Högskolan i Skövde

his.sePublikationer
Ändra sökning
Länk till posten
Permanent länk

Direktlänk
Publikationer (10 of 24) Visa alla publikationer
Maroofian, R., Tajsharghi, H., Ejeskär, K. & Severino, M. (2023). Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders. Brain, 146(12), 5031-5043
Öppna denna publikation i ny flik eller fönster >>Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders
2023 (Engelska)Ingår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 146, nr 12, s. 5031-5043Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'. 

Nyckelord
cerebellar atrophy, cerebello-lental degeneration, dystonia, gene transcription, mediator complex, neurodevelopmental disorders, Adolescent, Adult, Atrophy, Cataract, Cerebellum, Child, Child, Preschool, Epilepsy, Epilepsy, Generalized, Female, Humans, Infant, Middle Aged, Movement Disorders, Phenotype, Young Adult, MED27 protein, human, diagnostic imaging, generalized epilepsy, genetics, human, mental disease, motor dysfunction, pathology, preschool child
Nationell ämneskategori
Medicinsk genetik Neurologi Pediatrik
Forskningsämne
Translationell medicin TRIM
Identifikatorer
urn:nbn:se:his:diva-23471 (URN)10.1093/brain/awad257 (DOI)001106767600001 ()37517035 (PubMedID)2-s2.0-85178648913 (Scopus ID)
Forskningsfinansiär
EU, FP7, Sjunde ramprogrammet, 608473Wellcome trust, WT093205MAWellcome trust, WT104033AIAEU, FP7, Sjunde ramprogrammet, 2012-305121Wellcome trust, 203141/Z/16/Z
Anmärkning

CC BY 4.0 DEED

© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.

Correspondence to: Mariasavina Severino Neuroradiology Unit, IRCCS Istituto Giannina Gaslini Via Gerolamo Gaslini 5, 16147 Genova, GE, Italy E-mail: mariasavinaseverino@gaslini.org

Correspondence may also be addressed to: Reza Maroofian Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology Queen Square, London WC1N 3BG, UK E-mail: r.maroofian@ucl.ac.uk

Part of this research was possible thanks to the Deciphering Developmental Disorders (DDD) study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). R.K. was supported by the European Academy of Neurology Research Training Fellowship and Rosetrees Trust PhD Plus award (PhD2022\100042). J.R.L. was supported by the National Institute for Neurological Disorders and Stroke Research Program Award R35 NS105078 and the Baylor College of Medicine-GREGoR Program (NHGRI U01 HG001758). H.T. was supported by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 608473. M.A.K. and R.S. were supported by a National Institute for Health Research professorship, Sir Jules Thorn Charitable Trust Award for Biomedical Research and the Rosetrees Trust. This study was also supported by the Wellcome Trust (WT093205MA and WT104033AIA), the Medical Research Council (H.H.), European Union’s Seventh Framework Programme (FP7/2007-2013, under grant agreement no. 2012-305121), the National Institute for Health Research (NIHR), University College London Hospitals (UCLH) and UCLH Biomedical Research Centre (BRC). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The NIHR Oxford Biomedical Research Centre Programme and a Wellcome Trust Core Award (203141/Z/16/Z). P.I. was supported by Foundation for Pediatric Research.

