Markers of cell division cycle in glioblastoma: significance in prediction of treatment response and patient prognosis

Br J Neurosurg. 2013 Dec;27(6):752-8. doi: 10.3109/02688697.2013.773287. Epub 2013 Mar 11.

Abstract

Objective: To investigate whether expression of regulatory components of the cell division cycle can be used independently to predict survival and response to adjuvant therapy in glioblastomas.

Method: A tissue micro-array, constructed using glioblastomas (n = 66), was stained using antibodies against minichromosome maintenance protein-2 (Mcm-2), expressed throughout the cell-division cycle; geminin, a protein that prevents re-initiation of DNA replication; and cyclin A, an S-phase cyclin. A semi-quantitative labelling index (LI) was calculated using an average of 18 high-power fields (hpf) in three replicate cores. The patients were divided into two groups: Group 1 (n = 50) underwent surgery and radiotherapy with 24 patients receiving temozolomide, and Group 2 (n = 16) received surgical treatment only.

Results: The LIs (median +/- IQR) for Group 1 were as follows: Mcm-2, 36.7% (22.9%-51.8%); geminin, 7.8% (5.8%-10.5%); and cyclin A, 4.2% (2.4%-6.9%). Elevated LIs, higher than the median, for geminin and cyclin A correlated with prolonged survival when the tumours received adjuvant therapy (Kaplan-Meier curves, p = 0.0046 and p = 0.0063 for geminin and cyclin A, respectively). Linear regression analysis revealed positive correlations with survival for Mcm-2 (p = 0.0376), geminin (p = 0.0006) and cyclin A (p = 0.004). In Group 2, there was no relationship between the patient survival and the LI for any marker.

Conclusions: Geminin and cyclin A, each show potential as independent prognostic markers in glioblastomas receiving adjuvant therapy. This may reflect the fact that both geminin and cyclin A estimate proliferating tumour cell subpopulations sensitive to radio/chemotherapy. These markers could provide valuable prognostic information, even in small biopsies, especially if combined with O(6)MGMT expression and 1p;19q deletion status.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor
  • Biopsy
  • Brain Neoplasms / pathology*
  • Brain Neoplasms / surgery
  • Cell Cycle / physiology*
  • Cell Cycle Proteins / analysis
  • Cell Division / physiology*
  • Chemoradiotherapy
  • Combined Modality Therapy
  • Cyclin A / analysis
  • Cyclin A / metabolism
  • Female
  • Geminin / analysis
  • Geminin / metabolism
  • Glioblastoma / pathology*
  • Glioblastoma / surgery
  • Humans
  • Immunohistochemistry
  • Karnofsky Performance Status
  • Male
  • Microarray Analysis
  • Middle Aged
  • Minichromosome Maintenance Complex Component 2 / analysis
  • Minichromosome Maintenance Complex Component 2 / metabolism
  • Neoplasm Recurrence, Local / epidemiology
  • Neoplasm Recurrence, Local / pathology
  • Prognosis
  • S Phase / drug effects
  • Survival Analysis
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • Cyclin A
  • Geminin
  • MCM2 protein, human
  • Minichromosome Maintenance Complex Component 2