CDC4/FBXW7 and the 'just enough' model of tumourigenesis

There is good evidence to show that cancer-causing mutations are not always simple gain- and loss-of-function changes. One example is the APC gene, where the combination of mutations produces a 'just-right' level of Wnt signalling. A recent article by Berger and colleagues posited a 'continuum model' in which increasing or decreasing gene expression of function was linearly associated with tumourigenesis. Berger also proposed an 'obligate haploinsufficiency' or 'fail-safe' model, whereby heterozygous mutations produce sufficient derangement for tumourigenesis, yet homozygous mutations are cell-lethal or senescence-causing. One gene highlighted by Berger and colleagues as an example of a gene following a 'continuum' or 'fail-safe' model was FBXW7/CDC4, a gene mutated in several different types of malignancy. We have analysed the COSMIC FBXW7 data. FBXW7 does not obviously follow a 'continuum' or 'fail-safe' model and the most common mutant genotypes are mono-allelic missense changes that affect critical arginine residues involved in interactions with substrates. There is no strong selection for complete loss of FBXW7 protein function, but bi-allelic inactivating mutations do occur. For FBXW7, we suggest a variant of 'just right' which we call 'just enough'. For FBXW7 mutations that occur away from the propellor tips, the heterozygote may have some effect on tumourigenesis, but there is selective pressure for a 'second hit'. For propellor tip mutations, by contrast, there is weak pressure for a 'second hit' because they usually provide sufficient functional derangement on their own. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.