Tillgänglig från: 2023-12-14 Skapad: 2023-12-14 Senast uppdaterad: 2023-12-28Bibliografiskt granskad
Jurcevic, S., Keane, S., Borgmästars, E., Lubovac-Pilav, Z. & Ejeskär, K. (2022). Bioinformatics analysis of miRNAs in the neuroblastoma 11q-deleted region reveals a role of miR-548l in both 11q-deleted and MYCN amplified tumour cells. Scientific Reports, 12(1), Article ID 19729.
Öppna denna publikation i ny flik eller fönster >>Bioinformatics analysis of miRNAs in the neuroblastoma 11q-deleted region reveals a role of miR-548l in both 11q-deleted and MYCN amplified tumour cells
Visa övriga...
2022 (Engelska)Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 12, nr 1, artikel-id 19729Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Neuroblastoma is a childhood tumour that is responsible for approximately 15% of all childhood cancer deaths. Neuroblastoma tumours with amplification of the oncogene MYCN are aggressive, however, another aggressive subgroup without MYCN amplification also exists; rather, they have a deleted region at chromosome arm 11q. Twenty-six miRNAs are located within the breakpoint region of chromosome 11q and have been checked for a possible involvement in development of neuroblastoma due to the genomic alteration. Target genes of these miRNAs are involved in pathways associated with cancer, including proliferation, apoptosis and DNA repair. We could show that miR-548l found within the 11q region is downregulated in neuroblastoma cell lines with 11q deletion or MYCN amplification. In addition, we showed that the restoration of miR-548l level in a neuroblastoma cell line led to a decreased proliferation of these cells as well as a decrease in the percentage of cells in the S phase. We also found that miR-548l overexpression suppressed cell viability and promoted apoptosis, while miR-548l knockdown promoted cell viability and inhibited apoptosis in neuroblastoma cells. Our results indicate that 11q-deleted neuroblastoma and MYCN amplified neuroblastoma coalesce by downregulating miR-548l.

Ort, förlag, år, upplaga, sidor
Springer Nature, 2022
Nationell ämneskategori
Bioinformatik och systembiologi Biomedicinsk laboratorievetenskap/teknologi Bioinformatik (beräkningsbiologi) Cancer och onkologi Medicinsk genetik Cell- och molekylärbiologi
Forskningsämne
Infektionsbiologi; Translationell medicin TRIM; Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-22068 (URN)10.1038/s41598-022-24140-6 (DOI)000885172100065 ()36396668 (PubMedID)2-s2.0-85142197814 (Scopus ID)
Forskningsfinansiär
Barncancerfonden
Anmärkning

CC BY 4.0

© 2022 Springer Nature Limited

We thank the Swedish Childhood Cancer Fund and Assar Gabrielsson Found for financial support.

Open access funding provided by University of Skövde.

Correspondence and requests for materials should be addressed to S.J.

Tillgänglig från: 2022-11-21 Skapad: 2022-11-21 Senast uppdaterad: 2023-01-16Bibliografiskt granskad
Lindholm, H., Ejeskär, K. & Szekeres, F. (2022). Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype. International Journal of Molecular Sciences, 23(15), 1-14, Article ID 8237.
Öppna denna publikation i ny flik eller fönster >>Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype
2022 (Engelska)Ingår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, nr 15, s. 1-14, artikel-id 8237Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Digitoxin has repeatedly shown to have negative effects on cancer cell viability; however, the actual mechanism is still unknown. In this study, we investigated the effects of digitoxin (1-100 nM) in four pancreatic cancer cell lines, BxPC-3, CFPAC-1, Panc-1, and AsPC-1. The cell lines differ in their KRAS/BRAF mutational status and primary tumor or metastasis origin. We could detect differences in the basal rates of cell proliferation, glycolysis, and ROS production, giving the cell lines different phenotypes. Digitoxin treatment induced apoptosis in all four cell lines, but to different degrees. Cells derived from primary tumors (Panc-1 and BxPC-3) were highly proliferating with a high proportion of cells in the S/G2 phase, and were more sensitive to digitoxin treatment than the cell lines derived from metastases (CFPAC-1 and AsPC-1), with a high proportion of cells in G0/G1. In addition, the effects of digitoxin on the rate of glycolysis, ROS production, and proliferation were dependent on the basal metabolism and origin of the cells. The KRAS downstream signaling pathways were not altered by digitoxin treatment, thus the effects exerted by digitoxin were probably disconnected from these signaling pathways. We conclude that digitoxin is a promising treatment in highly proliferating pancreatic tumors.

Ort, förlag, år, upplaga, sidor
MDPI, 2022
Nyckelord
pancreatic cancer, digitoxin, cardiac glycosides, PDAC, KRAS, metabolism, ROS, cell proliferation
Nationell ämneskategori
Medicin och hälsovetenskap Klinisk laboratoriemedicin
Forskningsämne
Translationell medicin TRIM
Identifikatorer
urn:nbn:se:his:diva-21727 (URN)10.3390/ijms23158237 (DOI)000839229300001 ()35897809 (PubMedID)2-s2.0-85137100614 (Scopus ID)
Anmärkning

CC BY 4.0

Correspondence: ferenc.szekeres@his.se

Funding: This research was funded by Assar Gabrielsson Foundation, grant FB19-80.

