Evolution of Premalignant Disease

Abstract

Where does cancer come from? Although the cell-of-origin is difficult to pinpoint, cancer clones harbor information about their clonal ancestries. In an effort to find cells before they evolve into a life-threatening cancer, physicians currently diagnose premalignant diseases at frequencies that substantially exceed those of clinical cancers. Cancer risk prediction relies on our ability to distinguish between which premalignant features will lead to cancer mortality and which are characteristic of inconsequential disease. Here, we review the evolution of cancer from premalignant disease, and discuss the concept that even phenotypically normal cell progenies inherently gain more malignant potential with age. We describe the hurdles of prognosticating cancer risk in premalignant disease by making reference to the underlying continuous and multivariate natures of genotypes and phenotypes and the particular challenge inherent in defining a cell lineage as "cancerized."

Figure 1.

Trajectory of premalignant evolution via the genotype–phenotype (G-P) map. The G-P map traces the evolutionary path of cells in the two infinite spaces of genotype and phenotype. (A) Time points are specified to illustrate the progression through phenotype space (pink regions denote regions of similar phenotype) from normal to precancerous to cancer, driven by changes in genotype. Movement through the spaces is caused by: (1) the projection of the genotype through epigenetic and microenvironmental “filters” accounted for in the G-P map that produces a phenotype from a genotype; (2) the action of natural selection in the phenotype space, influencing-variation generated in genotype space that moves the population to points of higher (contextual) fitness; (3) genotype of fit parents is preserved deterministically; (4) somatic mutation and/or other genetic event(s) moves average point in genotype space. We highlight the overlap in defined phenotypic regions—at one time point during progression to cancer, this cell population could be classified as either metaplastic or dysplastic histologically. (B) A second example of a stochastic trajectory that jumps as a result of a punctuated event in genotype space, such as whole-genome doubling, without discernable phenotypic change. (C) Small changes in genotype space may also lead to large changes in phenotype space possibly caused by rare variants having large phenotypic effects, epistatic effects between accumulated mutations, and/or other epigenetic or microenvironmental effects. For example, a TP53 inactivating mutation may occur in morphologically normal tissue, but not be selected until subsequent events (e.g., genome doubling) occurs. N, normal tissue; M, metaplasia; H, hyperplasia; D, dysplasia; C, cancer.