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Brännström, Thomas
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Forsberg, K., Graffmo, K. S., Pakkenberg, B., Weber, M., Nielsen, M., Marklund, S. L., . . . Munch Andersen, P. (2019). Misfolded SOD1 inclusions in patients with mutations in C9orf72 and other ALS/FTD-associated genes. Journal of Neurology, Neurosurgery and Psychiatry, 90(8), 861-869
Öppna denna publikation i ny flik eller fönster >>Misfolded SOD1 inclusions in patients with mutations in C9orf72 and other ALS/FTD-associated genes
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2019 (Engelska)Ingår i: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 90, nr 8, s. 861-869Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Objective: A hallmark of amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase-1 (SOD1) are inclusions containing SOD1 in motor neurons. Here, we searched for SOD1-positive inclusions in 29 patients carrying ALS-linked mutations in six other genes.

Methods: A panel of antibodies that specifically recognise misfolded SOD1 species were used for immunohistochemical investigations of autopsy tissue.

Results: The 18 patients with hexanucleotide-repeat-expansions in C9orf72 had inclusions of misfolded wild type (WT) SOD1(WT) in spinal motor neurons. Similar inclusions were occasionally observed in medulla oblongata and in the motor cortex and frontal lobe. Patients with mutations in FUS, KIF5A, NEK1, ALSIN or VAPB, carried similar SOD1(WT) inclusions. Minute amounts of misSOD1(WT) inclusions were detected in 2 of 20 patients deceased from non-neurological causes and in 4 of 10 patients with other neurodegenerative diseases. Comparison was made with 17 patients with 9 different SOD1 mutations. Morphologically, the inclusions in patients with mutations in C9orf72HRE, FUS, KIF5A, NEK1, VAPB and ALSIN resembled inclusions in patients carrying the wildtype-like SOD1(D90A) mutation, whereas patients carrying unstable SOD1 mutations (A4V, V5M, D76Y, D83G, D101G, G114A, G127X, L144F) had larger skein-like SOD1-positive inclusions.

Conclusions and relevance Abundant inclusions containing misfolded SOD1(WT) are found in spinal and cortical motor neurons in patients carrying mutations in six ALS-causing genes other than SOD1. This suggests that misfolding of SOD1(WT) can be part of a common downstream event that may be pathogenic. The new anti-SOD1 therapeutics in development may have applications for a broader range of patients.

Ort, förlag, år, upplaga, sidor
BMJ Publishing Group Ltd, 2019
Nyckelord
amyotrophic lateral sclerosis, neuronal inclusions, C9orf72, KIF5A, superoxide dismutase-1
Nationell ämneskategori
Neurologi Neurovetenskaper
Identifikatorer
urn:nbn:se:umu:diva-163689 (URN)10.1136/jnnp-2018-319386 (DOI)000482509400004 ()30992335 (PubMedID)
Tillgänglig från: 2019-10-17 Skapad: 2019-10-17 Senast uppdaterad: 2019-11-25Bibliografiskt granskad
Brännström, T., Andersen, P. M., Bergh, J., Ekhtiari Bidhendi, E. & Marklund, S. M. (2019). Mutant SOD1 aggregates from human ventral horn transmit templated aggregation and fatal ALS-like disease. Paper presented at 19th International Congress of Neuropathology, SEP 23-27, 2018, Tokyo, JAPAN. Brain Pathology, 29, 90-90
Öppna denna publikation i ny flik eller fönster >>Mutant SOD1 aggregates from human ventral horn transmit templated aggregation and fatal ALS-like disease
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2019 (Engelska)Ingår i: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 29, s. 90-90Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2019
Nationell ämneskategori
Neurologi Neurovetenskaper
Identifikatorer
urn:nbn:se:umu:diva-157592 (URN)000459814800279 ()
Konferens
19th International Congress of Neuropathology, SEP 23-27, 2018, Tokyo, JAPAN
Anmärkning

