Grade-specific expression of insulin-like growth factor-binding proteins-2, -3, and -5 in astrocytomas: IGFBP-3 emerges as a strong predictor of survival in patients with newly diagnosed glioblastoma.
BACKGROUND
Insulin-like growth factor (IGF)-binding protein (IGFBP) isoforms have been implicated in the pathogenesis of human neoplasms including glioma. In view of this, we evaluated the expression of IGFBP isoforms (IGFBP-2, -3, and -5) during malignant progression of astrocytoma and their prognostic significance in glioblastoma.


METHODS
The expression of IGFBP isoforms was analyzed in diffusely infiltrating astrocytomas by real-time quantitative PCR (n = 203) and immunohistochemistry (n = 256). Statistical methods were used to assess their grade-specific expression pattern and mRNA-protein intercorrelation. Survival analyses were done on a uniformly treated, prospective cohort of adult patients with newly diagnosed glioblastoma (n = 136) by using Cox regression models.


RESULTS
The mean transcript levels of IGFBP-2 and -3 were significantly higher in glioblastomas (GBM) relative to anaplastic astrocytoma (AA), diffuse astrocytoma (DA), and controls whereas IGFBP-5 mRNA was higher in GBM relative to AA and controls (P < 0.05). By immunohistochemistry, the mean labeling index of all isoforms was significantly higher in GBM compared with AA, DA, and control (P < 0.05). A strong positive correlation was observed between their respective mRNA and protein expressions (P < 0.01). Multivariate analysis revealed IGFBP-3 expression (hazard ratio, 1.021; P = 0.030) and patient age (hazard ratio, 1.027; P = 0.007) to be associated with shorter survival in glioblastoma.


CONCLUSIONS
This study shows the associations of IGFBP-2, -3, and -5 expression with increasing grades of malignancy in astrocytomas. IGFBP-3 is identified as a novel prognostic glioblastoma biomarker. The strong correlation between their mRNA and protein expression patterns suggests their role in the pathogenesis of these tumors.


CONCLUSIONS
IGFBP isoforms have emerged as biomarkers with diagnostic and prognostic utility in astrocytomas.
Santosh
Vani
V
Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India.
Arivazhagan
Arimappamagan
A
Sreekanthreddy
Peddagangannagari
P
Srinivasan
Harish
H
Thota
Balaram
B
Srividya
Mallavarapu R
MR
Vrinda
Marigowda
M
Sridevi
Sambandam
S
Shailaja
Bangalore C
BC
Samuel
Cini
C
Prasanna
Krishnarao V
KV
Thennarasu
Kandavel
K
Balasubramaniam
Anandh
A
Chandramouli
Bangalore A
BA
Hegde
Alangar S
AS
Somasundaram
Kumaravel
K
Kondaiah
Paturu
P
Rao
Manchanahalli R S
MR
D000293:Adolescent; D000328:Adult; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D018450:Disease Progression; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000096:biosynthesis* / Q000235:genetics; D018972:Insulin-Like Growth Factor Binding Protein 3; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000096:biosynthesis* / Q000235:genetics; D018969:Insulin-Like Growth Factor Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016019:Survival Analysis; D055815:Young Adult
C515497:IGFBP3 protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D018975:Insulin-Like Growth Factor Binding Protein 5; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger