In: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 36:2, s. 164-178
-
Journal article (peer-reviewed)abstract
- KIF1B beta is a candidate 1p36 tumor suppressor that regulates apoptosis in the developing sympathetic nervous system. We found that KIF1B beta activates the Ca2+-dependent phosphatase calcineurin (CN) by stabilizing the CN-calmodulin complex, relieving enzymatic autoinhibition and enabling CN substrate recognition. CN is the key mediator of cellular responses to Ca2+ signals and its deregulation is implicated in cancer, cardiac, neurodegenerative, and immune disease. We show that KIF1B beta affects mitochondria! dynamics through CN-dependent dephosphorylation of Dynamin-related protein 1 (DRP1), causing mitochondria! fission and apoptosis. Furthermore, KIF1B beta actuates recognition of all known CN substrates, implying a general mechanism for KIF1B beta in Ca2+ signaling and how Ca2+-dependent signaling is executed by CN. Pathogenic KIF1B beta mutations previously identified in neuroblastomas and pheochromocytomas all fail to activate CN or stimulate DRP1 dephosphorylation. Importantly, KIF1B beta and DRP1 are silenced in 1p36 hemizygous-deleted neuroblastomas, indicating that deregulation of calcineurin and mitochondria! dynamics contributes to high-risk and poor-prognosis neuroblastoma.
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| 16. |
- Mondal, Tanmoy, 1981, et al.
(author)
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Sense-antisense lncRNA pair encoded by locus 6p22.3 determines neuroblastoma susceptibility via the USP36-CHD7-SOX9 regulatory axis
- 2018
-
In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 33:3
-
Journal article (peer-reviewed)abstract
- Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.
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| 17. |
- Olsson, Maja, 1975, et al.
(author)
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Genome-wide methylation profiling identifies novel methylated genes in neuroblastoma tumors
- 2016
-
In: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 11:1, s. 74-84
-
Journal article (peer-reviewed)abstract
- Neuroblastoma is a very heterogeneous tumor of childhood. The clinical spectra range from very aggressive metastatic disease to spontaneous regression, even without therapy. Aberrant DNA methylation pattern is a common feature of most cancers. For neuroblastoma, it has been demonstrated both for single genes as well as genome-wide, where a so-called methylator phenotype has been described. Here, we present a study using Illumina 450K methylation arrays on 60 neuroblastoma tumors. We show that aggressive tumors, characterized by International Neuroblastoma Risk Group (INRG) as stage M, are hypermethylated compared to low-grade tumors. On the contrary, INRG stage L tumors display more non-CpG methylation. The genes with the highest number of hypermethylated CpG sites in INRG M tumors are TERT, PCDHGA4, DLX5, and DLX6-AS1. Gene ontology analysis showed a representation of neuronal tumor relevant gene functions among the differentially methylated genes. For validation, we used a set of independent tumors previously analyzed with the Illumina 27K methylation arrays, which confirmed the differentially methylated sites. Top candidate genes with aberrant methylation were analyzed for altered gene expression through the R2 platform ( ), and for correlations between methylation and gene expression in a public dataset. Altered expression in nonsurvivors was found for the genes B3GALT4 and KIAA1949, CLIC5, DLX6-AS, TERT, and PIRT, and strongest correlations were found for TRIM36, KIAA0513, and PIRT. Our data indicate that methylation profiling can be used for patient stratification and informs on epigenetically deregulated genes with the potential of increasing our knowledge about the underlying mechanisms of tumor development.
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| 18. |
- Tesan, Tajana, 1977, et al.
(author)
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A new GTF2I-BRAF fusion mediating MAPK pathway activation in pilocytic astrocytoma
- 2017
-
In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:4
-
Journal article (peer-reviewed)abstract
- Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. A recurrent feature of PA is deregulation of the mitogen activated protein kinase (MAPK) pathway most often through KIAA1549-BRAF fusion, but also by other BRAF- or RAF1-gene fusions and point mutations (e.g. BRAFV600E). These features may serve as diagnostic and prognostic markers, and also facilitate development of targeted therapy. The aims of this study were to characterize the genetic alterations underlying the development of PA in six tumor cases, and evaluate methods for fusion oncogene detection. Using a combined analysis of RNA sequencing and copy number variation data we identified a new BRAF fusion involving the 5' gene fusion partner GTF2I (7q11.23), not previously described in PA. The new GTF2I-BRAF 19-10 fusion was found in one case, while the other five cases harbored the frequent KIAA1549-BRAF 16-9 fusion gene. Similar to other BRAF fusions, the GTF2I-BRAF fusion retains an intact BRAF kinase domain while the inhibitory N-terminal domain is lost. Functional studies on GTF2I-BRAF showed elevated MAPK pathway activation compared to BRAF WT. Comparing fusion detection methods, we found Fluorescence in situ hybridization with BRAF break apart probe as the most sensitive method for detection of different BRAF rearrangements (GTF2I-BRAF and KIAA1549-BRAF). Our finding of a new BRAF fusion in PA further emphasis the important role of B-Raf in tumorigenesis of these tumor types. Moreover, the consistency and growing list of BRAF/RAF gene fusions suggests these rearrangements to be informative tumor markers in molecular diagnostics, which could guide future treatment strategies.
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