Minichromosome maintenance proteins in cancer screening


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Nick Coleman
Medical Research Council, Cambridge, United Kingdom

Abstract

Early detection of cancer leads to more effective treatment and improved patient survival. While many cancer screening tests sample the surface of stratified epithelia, identification of malignant or pre-malignant cells in conventionally stained cytological preparations is difficult. Biomarkers capable of detecting abnormal cells with adequate clinical sensitivity and specificity would represent a significant translational advance, by providing improved diagnostic accuracy, reproducibility and the potential for automation. Minichromosome maintenance proteins 2-7 (MCMs) have emerged as excellent markers suitable for detection of several different cancer types in cytological specimens. These proteins form a hetero-hexameric complex that is indispensable for DNA replication during S phase of the cell cycle. MCMs are not cancer specific proteins, being essential for replication of normal as well as neoplastic cells. Their value comes from differences in their micro-anatomical distribution. In normal stratified epithelia, MCMs are restricted to basal proliferative compartments, being rapidly lost from differentiating cells. As cells obtained in cytological preparations generally emanate from surface layers, either through passive shedding or active sampling by swabbing, brushing etc., the normal cells present in cytological samples are MCM negative. In contrast, malignancy and premalignancy are characterised by cell cycle deregulation, leading to abundant expression of MCM proteins in nuclei throughout the full thickness of stratified epithelia, including in surface layers. Detection of MCM proteins in cytological preparations therefore enables neoplastic cells to be distinguished from their normal counterparts, both in liquid based cytology (LBC) and non-LBC samples (for example in developing countries). Current work in our group is focussed on generating algorithms for applying MCM immunocytochemistry in specific clinical settings, particularly in determining the most appropriate combination(s) with other screening approaches. The clinical potential of MCMs in improving early diagnosis of several common cancers continues to be supported by data emerging from ongoing translational studies.