Clonal evolution in cancer

Abstract

Cancers evolve by a reiterative process of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems. The dynamics are complex, with highly variable patterns of genetic diversity and resulting clonal architecture. Therapeutic intervention may destroy cancer clones and erode their habitats, but it can also inadvertently provide a potent selective pressure for the expansion of resistant variants. The inherently Darwinian character of cancer is the primary reason for this therapeutic failure, but it may also hold the key to more effective control.

Figure 1

The complexity of tissue ecosystems of cancer cells. Exposures, the constitutive genetics of the host cells, systemic regulators, local regulators and architectural constraints all impinge upon and constrain the evolution of somatic cells.

Figure 2

(a) Branching clonal architecture of clonal evolution in cancer. Selective pressures allow some mutant sub-clones to expand while others go extinct. (b) Darwin’s evolutionary tree of speciation (from his 1837 notebook B). Eco 1–4 (red boxes) different tissue ecosystems/habitats. Tx, therapy. CIS, carcinoma in situ.

Figure 3

Divergent (branching) clonal evolution of cancer with topographical separation. In each example, a clonal (single cell) ancestry is indicated by shared acquired mutations, e.g. ETV6-RUNX1 fusion for the leukaemias, c-kit mutation for the testicular cancers. The time at which the two subclones evolve (T₁, T₂) can be temporarily synchronous or develop several years apart^,–. The probabilities of sub-clones emerging as shown are independent and different (p₁, p₂). In most cases (90% for monozygotic twins), only one twin develops overt leukaemia. The penetrance of bilateral testicular cancer having a common origin is unknown.

Figure 4

Topography of cancer sub-clones. A. Tissue section of prostate to detect TMPRSS2/ERG fusion (ERG via rearrangement) and PTEN loss. B. Presumed sequence of clonal events. Modified from Clark et al.

Figure 4

Topography of cancer sub-clones. A. Tissue section of prostate to detect TMPRSS2/ERG fusion (ERG via rearrangement) and PTEN loss. B. Presumed sequence of clonal events. Modified from Clark et al.

Figure 5

SR, self-renewal. D⁺, differentiation. CSC, cancer stem cell. Selective pressures may include environmentally-derived genotoxicity, natural/physiological restraints, cancer therapy, etc.. 1 Mutation in progenitor cells may convert these cells ‘back’ to a self-renewing population. 2 Any phenotypic feature that allows cells to continue to survive and proliferate in the face of particular constraints.