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FGF2 as a potential prognostic biomarker for proneural glioma patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2015 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 3, 385-394 p.Article in journal (Refereed) Published
Abstract [en]

Background. The survival of high-grade glioma patients is poor and the treatment of these patients can cause severe side effects. This fosters the necessity to identify prognostic biomarkers, in order to optimize treatment and diminish unnecessary suffering of patients. The aim of this study was to identify prognostic biomarkers for high-grade glioma patients.

Methods. Eleven proteins were selected for analysis due to their suggested importance for survival of patients with other types of cancers and due to a high variation in protein levels between glioma patients (according to the Human Protein Atlas, www.proteinatlas.org). Protein expression patterns of these 11 proteins were analyzed by immunohistochemistry in tumor samples from 97 high-grade glioma patients. The prognostic values of the proteins were analyzed with univariate and multivariate Cox regression analyses for the high-grade glioma patients, including subgroup analyses of histological subtypes and immunohistochemically defined molecular subtypes.

Results. The proteins with the most significant (univariate and multivariate p < 0.05) correlations were analyzed further with cross-validated Kaplan-Meier analyses for the possibility of predicting survival based on the protein expression pattern of the corresponding candidate. Random Forest classification with variable subset selection was used to analyze if a protein signature consisting of any combination of the 11 proteins could predict survival for the high-grade glioma patients and the subgroup with glioblastoma patients. The proteins which correlated most significantly (univariate and multivariate p < 0.05) to survival in the Cox regression analyses were Myc for all high-grade gliomas and FGF2, CA9 and CD44 for the subgroup of proneural gliomas, with FGF2 having a strong negative predictive value for survival. No prognostic signature of the proteins could be found.

Conclusion. FGF2 is a potential prognostic biomarker for proneural glioma patients, and warrants further investigation.

Place, publisher, year, edition, pages
2015. Vol. 54, no 3, 385-394 p.
Keyword [en]
Prognostic biomarkers, tissue microarray, immunohistochemistry, FGF2, CA9, CD44
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-214802DOI: 10.3109/0284186X.2014.951492ISI: 000350646400012PubMedID: 25263081OAI: oai:DiVA.org:uu-214802DiVA: diva2:685644
Available from: 2014-01-09 Created: 2014-01-09 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Prognostic Biomarkers and Target Proteins for Treatment of High-grade Gliomas
Open this publication in new window or tab >>Prognostic Biomarkers and Target Proteins for Treatment of High-grade Gliomas
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The survival for high-grade glioma patients is poor and the treatment may cause severe side effects. A common obstacle in the treatment is chemoresistance. To improve the quality of life and prolong survival for these patients prognostic biomarkers and new approaches for chemotherapy are needed. To this end, a strategy to evade chemoresistance was evaluated by combining chemotherapeutic drugs with agents inhibiting resistance mechanisms identified by a bioinformatic analysis (paper I). The prognostic value of 13 different proteins was analyzed in this thesis (papers II-IV). Two of them, p38 mitogen-activated protein kinase (MAPK) and protein tyrosine phosphatase non-receptor type 6 (PTPN6, also known as SHP1) were analyzed for their potential as targets in combination chemotherapy (in paper III and IV, respectively).

 

We found that:

  1. PTPN6 expression and methylation status may be important for survival of anaplastic glioma patients, p38 MAPK phosphorylation may be a potential negative prognostic biomarker for high-grade glioma patients and FGF2 expression may be a potential negative prognostic biomarker for proneural glioma patients.
  2. PTPN6 may be a useful target for combination chemotherapy with cisplatin, melphalan or bortezomib in high-grade gliomas. The following drug combinations; camptothecin combined with an EGFR or RAC1 inhibitor, imatinib combined with a Notch or RAC1 inhibitor, temozolomide combined with an EGFR or FAK inhibitor and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for high-grade gliomas.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 965
Keyword
High-grade glioma, prognostic biomarkers, combination chemotherapy, DNA methylation, FGF2, p38 MAPK, PTPN6, camptothecin, imatinib, vandetanib, EGFR, RAC1, Notch
National Category
Cell and Molecular Biology Cancer and Oncology
Research subject
Medical Science; Oncology
Identifiers
urn:nbn:se:uu:diva-215079 (URN)978-91-554-8839-0 (ISBN)
Public defence
2014-03-07, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:15 (English)
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Available from: 2014-02-13 Created: 2014-01-10 Last updated: 2014-04-29

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Sooman, LindaFreyhult, EvaEdqvist, Per-HenrikPontén, FredrikTchougounova, ElenaSmits, AnjaElsir, TamadorGullbo, JoachimLennartsson, JohanBergqvist, MichaelEkman, Simon

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Sooman, LindaFreyhult, EvaEdqvist, Per-HenrikPontén, FredrikTchougounova, ElenaSmits, AnjaElsir, TamadorGullbo, JoachimLennartsson, JohanBergqvist, MichaelEkman, Simon
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OncologyCancer Pharmacology and Computational MedicineScience for Life Laboratory, SciLifeLabMolecular and Morphological PathologyCancer and Vascular BiologyNeurologyLudwig Institute for Cancer Research
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