Tillgänglig från: 2022-08-25 Skapad: 2022-08-25 Senast uppdaterad: 2023-04-27Bibliografiskt granskad
Keane, S., de Weerd, H. A. & Ejeskär, K. (2022). DLG2 impairs dsDNA break repair and maintains genome integrity in neuroblastoma. DNA Repair, 112, Article ID 103302.
Öppna denna publikation i ny flik eller fönster >>DLG2 impairs dsDNA break repair and maintains genome integrity in neuroblastoma
2022 (Engelska)Ingår i: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 112, artikel-id 103302Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background

In primary neuroblastoma, deletions on chromosome 11q are known to result in an increase in the total number of chromosomal breaks. The DNA double-strand break repair pathways mediated by NHEJ are often upregulated in cancer. DLG2, a candidate tumor suppressor gene on chromosome 11q, has previously been implicated in DNA repair.

Methods

We evaluated an association between gene expression and neuroblastoma patient outcome, risk categorization, and 11q status using publicly available microarray data from independent neuroblastoma patient datasets. Functional studies were conducted using comet assay and H2AX phosphorylation in neuroblastoma cell lines and in the fruit fly with UVC-induced DNA breaks.

Results

We show that the NHEJ genes PARP1 and FEN1 are over expressed in neuroblastoma and restoration of DLG2 impairs their gene and protein expression. When exposed to UVC radiation, cells with DLG2 over expression show less DNA fragmentation and induce apoptosis in a p53 S46 dependent manner. We could also confirm that DLG2 over expression results in CHK1 phosphorylation consistent with previous reports of G2/M maintenance.

Conclusions

Taken together, we show that DLG2 over expression increases p53 mediated apoptosis in response to etoposide and UVC mediated genotoxicity and reduced DNA replication machinery.

Ort, förlag, år, upplaga, sidor
Elsevier, 2022
Nyckelord
DLG2, DNA, Damage, Neuroblastoma, Cancer
Nationell ämneskategori
Cancer och onkologi Cell- och molekylärbiologi
Forskningsämne
Translationell medicin TRIM; Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-20940 (URN)10.1016/j.dnarep.2022.103302 (DOI)000782613400003 ()35217496 (PubMedID)2-s2.0-85124996325 (Scopus ID)
Forskningsfinansiär
Barncancerfonden, PR2016–0060Kungliga Fysiografiska Sällskapet i Lund
Anmärkning

CC BY 4.0

Corresponding author: E-mail address: simon.keane@his.se (S. Keane).

We thank the Swedish Childhood Cancer Fund [PR2016–0060], Jane and Dan Olsson Foundation [2020–29], Assar Gabrielssons Foundation [FB20–13], Nilsson-Ehle Endowments, Kungliga Fysiografiska sällskapet i Lund and University of Skövde for financial support.

Tillgänglig från: 2022-02-25 Skapad: 2022-02-25 Senast uppdaterad: 2022-12-16Bibliografiskt granskad
Keane, S., Herring, M., Rolny, P., Wettergren, Y. & Ejeskär, K. (2022). Inflammation suppresses DLG2 expression decreasing inflammasome formation. Journal of Cancer Research and Clinical Oncology, 149(9), 2295-2311
Öppna denna publikation i ny flik eller fönster >>Inflammation suppresses DLG2 expression decreasing inflammasome formation
Visa övriga...
2022 (Engelska)Ingår i: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 149, nr 9, s. 2295-2311Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Purpose

Loss of expression of DLG2 has been identified in a number of cancers to contribute to the disease by resulting in increased tumor cell proliferation and poor survival. In light of the previous evidence that DLG2 alters the cell cycle and affects proliferation, combined with indications that DLG2 is involved in NLRP3 inflammasome axis we speculated that DLG2 has an immune function. So far, there is no data that clearly elucidates this role, and this study was designed to investigate DLG2 in inflammatory colon disease and in colon cancer as well as its impact on inflammasome induction.

Methods

The DLG2 expression levels were established in publicly available inflammation, colon cancer and mouse model datasets. The overexpression and silencing of DLG2 in colon cancer cells were used to determine the effect of DLG2 expression on the activation of the inflammasome and subsequent cytokine release.

