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A continuum model for tumour suppression

Abstract

This year, 2011, marks the forty-year anniversary of the statistical analysis of retinoblastoma that provided the first evidence that tumorigenesis can be initiated by as few as two mutations. This work provided the foundation for the two-hit hypothesis that explained the role of recessive tumour suppressor genes (TSGs) in dominantly inherited cancer susceptibility syndromes. However, four decades later, it is now known that even partial inactivation of tumour suppressors can critically contribute to tumorigenesis. Here we analyse this evidence and propose a continuum model of TSG function to explain the full range of TSG mutations found in cancer.

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Figure 1: Paradigms of tumour suppression.
Figure 2: Tissue specificity and context dependency of tumour suppression.
Figure 3: The continuum model of tumour suppression.
Figure 4: Mechanisms of regulation of TSG dosage.
Figure 5: Opportunities for therapeutic intervention after partial or complete loss of TSG expression.

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Acknowledgements

We thank L. Salmena, L. Poliseno and all Pandolfi laboratory members for advice and critical discussions. This work was supported in part by NIH core grant CA06927 and an appropriation from the Commonwealth of Pennsylvania to the Fox Chase Cancer Center to A.G.K. and NIH grant R01CA142787 to A.H.B. and P.P.P.

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A.H.B., A.G.K. and P.P.P. together contributed to all aspects of this work.

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Correspondence to Pier Paolo Pandolfi.

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Berger, A., Knudson, A. & Pandolfi, P. A continuum model for tumour suppression. Nature 476, 163–169 (2011). https://doi.org/10.1038/nature10275

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