Supplement: 1

Special Issue: SI

Meeting Abstract: P2-66

Tillgänglig från: 2019-03-28 Skapad: 2019-03-28 Senast uppdaterad: 2019-11-25Bibliografiskt granskad
Wu, W.-Y. Y., Johansson, G., Wibom, C., Brännström, T., Malmström, A., Henriksson, R., . . . Melin, B. S. (2019). The Genetic Architecture of Gliomagenesis-Genetic Risk Variants Linked to Specific Molecular Subtypes. Cancers, 11(12), Article ID 2001.
Öppna denna publikation i ny flik eller fönster >>The Genetic Architecture of Gliomagenesis-Genetic Risk Variants Linked to Specific Molecular Subtypes
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2019 (Engelska)Ingår i: Cancers, ISSN 2072-6694, Vol. 11, nr 12, artikel-id 2001Artikel, forskningsöversikt (Refereegranskat) Published
Abstract [en]

Genome-wide association studies have identified 25 germline genetic loci that increase the risk of glioma. The somatic tumor molecular alterations, including IDH-mutation status and 1p/19q co-deletion, have been included into the WHO 2016 classification system for glioma. To investigate how the germline genetic risk variants correlate with the somatic molecular subtypes put forward by WHO, we performed a meta-analysis that combined findings from 330 Swedish cases and 876 controls with two other recent studies. In total, 5,103 cases and 10,915 controls were included. Three categories of associations were found. First, variants in TERT and TP53 were associated with increased risk of all glioma subtypes. Second, variants in CDKN2B-AS1, EGFR, and RTEL1 were associated with IDH-wildtype glioma. Third, variants in CCDC26 (the 8q24 locus), C2orf80 (close to IDH), LRIG1, PHLDB1, ETFA, MAML2 and ZBTB16 were associated with IDH-mutant glioma. We therefore propose three etiopathological pathways in gliomagenesis based on germline variants for future guidance of diagnosis and potential functional targets for therapies. Future prospective clinical trials of patients with suspicion of glioma diagnoses, using the genetic variants as biomarkers, are necessary to disentangle how strongly they can predict glioma diagnosis.

Ort, förlag, år, upplaga, sidor
MDPI, 2019
Nyckelord
glioma, IDH mutant, 1p/19q co-deletion, gliomagenesis, genotype phenotype, etiopathogenesis
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-167615 (URN)10.3390/cancers11122001 (DOI)000507382100178 ()31842352 (PubMedID)2-s2.0-85076550363 (Scopus ID)
Tillgänglig från: 2020-02-06 Skapad: 2020-02-06 Senast uppdaterad: 2020-02-06Bibliografiskt granskad
Ekhtiari Bidhendi, E., Bergh, J., Zetterström, P., Forsberg, K., Pakkenberg, B., Andersen, P. M., . . . Brännström, T. (2018). Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis. Acta Neuropathologica, 136(6), 939-953
Öppna denna publikation i ny flik eller fönster >>Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis
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2018 (Engelska)Ingår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 136, nr 6, s. 939-953Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Motor neurons containing aggregates of superoxide dismutase 1 (SOD1) are hallmarks of amyotrophic lateral sclerosis (ALS) caused by mutations in the gene encoding SOD1. We have previously reported that two strains of mutant human (h) SOD1 aggregates (denoted A and B) can arise in hSOD1-transgenic models for ALS and that inoculation of such aggregates into the lumbar spinal cord of mice results in rostrally spreading, templated hSOD1 aggregation and premature fatal ALS-like disease. Here, we explored whether mutant hSOD1 aggregates with prion-like properties also exist in human ALS. Aggregate seeds were prepared from spinal cords from an ALS patient carrying the hSOD1G127Gfs*7 truncation mutation and from mice transgenic for the same mutation. To separate from mono-, di- or any oligomeric hSOD1 species, the seed preparation protocol included ultracentrifugation through a density cushion. The core structure of hSOD1G127Gfs*7 aggregates present in mice was strain A-like. Inoculation of the patient- or mouse-derived seeds into lumbar spinal cord of adult hSOD1-expressing mice induced strain A aggregation propagating along the neuraxis and premature fatal ALS-like disease (p < 0.0001). Inoculation of human or murine control seeds had no effect. The potencies of the ALS patient-derived seed preparations were high and disease was initiated in the transgenic mice by levels of hSOD1G127Gfs*7 aggregates much lower than those found in the motor system of patients carrying the mutation. The results suggest that prion-like growth and spread of hSOD1 aggregation could be the primary pathogenic mechanism, not only in hSOD1 transgenic rodent models, but also in human ALS.

