Human cancers express mutator phenotypes: origin, consequences and targeting

Abstract

Recent data on DNA sequencing of human tumours have established that cancer cells contain thousands of mutations. These data support the concept that cancer cells express a mutator phenotype. This Perspective considers the evidence supporting the mutator phenotype hypothesis, the origin and consequences of a mutator phenotype, the implications for personalized medicine and the feasibility of ablating tumours by error catastrophe.

Figure 1. Cascade of mutations during tumour progression

In the case of solid tumours, epidemiological evidence indicates that as many as 20 years pass between the time an individual is exposed to a carcinogen to the clinical appearance of a tumour. Various barriers to tumour progression exist, including DNA repair processes, the availability of nutrition, the requirement of angiogenesis to allow the tumour to increase in size and responses to hypoxia. Circles represent mutations in genes that result in enhanced mutagenesis, triangles indicate driver mutations that are selected on the basis of changes in the tumour microenvironment and white rectangles represent passenger mutations.

Figure 2. Dissemination of metastasis early and late during tumour progression

Metastatic spread may occur throughout tumour progression, both early in tumour evolution and as the tumour evolves more genetic alterations. The metastases may then evolve to develop metastasis-specific mutations that are different to those found in the primary tumour.