Results

The expression of DLG2 is repressed in inflammatory colon diseases IBD and Ulcerative colitis as well as colorectal cancer tissue compared to healthy individuals. We subsequently show that induction with inflammatory agents in cell and animal models results in a biphasic alteration of DLG2 with an initial increase followed by an ensuing decrease. DLG2 overexpression leads to a significant increase in expression of IL1B, IκBζ and BAX, components that result in inflammasome formation. DLG2 silencing in THP1 cells resulted in increased release of IL-6 into the microenvironment which once used to treat bystander COLO205 cells resulted in an increase in STAT3 phosphorylation and an increase proliferating cells and more cells in the G2/M phase. Restoration of DLG2 to the colon resulted in reduced AKT and S6 signaling.

Conclusion

DLG2 expression is altered in response to inflammation in the gut as well as colon cancer, resulting in altered ability to form inflammasomes.

Trial registration

NCT03072641.

Ort, förlag, år, upplaga, sidor
Springer Nature Switzerland AG, 2022
Nyckelord
DLG2, Inflammasome, NFKBIZ, Ulcerative colitis, Colon cancer
Nationell ämneskategori
Gastroenterologi Immunologi inom det medicinska området
Forskningsämne
Translationell medicin TRIM; Infektionsbiologi
Identifikatorer
urn:nbn:se:his:diva-21117 (URN)10.1007/s00432-022-04029-7 (DOI)000789726400001 ()35499706 (PubMedID)2-s2.0-85129231846 (Scopus ID)
Forskningsfinansiär
Kungliga Fysiografiska Sällskapet i Lund
Anmärkning

CC BY 4.0

Simon Keane simon.keane@his.se

Published: 02 May 2022

© 2022 Springer Nature Switzerland AG. Part of Springer Nature.

Springer

We thank the Jane and Dan Olsson foundation, Assar Gabrielssons Foundation, Royal Physiographic Society of Lund and University of Skövde for financial support. We thank the staff at the Centre for Cellular Imaging at the University of Gothenburg for their advice and assistance in fluorescence imaging. A-L. Helminen and H. Björkqvist are acknowledged for help with implementation of the NCT03072641 study and collection of patient samples. We thank L. Munro for clinical database assistance, and J. Flach and M. Åkerström for technical assistance.

Open access funding provided by University of Skövde. Jane and Dan Olsson foundation (2020–2029), Assar Gabrielssons Foundation (FB21-06), Royal Physiographic Society of Lund (NA) and University of Skövde.

The datasets generated during and/or analysed during the current study are available in the R2: genomics analysis visualization platform, http://r2.amc.n listed in the methods by GSE identification number.

Tillgänglig från: 2022-05-04 Skapad: 2022-05-04 Senast uppdaterad: 2022-08-15Bibliografiskt granskad
Lindholm, H., Ejeskär, K. & Szekeres, F. (2022). Na+/K+‑ATPase subunit α3 expression is associated with the efficacy of digitoxin treatment in pancreatic cancer cells. Medicine International, 2(5), Article ID 27.
Öppna denna publikation i ny flik eller fönster >>Na+/K+‑ATPase subunit α3 expression is associated with the efficacy of digitoxin treatment in pancreatic cancer cells
2022 (Engelska)Ingår i: Medicine International, ISSN 2754-3242, Vol. 2, nr 5, artikel-id 27Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The alpha subunits (ATP1A1-3) of Na+/K+-ATPase binds digitoxin with varying affinity. The expression levels of these subunits dictate the anticancer effects of digitoxin. In the present study, three pancreatic cancer cell lines, AsPC-1, Panc-1 and CFPAC-1, were used to investigate the effects of digitoxin in relation to the expression of the subunits ATP1A1 and ATP1A3. Cell viability and intracellular calcium concentrations was measured in relation to the gene and protein expression of ATP1A1 and ATP1A3. Digitoxin was used to treat the cells at concentrations of 1-100 nM, and the intracellular calcium concentrations increased in a concentration-dependent manner in the Panc-1 and in the CFPAC-1 cells with treatment at 100 nM. In the AsPC-1 cells only the supraphysiological concentration of digitoxin (100 nM) resulted in a decrease in the number of viable cells (unviable cells increased to 22%), whereas it had no effect on intracellular calcium levels. The number of viable Panc-1 and CFPAC-1 cells decreased after digitoxin treatment at 25-100 nM (unviable Panc-1 cells increased to 33-59%; unviable CFPAC-1 cells increased to 22-56%). Digitoxin treatment also affected the transcriptional expression of the ATP1A1 and ATP1A3 subunits. In Panc-1 cells, ATP1A3 gene expression was negatively associated with the digitoxin concentration (25-100 nM). In the AsPC-1 and CFPAC-1 cells, the expression of the ATP1A1 gene increased in the cells treated with the 100 nM digitoxin concentration. The protein expression of ATP1A1 and ATP1A3 was not altered with digitoxin treatment. The basal protein expression of ATP1A1 was high in the AsPC-1 and CFPAC-1 cells, compared to the Panc-1 cells, in contrast to the basal expression of ATP1A3, which was higher in the Panc-1 cells, compared to the other pancreatic cancer cells used. On the whole, the present study demonstrates that the high expression of ATP1A3 renders pancreatic cancer cells more susceptible to digitoxin-induced cell death. The findings suggest that the expression of ATP1A3 may be used as a marker for tumor sensitivity to digitoxin treatment, where a high expression of ATP1A3 is favorable for the anticancer effects of digitoxin.