Ort, förlag, år, upplaga, sidor
Springer, 2018
Nyckelord
Superoxide dismutase, prion-like, aggregation, propagation, motor neuron disease
Nationell ämneskategori
Neurovetenskaper
Forskningsämne
neurologi; patologi
Identifikatorer
urn:nbn:se:umu:diva-150909 (URN)10.1007/s00401-018-1915-y (DOI)000451952700008 ()30284034 (PubMedID)
Forskningsfinansiär
Knut och Alice Wallenbergs StiftelseTorsten Söderbergs stiftelseHjärnfondenKempestiftelsernaVästerbottens läns landsting
Anmärkning

Originally included in thesis in manuscript form.

Tillgänglig från: 2018-08-18 Skapad: 2018-08-18 Senast uppdaterad: 2019-09-12Bibliografiskt granskad
Tjust, A. E., Danielsson, A., Andersen, P. M., Brännstrom, T. & Pedrosa-Domellöf, F. (2017). Impact of Amyotrophic Lateral Sclerosis on Slow Tonic Myofiber Composition in Human Extraocular Muscles. Investigative Ophthalmology and Visual Science, 58(9), 3708-3715
Öppna denna publikation i ny flik eller fönster >>Impact of Amyotrophic Lateral Sclerosis on Slow Tonic Myofiber Composition in Human Extraocular Muscles
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2017 (Engelska)Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 58, nr 9, s. 3708-3715Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

PURPOSE. To analyze the proportion and cross-sectional area of myofibers containing myosin heavy chain slow-twitch (MyHCI) and myosin heavy chain slow tonic (MyHCsto) in extraocular muscles of autopsied amyotrophic lateral sclerosis (ALS) patients with either spinal or bulbar site of disease onset. METHODS. Whole-muscle cross sections from the middle portion of the medial rectus were labeled with antibodies against MyHCI or MyHCsto and laminin. Myofibers labeled with the MyHC antibodies (MyHCI+sto) and the total number of myofibers were quantified in the orbital and global layer of 6 control individuals and 18 ALS patients. The cross-sectional area of myofibers labeled for either MyHC was quantified in 130 to 472 fibers/individual in the orbital and in 180 to 573 fibers/individual in the global layer of each specimen. RESULTS. The proportion of MyHCI+sto myofibers was significantly smaller in the orbital and global layer of ALS compared to control individuals. MyHCI+sto myofibers were significantly smaller in the global layer than in the orbital layer of ALS, whereas they were of similar size in control subjects. The decreased proportion of MyHCI+sto fibers correlated significantly with the age of death, but not disease duration, in patients who had the bulbar-onset variant of ALS but not in patients with spinal variant. CONCLUSIONS. ALS, regardless of site of onset, involves a loss of myofibers containing MyHCI+sto. Only in bulbar-onset cases did aging seem to play a role in the pathophysiological processes underlying the loss of MyHCI+sto fibers.

Ort, förlag, år, upplaga, sidor
ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2017
Nyckelord
amyotrophic lateral sclerosis, extraocular muscles, MyH14, slow tonic, muscle fibers
Nationell ämneskategori
Oftalmologi
Identifikatorer
urn:nbn:se:umu:diva-140482 (URN)10.1167/iovs.17-22098 (DOI)000410931200051 ()28738414 (PubMedID)
Tillgänglig från: 2017-10-20 Skapad: 2017-10-20 Senast uppdaterad: 2019-11-19Bibliografiskt granskad
Johansson, G., Brannstrom, T., Andersson, U., Golovleva, I. & Melin, B. (2017). Molecular classification of malignat glioma. Paper presented at 5th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology-Societies (WFNOS), Zurich, Switzerland, May 4-7, 2017. Neuro-Oncology, 19(S3), 88-88, Article ID P10.15.
Öppna denna publikation i ny flik eller fönster >>Molecular classification of malignat glioma
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2017 (Engelska)Ingår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 19, nr S3, s. 88-88, artikel-id P10.15Artikel i tidskrift, Meeting abstract (Refereegranskat) Published
Abstract [en]

Background: Malignant glioma are devastating tumors with poor prognosis. In recent years, the classification of glioma have evolved greatly due to exploration of several molecular tools in addition to the traditional immunohistochemistry.

