gms | German Medical Science

Objective: Recently, tumour initiation, tumour recurrence and therapy-resistance in astrocytic gliomas have been attributed to the existence of brain tumour stem-like cells. ASPM (abnormal spindle-like, microcephaly associated), a stem-cell associated protein, is a key regulator of the symmetric division of neural stem cells that controls spindle orientation during cell division and therefore localizes to the cytoplasmic centromeres during interphase (cASPM) and around the nucleus during mitosis (nASPM). In this study, we correlated its expression in a tissue microarray (TMA) comprising samples of 334 gliomas to WHO grade, the proliferation marker Ki-67 and patient outcome.

Methods: Formalin-fixed, paraffin-embedded tissue samples of 283 primary astrocytic gliomas WHO II-IV and 51 recurrencies were used for TMA design. Detection of primary antibodies directed against ASPM, Ki-67 and the appropriate secondary antibodies was carried out with Vectastain ELITE ABC Kit. Staining was graded semiquantitatively from 0 to 5 according to the percentage of positive cells covering the whole tissue spot. Cytoplasmic and perinuclear staining was analyzed independently. The relationship between ASPM expression, WHO grade and Ki-67 was quantified by Spearman’s rank correlation rho. To exclude potential prognostic confounders of survival, WHO grade, age at diagnosis, and extent of resection were included in a multivariate Cox proportional hazards regression.

Results: Perinuclear expression of ASPM was neither associated with WHO grade nor with patient outcome. Cytoplasmic expression of ASPM, however, resulted in a significant prolongation of overall survival (OS) both in gliomas of all WHO grades (p=0.021) and in the subgroup of glioblastomas (p=0.026) as well as time to malignant progression (p=0.026) in gliomas WHO II-IV, independent of known prognostic confounders. Even though no significant correlation between WHO grade and cASPM expression was found, there was a trend towards a decreased expression both in case of malignant progression and recurrent glioblastoma. Importantly, a significant inverse correlation between cASPM and Ki-67 was found both in tumours of all WHO grades (p<0.0001) and in glioblastomas (p=0.0002).

Conclusions: Our study indicates that overexpression of cytoplasmic ASPM in astrocytic gliomas WHO II-IV is a strong prognostic factor for a favourable patient outcome and is associated with a less aggressive phenotype in terms of proliferative capacity and tumour recurrence.