Clonal Expansion

Definition

Clonal expansion is the proliferation of a cell lineage that has acquired a fitness-affecting mutation, causing it to outcompete neighboring cells and increase in relative frequency within the tissue. Clonal expansions are the visible manifestation of positive-selection acting on driver-mutations in somatic tissues.

Mechanism

In Nowell’s (1976) original model, clonal expansion begins immediately after the initiating mutation: “Tumor initiation occurs…by an induced change in a single previously normal cell which makes it ‘neoplastic’ and provides it with a selective growth advantage over adjacent normal cells. Neoplastic proliferation then proceeds, either immediately or after a latent period” (p. 23).

Subsequent driver mutations produce further clonal expansions within the existing tumor population. Each expansion represents a clonal-sweep — the new variant subpopulation becomes the predominant clone until an even more favorable variant appears (Nowell, 1976).

Selective Sweeps vs. Clonal Interference

The traditional model posits that a series of clonal expansions successively dominate the neoplasm through complete selective sweeps. However, this can occur only if the time to the next driver mutation is longer than the time required for a clone to sweep through the population (Greaves & Maley, 2012).

In practice, given the large population sizes and high mutation rates typical of neoplasms, clonal-interference — mutual competition between expanding clones that restrains the growth of each — is probably common (Greaves & Maley, 2012). This means that clonal expansions are often incomplete and overlapping rather than sequential and complete.

Temporal Patterns

Data from serial sampling suggest that parallel clonal expansions occur before any single subclone dominates (Greaves & Maley, 2012). Direct evidence from longitudinal studies of oncogenic mutations in advanced disease, metastasis, and post-chemotherapy relapse “indicates selective sweeps originate from pre-existing genetic variants or subclones” (Greaves & Maley, 2012, p. 307).

Clinical Significance

The size and timing of clonal expansions have direct clinical relevance. Gerstung et al. (2020) demonstrated that driver mutations often precede diagnosis by many years or decades, meaning the clonal expansions that give rise to clinically apparent tumors begin long before symptoms appear. This finding provides an evolutionary rationale for cancer-early-detection: the genomic changes that drive cancer are present and detectable long before the tumor becomes symptomatic.

Growth Model Constraints

The detectability and dynamics of clonal expansions depend on the underlying tumor growth model. Under gompertzian-growth, the relative expansion rate declines as the tumor approaches carrying capacity. A driver-mutation arising early — when the population is small and growing near-exponentially — has both time and population growth to expand to detectable frequency (Castorina et al., 2009). The same driver arising late — when the tumor is near plateau and growth is near-zero — may never reach detectable size regardless of its selective advantage.

This temporal constraint is the core logic of the Big Bang model (Sottoriva et al., 2015): early-arising private mutations become pervasive simply because they had more doublings to expand, while late-arising mutations remain localized not due to lack of fitness but lack of time (see neutral-evolution). The practical consequence is that clonal expansions inferred from cancer-cell-fraction distributions may reflect timing during the growth curve as much as selective advantage.