Methods: To further evolve this classification, we thoroughly characterized the molecular and histological signature of 367 glioma patients from Sweden. We first obtained the full medical history and histological classification, along with matched blood samples and unstained tissue slides. We have performed extensive molecular characterization using genome wide association studies, methylation arrays and telomere length assays. We have extended the classification to include IDH1 mutations, chromosome 1p/19q co-deletion, EGFR amplification as well as the expression of two novel cell signaling regulators. The statistical analysis is ongoing and will reveal how well we can classify the tumors by combining the above mentioned techniques. 

Results: As expected we found EGFR upregulation in almost 50% of the patients with glioblastoma and one third of patients with anaplastic astrocytoma and anaplastic oligodendroglioma. No EGFR expression was found in any patient with low grade glioma. In consistence with previous studies 70% of the IDH1 mutated oligodendroglioma had 1p/19q co-deletion. In the IDH1 wildtype oligodendroglioma, about 50% of the low grade tumors had 1p/19q co-deletion. Interestingly, we found complete 1p/19q co-deletion in about 10% of the IDH1 wild type glioblastoma.

Conclusion: Today, 1p/19q co-deletion is normally only studied in suspected oligodendroglioma and not in all types of glioma. Pending the clinical relevance of the 1p/19q co-deleted glioblastoma, it might be wise to expand the 1p/19q classification by including all types of glioma.

Ort, förlag, år, upplaga, sidor
Oxford University Press, 2017
Nyckelord
signal transduction, immunohistochemistry, j mutationa, naplastic astrocytoma, glioblastoma, chromosomes, glioma, methylatio, noligodendroglioma, epidermal growth factor receptors, telomere, up-regulation (physiology), medical history, neoplasms, glioma, malignant, anaplastic oligodendroglioma, amplification, genome-wide association study, idh1 gene, low grade glioma
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-136983 (URN)10.1093/neuonc/nox036.333 (DOI)000402732900335 ()
Konferens
5th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology-Societies (WFNOS), Zurich, Switzerland, May 4-7, 2017
Anmärkning

Volume 19, Supplement 3, 1 May 2017

5th Quadrennial Meeting of the World Federation of Neuro-Oncology Societies (WFNOS), May 4-7, 2017, Zurich, Switzerland

Tillgänglig från: 2017-06-30 Skapad: 2017-06-30 Senast uppdaterad: 2020-03-12Bibliografiskt granskad
Tabatabaei, P., Visse, E., Bergström, P., Brännström, T., Siesjö, P. & Bergenheim, A. T. (2017). Radiotherapy induces an immediate inflammatory reaction in malignant glioma: a clinical microdialysis study. Journal of Neuro-Oncology, 131(1), 83-92
Öppna denna publikation i ny flik eller fönster >>Radiotherapy induces an immediate inflammatory reaction in malignant glioma: a clinical microdialysis study
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2017 (Engelska)Ingår i: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 131, nr 1, s. 83-92Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The knowledge of response to radiation in the immuno-microenvironment of high grade gliomas is sparse. In vitro results have indicated an inflammatory response of myeloid cells after irradiation. Therefore, microdialysis was used to verify whether this is operative in tumor tissue and brain adjacent to tumor (BAT) after clinical radiotherapy of patients with high grade glioma. Stereotactic biopsies and implantation of microdialysis catheters in tumor tissue and BAT were performed in eleven patients with high-grade glioma. The patients were given daily radiation fractions of 2-3.4 Gy. Microdialysis samples were collected before radiotherapy and during the first five days of radiation. Cytokines, glucose metabolites, glutamate and glycerol were analyzed. Immunohistochemistry was performed to detect macrophages (CD68) and monocytes (CD163) as well as IL-6, IL-8 and MCP-1. A significant increase of IL-8, MCP-1 and MIP-1a were detected in tumor tissue already after the first dose of radiation and increased further during 5 days of radiation. IL-6 did also increase but after five fractions of radiation. In BAT, the cytokine response was modest with significant increase of IL-8 after third dose of radiation. We found a positive correlation between baseline IL-8 and IL-6 microdialysis levels in tumor tissue and survival. Glucose metabolites or glycerol and glutamate did not change during radiation. In all tumors staining for macrophages was demonstrated. IL-6 was found in viable tumor cells while MCP-1 was demonstrated in macrophages or tumor matrix. Our findings suggest that radiation induces a rapid enhancement of the prevailing inflammation in high-grade glioma tissue. The microdialysis technique is feasible for this type of study and could be used to monitor metabolic changes after different interventions.

