A continuum model for tumour suppression

Tumour suppression modelled The 'two-hit' hypothesis of tumorigenesis, originally proposed in 1971 by Alfred Knudson using retinoblastoma as a model, explained the role of recessive tumour suppressor genes (TSGs) in dominantly inherited cancer-susceptibility syndromes, in which tumorigenesis was later shown to require two mutations, one in each copy of a single tumour suppressor gene. Four decades later, it is clear that even partial inactivation of tumour suppressors can critically contribute to tumorigenesis. This Review by Alice Berger, Alfred Knudson and Pier Paolo Pandolfi proposes a continuum model of TSG function to explain the full range of TSG mutations found in cancer. 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.