Clonal Evolution Model
Definition of a Clone
The standard and common definition in cancer biology define a clone as "a group of cancer cells from the same ancestor". However, the plastic nature of cancer cells makes defining the clone using phenotype difficult.
Fig.1 Intertumor and intratumor heterogeneity. (Burrell, 2013)
Tumor Evolution Models to Explain Clonal Lineages Observed in Tumors
A single cancer cell accumulates genetic aberrations over time and is able to transform in the complex process of tumor evolution. As a result, different cancer cell subpopulations form clonal lineages within a single tumor. To explain the observed tumor clonal evolution, several models have been proposed: the liner evolution model, the branched evolution model, the neutral evolution model, and the punctuated evolution model.
Fig.2 Clonal evolution model. (Liu, 2017)
Linear Tumor Evolution
According to the linear evolution model, mutations are acquired in a linear manner over time, resulting in more malignant or aggressive cancer stages. Acquiring new driver mutations gives cancer cells a significant selective advantage, allowing them to outcompete previous clones. A dominant clone is present at each stage of tumor growth, with the possibility of a minor clone.
Fig.3 Linear form of tumor clonal evolution. (Roberts, 2019)
Branched Tumor Evolution
Clones diverge from the ancestral cell and gradually develop in the tumor without competing in the branched evolution model. The clones have increased fitness and growth at the same time, resulting in a "rainbow" tumor scenario when the clones are analyzed. In branching evolution, the phylogenetic tree shows clones that have expanded due to driver mutations in subclonal lineages.
Fig.4 Branched form of tumor clonal evolution. (Roberts, 2019)
Neutral Tumor Evolution
Random mutations are acquired over time in the neutral evolution model, resulting in extensive intratumor heterogeneity, which makes this an extraordinary form of branching evolution. There is no selection pressure on the tumor during its lifetime, and multiple clones coexist, resulting in extensive intratumor heterogeneity. The phylogenetic tree derived from neutral evolution is highly branched.
Fig.5 Neutral form of tumor clonal evolution. (Davis, 2017)
Punctuated Tumor Evolution
Not all tumors acquire mutations gradually over time. The result of the sequential acquisition of mutations over time is that intratumor heterogeneity peaks at later stages of tumor growth. However, in the punctuated evolution model, rapid bursts of genetic change may occur in a short period, followed by the growth of one or two dominant clones. Intratumor heterogeneity peaks in the early stages of tumor growth in this model, resulting in the tumor consisting of one or two clones. A long root node followed by one or two clones is the inferred evolutionary path. This model is also known as the "big bang" evolution model because there are no intermediate clones.
Fig.6 Punctuated tumor evolution model. (Dzobo, 2019)
References
- Burrell, R.A.; et al. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013, 501: 338-345.
- Liu, J.L.; et al. Current progresses of single cell DNA sequencing in breast cancer research. International Journal of Biological Sciences. 2017, 13(8): 949-960.
- Robert, C.M.; et al. The role of intra-tumoral heterogeneity and its clinical relevance in epithelial ovarian cancer recurrence and metastasis. Cancers. 2019, 11(8): 1083.
- Davis, A.; et al. Tumor evolution: linear, branching, neutral or punctuated. Biochimica et Biophysica Acta - Reviews on Cancer. 2017, 1867(2): 151-161.
- Dzobo, K.; et al. Single-cell omics: deciphering tumor clonal architecture. Single-Cell Omics. 2019, 1: 61-97.
