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Towards Novel Biomarkers for Low-grade Glioma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Gliomas are common primary brain tumours that occur as low-grade (LGG) and high-grade gliomas (HGG). Typically occurring in younger adults, LGG has an indolent course with a median survival of 5-10 years, but carries an inherent potential for transforming into HGG. The thesis focused on LGG in adults, with the aim of identifying prognostic biomarkers for LGG.

Paper I. Epileptic seizures are common symptoms in LGG. In a retrospective study, the correlation between 11C-methionine (MET) uptake, measured by Positron Emission Tomography (PET), and seizure activity was assessed in 101 patients with LGG. Although there was no correlation between MET uptake and seizure activity, survival was longer in patients who were seizure-free before surgery.

Paper II. This finding prompted the search for common genetic pathways for both tumour and seizure development and a review of genetic polymorphisms in focal epilepsy and glioma risk. Cell cycle and immune response genes affecting both glioma and seizure risk were identified, and genes involved in synaptic transmission presented potential candidates for future studies.

Paper III. The transcription factor PROX1 plays a pivotal role in normal development and carcinogenesis of various organs. The prognostic value of PROX1, together with established clinical and molecular prognostic factors for survival, was retrospectively assessed in 116 patients with LGG. High PROX1 expression in the tumour was associated with shorter survival.

Paper IV. DNA repair enzymes, such as ERCC6, are crucial for maintaining genomic stability in glioma response to radiotherapy. An association between the polymorphism rs4253079, mapped to ERCC6, and longer survival in patients with LGG and HGG was identified.

Paper V. As LGG typically presented as non-contrast enhancing tumours on morphological MRI (magnetic resonance imaging), the value of combined MET PET with physiological MRI for preoperative diagnosis was assessed in a prospective study of 32 patients with suspected LGG. Representative tumour areas were identified through a combination of perfusion-MRI with MET PET, which can be used as a baseline investigation for follow-up over time.

Conclusions: The parameters seizure-freedom before surgery, the polymorphism rs4253079 in ERCC6 and low PROX1 expression in the tumor were identified as favorable prognostic biomarkers.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 834
Keyword [en]
Low-grade glioma, prognosis, epilepsy, PROX1, DNA repair enzyme, PET, Physiological MRI
National Category
Medical and Health Sciences
Research subject
Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-183363ISBN: 978-91-554-8518-4 (print)OAI: oai:DiVA.org:uu-183363DiVA: diva2:562518
Public defence
2012-12-10, Rosénsalen, Akademiska sjukhuset, ing. 95, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2012-11-19 Created: 2012-10-24 Last updated: 2013-01-23Bibliographically approved
List of papers
1. Epileptic seizures and survival in early disease of grade 2 gliomas
Open this publication in new window or tab >>Epileptic seizures and survival in early disease of grade 2 gliomas
2009 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 16, no 7, 823-831 p.Article in journal (Refereed) Published
Abstract [en]

Background and purpose

The aims of this study were (i) to determine the correlation between seizure activity and the metabolic rate of the tumour measured by 11Cmethionine PET (MET PET) in patients with grade 2 gliomas, and (ii) to assess the prognostic impact of early seizure manifestations on patient survival.

Methods

In this retrospective review, early seizure manifestations were studied in 101 patients with supratentorial grade 2 gliomas subjected to MET PET as part of the pretreatment tumour investigation. Seizure manifestations as a variable was then used in multivariate survival analyses, together with established prognostic factors for this patient group.

Results

Of all 101 cases, 88 patients had seizures at tumour presentation. Fortyseven were seizure free at the early stage of the disease, whereas 54 had recurrent seizures. Patients with seizures at tumour presentation had a more favourable outcome before and after (P = 0.006) adjustment for conventional prognostic factors. However, for those who continued to have seizures early in the disease, the outcome was worse (P = 0.003). We found no significant correlation between MET PET and the seizure manifestations of the patients.

Conclusion

The presence and termination of early seizure manifestations may be favourable prognostic factors in patients with low-grade gliomas.

 

Keyword
11C methionine positron emission tomography, epileptic seizures, low-grade glioma, survival
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-105434 (URN)10.1111/j.1468-1331.2009.02599.x (DOI)000266637000012 ()
Available from: 2009-06-03 Created: 2009-06-03 Last updated: 2017-12-13Bibliographically approved
2. Tumor-associated epilepsy and glioma: are there common genetic pathways?
Open this publication in new window or tab >>Tumor-associated epilepsy and glioma: are there common genetic pathways?
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2009 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 48, no 7, 955-963 p.Article, review/survey (Refereed) Published
Abstract [en]