Ort, förlag, år, upplaga, sidor
Springer, 2017
Nyckelord
Cytokine, Glioblastoma, Radiotherapy, Microdialysis, Inflammation
Nationell ämneskategori
Cancer och onkologi Neurologi
Identifikatorer
urn:nbn:se:umu:diva-131132 (URN)10.1007/s11060-016-2271-1 (DOI)000393065400010 ()27664151 (PubMedID)
Tillgänglig från: 2017-02-06 Skapad: 2017-02-06 Senast uppdaterad: 2019-05-09Bibliografiskt granskad
Nordin, A., Akimoto, C., Wuolikainen, A., Alstermark, H., Forsberg, K., Baumann, P., . . . Andersen, P. M. (2017). Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 18(3-4), 256-264
Öppna denna publikation i ny flik eller fönster >>Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study
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2017 (Engelska)Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 18, nr 3-4, s. 256-264Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

A large GGGGCC-repeat expansion mutation (HREM) in C9orf72 is the most common known cause of ALS and FTD in European populations. Sequence variations immediately downstream of the HREM region have previously been observed and have been suggested to be one reason for difficulties in interpreting RP-PCR data. Our objective was to determine the properties of these sequence variations with regard to prevalence, the range of variation, and effect on disease prognosis. We screened a multi-national cohort (n = 6981) for the HREM and samples with deviant RP-PCR curves were identified. The deviant samples were subsequently sequenced to determine sequence alteration. Our results show that in the USA and European cohorts (n = 6508) 10.7% carried the HREM and 3% had a sequence variant, while no HREM or sequence variants were observed in the Japanese cohort (n = 473). Sequence variations were more common on HREM alleles; however, certain population specific variants were associated with a non-expanded allele. In conclusion, we identified 38 different sequence variants, most located within the first 50 bp downstream of the HREM region. Furthermore, the presence of an HREM was found to be coupled to a lower age of onset and a shorter disease survival, while sequence variation did not have any correlation with these parameters.

Nyckelord
ALS, C9orf72, FTD, RP-PCR interpretation, variants
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:umu:diva-134981 (URN)10.1080/21678421.2016.1262423 (DOI)000400792800012 ()27936955 (PubMedID)
Tillgänglig från: 2017-05-15 Skapad: 2017-05-15 Senast uppdaterad: 2019-05-09Bibliografiskt granskad
Andersson, U., Degerman, S., Dahlin, A., Brannstrom, T., Roos, G. & Melin, B. S. (2017). Telomere length, allergies and risk of Glioma. Paper presented at 5th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology-Societies (WFNOS), Zurich, Switzerland, May 4-7, 2017. Neuro-Oncology, 19(S3), 23-23, Article ID P01.03.
Öppna denna publikation i ny flik eller fönster >>Telomere length, allergies and risk of Glioma
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2017 (Engelska)Ingår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 19, nr S3, s. 23-23, artikel-id P01.03Artikel i tidskrift, Meeting abstract (Refereegranskat) Published
Abstract [en]

Background: In glioma, a malignant brain tumour with poor prognosis, the etiology is largely unkown. Rare inherited syndromes, and high doses of ionising radiation are associated with increased risk of glioma. Common genetic variants have been associated with risk of glioma, and familial glioma have been associated with genetic variants in genes functionally important in telomere regulation (e.g. RTEL, TERT and POT1). The association between telomere length and risk of cancer is complex and seems to be tumour type dependent. Patients with asthma have significantly shorter telomeres than those of control subjects, and a protective effect has been observed with an inverse association with allergies and asthma and glioma risk. 

Methods: We investigated population based glioma case-control series (431 cases and 672 controls) from Sweden at diagnosis with a quantitative PCR method for relative leukocyte telomere length measured in blood confirming with direct measurement of the association between telomere length and risk of glioma. We also explored the relationship between, age, gender, allergies and asthma, as these are established factors associated both with telomere length and glioma.

