1. ¹Academic Unit of Pathology, University of Sheffield, UK
2. ²Department of Histopathology, Royal Hallamshire Hospital, Sheffield, UK
3. ³Wolfson Institute for Biomedical Research, University College London, London, UK
4. ⁴Department of Neurosurgery, Royal Hallamshire Hospital, Sheffield, UK
5. ⁵Clinical Oncology, Weston Park Hospital, Sheffield, UK
6. ⁶Department of Histopathology, University College London, London, UK

Correspondence: Professor GH Williams, Wolfson Institute for Biomedical Research and Department of Histopathology, University College London, The Cruciform Building, Gower Street, London WC1E 6BT, UK. E-mail: gareth.williams@ucl.ac.uk

Received 20 January 2004; Revised 15 April 2004; Accepted 27 April 2004; Published online 15 June 2004.

Abstract

The convergence point of growth-signalling pathways that control cell proliferation is the initiation of genome replication, the core of which is the assembly of pre-replicative complexes (pre-RCs), resulting in chromatin being 'licensed' for DNA replication in the subsequent S phase. The Mcm2–7 complex is a core constituent of the pre-RC, whose recruitment to replication origins is dependent on the Cdt1 loading factor. Geminin is a potent inhibitor of the initiation of DNA replication by preventing Mcm2–7 assembly at origins via its interaction with Cdt1, ensuring genomic integrity through suppression of re-initiation events in S phase. Here we investigate the regulation of Ki67, Mcm2, p21, caspase 3 and Geminin in a series of 55 oligodendrogliomas to provide an integrated picture of how cellular proliferation and programmed cell death are dysregulated in these tumours. Geminin does not behave as an inhibitor of cell proliferation, its labelling index rising with increasing growth fraction as defined by Ki67 or Mcm2 expression. Geminin is expressed in a higher proportion of cells in higher grade tumours (P<0.001) and shows a strong correlation to proliferation and replication licensing (P<0.01), but not apoptosis. Increasing tumour anaplasia is not associated with loss of Geminin. Importantly, the G1 phase of the proliferative cell cycle, as assessed by the Geminin/Ki67 ratio, shortens with increasing anaplasia, providing new potential algorithms for prognostic assessment. Origin licensing proteins thus provide powerful novel tools for assessment of tumour cell cycle kinetics in routinely processed surgical biopsy material.