Ort, förlag, år, upplaga, sidor
Spandidos Publications, 2022
Nyckelord
Na+/K+-ATPase, Na+/K+-ATPase alpha subunits 1 and 3, calcium, digitoxin, pancreatic cancer
Nationell ämneskategori
Klinisk laboratoriemedicin Cell- och molekylärbiologi Cellbiologi Cancer och onkologi
Forskningsämne
Translationell medicin TRIM
Identifikatorer
urn:nbn:se:his:diva-22471 (URN)10.3892/mi.2022.52 (DOI)36698913 (PubMedID)
Anmärkning

CC BY-NC-ND 4.0

Correspondence to: Dr Ferenc Szekeres, Department of Biomedicine, Translational Medicine, School of Health Sciences, University of Skövde, Högskolevägen 1, 54145 Skövde, Sweden E‑mail: ferenc.szekeres@his.se

No funding was received.

Tillgänglig från: 2023-04-19 Skapad: 2023-04-27 Senast uppdaterad: 2023-07-14Bibliografiskt granskad
Deland, L., Keane, S., Bontell, T. O., Fagman, H., Sjögren, H., Lind, A. E., . . . Abel, F. (2022). Novel TPR::ROS1 Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma. Cancer Genomics & Proteomics, 19(6), 711-726
Öppna denna publikation i ny flik eller fönster >>Novel TPR::ROS1 Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma
Visa övriga...
2022 (Engelska)Ingår i: Cancer Genomics & Proteomics, ISSN 1109-6535, E-ISSN 1790-6245, Vol. 19, nr 6, s. 711-726Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND/AIM: Although fusion genes involving the proto-oncogene receptor tyrosine kinase ROS1 are rare in pediatric glioma, targeted therapies with small inhibitors are increasingly being approved for histology-agnostic fusion-positive solid tumors. PATIENT AND METHODS: Here, we present a 16-month-old boy, with a brain tumor in the third ventricle. The patient underwent complete resection but relapsed two years after diagnosis and underwent a second operation. The tumor was initially classified as a low-grade glioma (WHO grade 2); however, methylation profiling suggested the newly WHO-recognized type: infant-type hemispheric glioma. To further refine the molecular background, and search for druggable targets, whole genome (WGS) and whole transcriptome (RNA-Seq) sequencing was performed. RESULTS: Concomitant WGS and RNA-Seq analysis revealed several segmental gains and losses resulting in complex structural rearrangements and fusion genes. Among the top-candidates was a novel TPR::ROS1 fusion, for which only the 3' end of ROS1 was expressed in tumor tissue, indicating that wild type ROS1 is not normally expressed in the tissue of origin. Functional analysis by Western blot on protein lysates from transiently transfected HEK293 cells showed the TPR::ROS1 fusion gene to activate the MAPK-, PI3K- and JAK/STAT- pathways through increased phosphorylation of ERK, AKT, STAT and S6. The downstream pathway activation was also confirmed by immunohistochemistry on tumor tissue slides from the patient. CONCLUSION: We have mapped the activated oncogenic pathways of a novel ROS1-fusion gene and broadened the knowledge of the newly recognized infant-type glioma subtype. The finding facilitates suitable targeted therapies for the patient in case of relapse. 