Results: Longer relative leukocyte telomere length was significantly associated with increased risk of glioma, adjusting for age and gender (OR=2.23, CI: 1.11–4.47). As expected, for patients with allergies there was a protective effect with an inverse association with glioma risk, adjusting for age and gender (OR=0.64, CI; 0.48–0.85). Nevertheless, when analysing specific types of allergy, eczema (OR=0.66, CI; 0.41–1.08) and water eyes (OR=0.52, CI; 0.31–0.88) appeared to be more protective against glioma, compared to asthma (OR=0.92, CI; 0.59–1.41), and respiratory symptoms (OR=1.14, CI; 0.71–1.84) which showed no protective effect against glioma. Additionally adjusting for allergies did not markedly change the OR between relative leukocyte telomere length and glioma risk, indicating that the protective effect having allergies seems not to be coupled to telomere length. Conclusions: The adverse association of longer telomere and risk of glioma displays the complexity in understanding the biological role of telomere length and risk of developing cancer.

Ort, förlag, år, upplaga, sidor
Oxford University Press, 2017
Nyckelord
polymerase chain reaction, hypersensitivity, asthma, brain tumors, cancer, eczema, genes, glioma, leukocytes, signs and symptoms, respiratory, telomere, diagnosis, eye, genetics, neoplasms, radiation, ionizing, gender, cancer risk, causality
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-136984 (URN)10.1093/neuonc/nox036.079 (DOI)000402732900081 ()
Konferens
5th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology-Societies (WFNOS), Zurich, Switzerland, May 4-7, 2017
Anmärkning

Volume 19, Supplement 3, 1 May 2017

5th Quadrennial Meeting of the World Federation of Neuro-Oncology Societies (WFNOS), May 4-7, 2017, Zurich, Switzerland

Tillgänglig från: 2017-06-30 Skapad: 2017-06-30 Senast uppdaterad: 2020-03-12Bibliografiskt granskad
Ghasimi, S., Wibom, C., Dahlin, A. M., Brännström, T., Golovleva, I., Andersson, U. & Melin, B. (2016). Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma. Journal of Neuro-Oncology, 127(3), 483-492
Öppna denna publikation i ny flik eller fönster >>Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma
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2016 (Engelska)Ingår i: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 127, nr 3, s. 483-492Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

During the last years, genome wide association studies have discovered common germline genetic variants associated with specific glioma subtypes. We aimed to study the association between these germline risk variants and tumor phenotypes, including copy number aberrations and protein expression. A total of 91 glioma patients were included. Thirteen well known genetic risk variants in TERT, EGFR, CCDC26, CDKN2A, CDKN2B, PHLDB1, TP53, and RTEL1 were selected for investigation of possible correlations with the glioma somatic markers: EGFR amplification, 1p/19q codeletion and protein expression of p53, Ki-67, and mutated IDH1. The CDKN2A/B risk variant, rs4977756, and the CDKN2B risk variant, rs1412829 were inversely associated (p = 0.049 and p = 0.002, respectively) with absence of a mutated IDH1, i.e., the majority of patients homozygous for the risk allele showed no or low expression of mutated IDH1. The RTEL1 risk variant, rs6010620 was associated (p = 0.013) with not having 1p/19q codeletion, i.e., the majority of patients homozygous for the risk allele did not show 1p/19q codeletion. In addition, the EGFR risk variant rs17172430 and the CDKN2B risk variant rs1412829, both showed a trend for association (p = 0.055 and p = 0.051, respectively) with increased EGFR copy number, i.e., the majority of patients homozygote for the risk alleles showed chromosomal gain or amplification of EGFR. Our findings indicate that CDKN2A/B risk genotypes are associated with primary glioblastoma without IDH mutation, and that there is an inverse association between RTEL1 risk genotypes and 1p/19q codeletion, suggesting that these genetic variants have a molecular impact on the genesis of high graded brain tumors. Further experimental studies are needed to delineate the functional mechanism of the association between genotype and somatic genetic aberrations.

Nyckelord
CDKN2A/B, EGFR, RTEL1, SNP, FISH, ASCAT
Nationell ämneskategori
Cancer och onkologi Neurologi
Identifikatorer
urn:nbn:se:umu:diva-121460 (URN)10.1007/s11060-016-2066-4 (DOI)000374463800009 ()26839018 (PubMedID)
Tillgänglig från: 2016-06-22 Skapad: 2016-06-02 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
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