Clonal evolution
Clonal evolution is the model of cancer progression in which a tumor is a population of cells descended from a single common ancestor, within which heritable variation arises continuously and selection determines which lineages expand. Peter Nowell proposed it in 1976.
The model
Two ingredients drive the process:
- Variation. Genomic instability, replication errors, and environmental damage generate genetically diverse cells. Mutation supply sets the rate at which a tissue samples new variants.
- Selection. The microenvironment — resources, stroma, immune pressure, therapy — determines which variants expand. A clone that grows faster, resists death, or recruits blood supply expands at the others’ expense.
Progression is the repeated application of this cycle: a variant gains an advantage, expands, generates further diversity within itself, and a subclone with the next advantage expands within it. The result is a tumor structured as a branching lineage tree, with trunk mutations shared by all cells and branch mutations confined to subclones.
Consequences
- Heterogeneity. A single tumor contains many related but different genomes, which is why a biopsy samples only part of the population.
- Resistance. Therapy is a selection event. Maximum-tolerance treatment kills sensitive cells and removes their competition, so resistant clones expand into vacated space — the dynamic that adaptive therapy is designed to manage.
- Relapse. Tumors that regrow after treatment are re-seeded by the branch that survived it, which is why relapse tumors often differ from the diagnosed original.
Clonal evolution is the foundation of cancer ecology and of every treatment approach that treats the tumor as an evolving population.
Notes
- Draft stub - maintenance agent to expand with the 1976 Science paper, multiregion sequencing evidence, and the branch/trunk mutation framework.