Ort, förlag, år, upplaga, sidor
Cancer Genomics & Proteomics, 2022
Nyckelord
childhood cancer, chromosomal rearrangement, Pediatric glioma, precision medicine, TKI, tyrosine kinases
Nationell ämneskategori
Cancer och onkologi Medicinsk genetik
Forskningsämne
Translationell medicin TRIM
Identifikatorer
urn:nbn:se:his:diva-22033 (URN)10.21873/cgp.20354 (DOI)36316040 (PubMedID)2-s2.0-85140937065 (Scopus ID)
Forskningsfinansiär
Cancerfonden, 2018/825Cancerfonden, 2018/652Barncancerfonden, PR2017-0029Barncancerfonden, PR2019-0079Barncancerfonden, KP2019-0010
Anmärkning

CC BY-NC-ND 4.0

Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Correspondence to: Frida Abel

This work was supported by the Swedish Cancer Society (www.cancerfonden.se, grant number 2018/825 to FA and grant number 2018/652 to JAN), the Swedish Children’s Cancer Foundation (www.barncancerfonden.se, grant number PR2017-0029 to FA, PR2019-0079 to KE, and KP2019-0010 to HC), and the ALF-agreement (www.researchweb.org/is/alfgbg, ALFGBG-716231 to FA, ALFGBG-965828 to HC, and ALFGBG-719301 to JAN).

Tillgänglig från: 2022-11-10 Skapad: 2022-11-10 Senast uppdaterad: 2023-01-16Bibliografiskt granskad
Pagnamenta, A. T., Diaz-Gonzalez, F., Banos-Pinero, B., Ferla, M. P., Toosi, M. B., Calder, A. D., . . . Taylor, J. C. (2022). Variable skeletal phenotypes associated with biallelic variants in PRKG2. Journal of Medical Genetics, 59(10), 947-950
Öppna denna publikation i ny flik eller fönster >>Variable skeletal phenotypes associated with biallelic variants in PRKG2
Visa övriga...
2022 (Engelska)Ingår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 59, nr 10, s. 947-950Artikel i tidskrift (Refereegranskat) Published
Ort, förlag, år, upplaga, sidor
BMJ Publishing Group Ltd, 2022
Nyckelord
Genetics (clinical), Genetics
Nationell ämneskategori
Medicinsk genetik
Forskningsämne
Translationell medicin TRIM
Identifikatorer
urn:nbn:se:his:diva-20732 (URN)10.1136/jmedgenet-2021-108027 (DOI)000839164900001 ()34782440 (PubMedID)2-s2.0-85139374485 (Scopus ID)
Forskningsfinansiär
Wellcome trust, 203141/Z/16/ZEU, FP7, Sjunde ramprogrammet, 608473
Anmärkning

CC BY 4.0

Published Online First: 15 November 2021

Brief communication

The Genomics England Research Consortium

Correspondence to Dr Deborah Shears; debbie.shears@ouh.nhs.uk Dr Jenny C Taylor; jenny@well.ox.ac.uk

Tillgänglig från: 2021-11-30 Skapad: 2021-11-30 Senast uppdaterad: 2022-10-18Bibliografiskt granskad
Deland, L., Keane, S., Olsson Bontell, T., Sjögren, H., Fagman, H., Øra, I., . . . Abel, F. (2021). Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib. Cancer Biology & Therapy, 22(3), 184-195
Öppna denna publikation i ny flik eller fönster >>Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib
Visa övriga...
2021 (Engelska)Ingår i: Cancer Biology & Therapy, ISSN 1538-4047, E-ISSN 1555-8576, Vol. 22, nr 3, s. 184-195Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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. 

