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Accommodating haploinsufficient tumour suppressor genes in Knudson's model

Oncogene volume 19, pages 3434–3438 (2000)Cite this article

A plethora of tumour suppressor genes (tsg) have been shown to exist, some of which still await cloning (Fearon, 1997). Loss of function of these genes is, as the name implies, tumorigenic. A central component of the Knudson model for this phenomenon is that loss of the gene is recessive, i.e. a single active allele is sufficient to suppress the development of tumours. Nevertheless there have been hints of haploinsufficiency in several tsg, culminating recently in two compelling reports regarding p53 and p27Kip1. This mini-review attempts to reconcile these observations with Knudson's model.

The best evidence in support of recessive loss of function of tsg (Knudson, 1971, 1985) has been gathered for the Rb and Apc genes, the human homologues of which suppress the development of retinoblastomas and colon carcinomas respectively. Hemizygous mice for each of these genes are prone to tumours which can be detected at extremely early stages, while they are microscopic. In each case, semi-quantitative PCR analysis has demonstrated that both alleles of the tsg are already inactivated, implying loss of function of the second allele is rate-limiting for initiation of the tumour (Nikitin and Lee, 1996; Levy et al., 1994).

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Acknowledgements

The authors are extremely grateful to Simon Foote, Douglas Hilton and Jerry Adams for thoughtful reading of the manuscript; to Simon Foote, Suzanne Cory, Colin Masters and Glenn Begley for extraordinary moral support, to Jo Marshall and Wendy Hertan for their hospitality in the WEHI library and to the Anti-Cancer Council of Victoria, the Lyndall and Jean Skea Trust, the Walter and Eliza Hall Institute of Medical Research, the University of Melbourne and the Bone Marrow Research Laboratories at the Royal Melbourne Hospital, for financial support.

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  1. Bone Marrow Research Laboratories, Royal Melbourne Hospital, Melbourne, 3050, Victoria, Australia

    Wendy D Cook

  2. Department of Pathology, University of Melbourne, Melbourne, 3050, Victoria, Australia

    Wendy D Cook & Benjamin J McCaw

  3. The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3050, Victoria, Australia

    Benjamin J McCaw

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Cook, W., McCaw, B. Accommodating haploinsufficient tumour suppressor genes in Knudson's model. Oncogene 19, 3434–3438 (2000). https://doi.org/10.1038/sj.onc.1203653

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