Background. Patients with glioma exhibit a great variability in clinical symptoms apart from variations in response to therapy and survival. Many patients present with epileptic seizures at disease onset, especially in case of low-grade gliomas, but not all have seizures. A large proportion of patients develop refractory seizures. It is likely that the variability in epileptic symptoms cannot exclusively be explained by tumor-related factors, but rather reflects complex interaction between tumor-related, environmental and hereditary factors. Material and methods. No data exist on susceptibility genes associated with epileptic symptoms in patients with glioma. However, an increasing number of candidate genes have been proposed for other focal epilepsies such as temporal lobe epilepsy. Some of the susceptibility candidate genes associated with focal epilepsy may contribute to epileptic symptoms also in patients with glioma. Results. This review presents an update on studies on genetic polymorphisms and focal epilepsy and brings forward putative candidate genes for tumor-associated epilepsy, based on the assumption that common etiological pathways may exist for glioma development and glioma-associated seizures. Conclusion. Genes involved in the immune response, in synaptic transmission and in cell cycle control are discussed that may play a role in the pathogenesis of tumor growth as well as epileptic symptoms in patients with gliomas.

National Category
Medical and Health Sciences
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-108658 (URN)10.1080/02841860903104145 (DOI)000271228400002 ()
Available from: 2009-09-25 Created: 2009-09-25 Last updated: 2017-12-13Bibliographically approved
3. PROX1 is a predictor of survival for gliomas WHO grade II
Open this publication in new window or tab >>PROX1 is a predictor of survival for gliomas WHO grade II
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2011 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, no 11, 1747-1754 p.Article in journal (Refereed) Published
Abstract [en]

Background:The clinical course of World Health Organisation grade II gliomas remains variable and their time point of transformation into a more malignant phenotype is unpredictable. Identification of biological markers that can predict prognosis in individual patients is of great clinical value. PROX1 is a transcription factor that has a critical role in the development of various organs. PROX1 has been ascribed both oncogenic and tumour suppressive functions in human cancers. We have recently shown that PROX1 may act as a diagnostic marker for high-grade gliomas. The aim of this study was to address the prognostic value of PROX1 in grade II gliomas.Methods:A total of 116 samples were evaluated for the presence of PROX1 protein. The number of immunopositive cells was used as a variable in survival analysis, together with established prognostic factors for this patient group.Results:Higher PROX1 protein was associated with poor outcome. In the multivariate analysis, PROX1 was identified as an independent factor for survival (P=0.024), together with the presence of mutated isocitrate dehydrogenase 1 R132H protein, and with combined losses of chromosomal arms 1p/19q in oligodendrocytic tumours.Conclusion:PROX1 is a novel predictor of survival for grade II gliomas.

Keyword
low-grade glioma, astrocytoma, oligodendroglioma, PROX1, prognosis, survival
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-154452 (URN)10.1038/bjc.2011.162 (DOI)000290953200014 ()21559010 (PubMedID)
Available from: 2011-06-01 Created: 2011-06-01 Last updated: 2017-12-11Bibliographically approved
4. Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas
Open this publication in new window or tab >>Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas
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2011 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 105, no 3, 531-538 p.Article in journal (Refereed) Published
Abstract [en]

The purpose of this study was to explore the variation in DNA repair genes in adults with WHO grade II and III gliomas and their relationship to patient survival. We analysed a total of 1,458 tagging single-nucleotide polymorphisms (SNPs) that were selected to cover DNA repair genes, in 81 grade II and grade III gliomas samples, collected in Sweden and Denmark. The statistically significant genetic variants from the first dataset (P < 0.05) were taken forward for confirmation in a second dataset of 72 grade II and III gliomas from northern UK. In this dataset, eight gene variants mapping to five different DNA repair genes (ATM, NEIL1, NEIL2, ERCC6 and RPA4) which were associated with survival. Finally, these eight genetic variants were adjusted for treatment, malignancy grade, patient age and gender, leaving one variant, rs4253079, mapped to ERCC6, with a significant association to survival (OR 0.184, 95% CI 0.054-0.63, P = 0.007). We suggest a possible novel association between rs4253079 and survival in this group of patients with low-grade and anaplastic gliomas that needs confirmation in larger datasets.

Keyword
Gliomas WHO grade II/III, DNA repair, ERCC6, Outcome, Polymorphism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-157135 (URN)10.1007/s11060-011-0614-5 (DOI)000297803100008 ()21643987 (PubMedID)
Available from: 2011-08-17 Created: 2011-08-17 Last updated: 2017-12-08
5. 11C-methionine PET combined with physiological MRI for the preoperative evaluation of suspected adult low-grade gliomas
Open this publication in new window or tab >>11C-methionine PET combined with physiological MRI for the preoperative evaluation of suspected adult low-grade gliomas
Show others...
(English)Article in journal (Refereed) Submitted
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-182573 (URN)
Available from: 2012-10-23 Created: 2012-10-11 Last updated: 2013-03-15Bibliographically approved

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