Ort, förlag, år, upplaga, sidor
Taylor & Francis, 2021
Nyckelord
GKAP1, larotrectinib, NTRK2, pediatric brain tumor, pLGG, precision medicine, TRKB; fusion gene
Nationell ämneskategori
Cancer och onkologi
Forskningsämne
Translationell medicin TRIM
Identifikatorer
urn:nbn:se:his:diva-19649 (URN)10.1080/15384047.2021.1899573 (DOI)000636984900001 ()33820494 (PubMedID)2-s2.0-85103915136 (Scopus ID)
Forskningsfinansiär
Europeiska kommissionen, PR2017-0029 PR2019-0079
Anmärkning

CC BY-NC-ND 4.0

© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.

Tillgänglig från: 2021-04-22 Skapad: 2021-04-22 Senast uppdaterad: 2022-10-26Bibliografiskt granskad
Keane, S., Martinsson, T., Kogner, P. & Ejeskär, K. (2021). The loss of DLG2 isoform 7/8, but not isoform 2, is critical in advanced staged neuroblastoma. Cancer Cell International, 21(1), Article ID 170.
Öppna denna publikation i ny flik eller fönster >>The loss of DLG2 isoform 7/8, but not isoform 2, is critical in advanced staged neuroblastoma
2021 (Engelska)Ingår i: Cancer Cell International, E-ISSN 1475-2867, Vol. 21, nr 1, artikel-id 170Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Neuroblastoma is a childhood neural crest tumor showing large clinical and genetic heterogeneity, one form displaying 11q-deletion is very aggressive. It has been shown that 11q-deletion results in decreased expression of DLG2, a gene residing in the deleted region. DLG2 has a number of different isoforms with the main difference is the presence or absence of a L27 domain. The L27 domain containing DLG proteins can form complexes with CASK/MPP and LIN7 protein family members, which will control cell polarity and signaling. Methods: We evaluated the DLG gene family and the LIN7 gene family for their expression in differently INSS staged neuroblastoma from publically available data and primary tumors, we included two distinct DLG1 and DLG2 N-terminal transcript isoforms encoding L27 domains for their expression. Functionality of DLG2 isoforms and of LIN7A were evaluated in the 11q-deleted neuroblastoma cell line SKNAS. Results: In neuroblastoma only two DLG2 isoforms were expressed: isoform 2 and isoform 7/8. Using the array data we could determine that higher expression of DLG members that contain L27 domains correlated to better survival and prognosis. Whilst DLG1 showed a decrease in both isoforms with increased INSS stage, only the full length L27 containing DLG2 transcripts DLG2-isoform 7/8 showed a decrease in expression in high stage neuroblastoma. We could show that the protein encoded by DLG2-isoform 7 could bind to LIN7A, and increased DLG2-isoform 7 gene expression increased the expression of LIN7A, this reduced neuroblastoma cell proliferation and viability, with increased BAX/BCL2 ratio indicating increased apoptosis. Conclusion: We have provided evidence that gene expression of the L27 domain containing DLG2-isoform 7/8 but not L27 domain lacking DLG2-isoform 2 is disrupted in neuroblastoma, in particular in the aggressive subsets of tumors. The presence of the complete L27 domain allows for the binding to LIN7A, which will control cell polarity and signaling, thus affecting cancer cell viability. 

Ort, förlag, år, upplaga, sidor
Springer Nature, 2021
Nyckelord
DLG, DLG2, Isoform, L27, LIN7A, Neuroblastoma
Nationell ämneskategori
Cancer och onkologi Cell- och molekylärbiologi
Forskningsämne
Translationell medicin TRIM
Identifikatorer
urn:nbn:se:his:diva-19546 (URN)10.1186/s12935-021-01851-w (DOI)000629888200003 ()33726762 (PubMedID)2-s2.0-85102533029 (Scopus ID)
Anmärkning

CC BY 4.0

The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

© 2021, The Author(s).

© 2021 BioMed Central Ltd unless otherwise stated. Part of Springer Nature.

Correspondence: Katarina.ejeskar@his.se

Tillgänglig från: 2021-03-25 Skapad: 2021-03-25 Senast uppdaterad: 2023-09-08Bibliografiskt granskad
Organisationer
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0001-8962-0860

Sök vidare i DiVA

Visa alla publikationer