Comparative studies of TIMP-1 immunohistochemistry, TIMP-1 FISH analysis and plasma TIMP-1 in glioblastoma patients

• Published in: Journal of neuro-oncology 2016-12, Vol.130 (3), p.439-448
• Main Authors: Aaberg-Jessen, Charlotte, Halle, Bo, Jensen, Stine S., Müller, Sven, Rømer, Unni Maria, Pedersen, Christian B., Brünner, Nils, Kristensen, Bjarne W.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Brain Neoplasms - blood; Brain Neoplasms - genetics; Cohort Studies; Denmark; DNA Copy Number Variations; Female; Glioblastoma - blood; Glioblastoma - genetics; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Laboratory Investigation; Male; Medicine; Medicine & Public Health; Middle Aged; Neurology; Oncology; Tissue Array Analysis; Tissue Inhibitor of Metalloproteinase-1 - blood; Tissue Inhibitor of Metalloproteinase-1 - genetics
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/s11060-016-2252-4

Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been associated with poor prognosis and resistance towards chemotherapy in several cancer forms. In a previous study we found an association between a low TIMP-1 tumor immunoreactivity and increased survival for glioblastoma patients, when compared to moderate and high TIMP-1 tumor immunoreactivity. The aim of the present study was to further evaluate TIMP-1 as a biomarker in gliomas by studying TIMP-1 gene copy numbers by fluorescence in situ hybridization (FISH) on 33 glioblastoma biopsies and by measuring levels of TIMP-1 in plasma obtained pre-operatively from 43 patients (31 gliomas including 21 glioblastomas) by enzyme-linked immunosorbent assay (ELISA). The results showed TIMP-1 gene copy numbers per cell ranging from 1 to 5 and the TIMP-1 /CEN-X ratio ranging between 0.7 and 1.09, suggesting neither amplification nor loss of the TIMP-1 gene. The TIMP-1 protein levels measured in plasma were not significantly higher than TIMP-1 levels measured in healthy subjects. No correlation was identified between TIMP-1 tumor cell immunoreactivities and the TIMP-1 gene copy numbers or the plasma TIMP-1 levels. In conclusion, high immunohistochemical TIMP-1 protein levels in glioblastomas were not caused by TIMP-1 gene amplification and TIMP-1 in plasma was low and not directly related to tumor TIMP-1 immunoreactivity. The study suggests that TIMP-1 immunohistochemistry is the method of choice for future clinical studies evaluating TIMP-1 as a biomarker in glioblastomas.