title: Markers of cell division cycle in glioblastoma: significance in prediction of treatment response and patient prognosis.
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.
  
  
  METHODS
  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.
authors.affiliation: Departments of Neurosurgery, Hull & East Yorkshire Hospitals NHS Trust , Hull Royal Infirmary, Hull , UK.
authors.forename: J
authors.initials: J
authors.lastname: Yousaf
authors.forename: C
authors.initials: C
authors.lastname: Hills
authors.forename: S
authors.initials: S
authors.lastname: Dixit
authors.forename: S
authors.initials: S
authors.lastname: Achawal
authors.forename: D
authors.initials: D
authors.lastname: O'Brien
authors.forename: J
authors.initials: J
authors.lastname: Greenman
authors.forename: I S
authors.initials: IS
authors.lastname: Scott
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D001706:Biopsy; D001932:Brain Neoplasms / Q000473:pathology* / Q000601:surgery; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000032:analysis; D002455:Cell Division / Q000502:physiology*; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D019925:Cyclin A / Q000032:analysis / Q000378:metabolism; D005260:Female; D064248:Geminin / Q000032:analysis / Q000378:metabolism; D005909:Glioblastoma / Q000473:pathology* / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D017567:Karnofsky Performance Status; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D064111:Minichromosome Maintenance Complex Component 2 / Q000032:analysis / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology / Q000473:pathology; D011379:Prognosis; D016196:S Phase / Q000187:drug effects; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D019925:Cyclin A; D064248:Geminin; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2