Postdoc - Biomedicine

Cancer evolution by non-Darwinian mechanisms

January 07, 2022

Photo by Suzanne D. Williams

In the Darwinian model of cancer evolution, the variations among cancer cells result in differential survival of some clones, which dominate the tumor mass. This view was challenged by discovering that tumors comprised multiple subclones that differ genetically and in their behavior. Sequencing studies later confirmed and expanded the extent of intratumor heterogeneity. As a result, features other than Darwinian selection were suggested and are now accepted to play an essential role in tumor development.

A recent review article by Vendramin *et al.* (2021) lists several evolutionary mechanisms that contribute to the development of the cancer phenotype. These mechanisms have long been recognized in the study of the evolution of species. Their application to cancer is proving to be very useful. They explain a range of empirical observations that are not otherwise accounted for. Examples include macroevolution and genetic drift. In addition, considerations such as these are reconciling the field of cancer evolution with findings from other modes of study that stress the importance of cell plasticity and the tumor microenvironment.

Short and intense bursts of evolution

The emerging view of evolutionary drivers goes beyond the slow and continuous accumulation of mutations. Instead, short and intense changes in the makeup of the cancer genomes drive cancer initiation, followed by little to no further selection. These events range from duplicating a gene or chromosome to a whole genome. Breakings and rearrangement of chromosomes also occur. Chromosomal aberrations were associated with aggressive forms of cancer, recurrence, and poor patient prognosis.

Random inheritance of traits

Copies of cancer genes can exist outside the chromosomes. The genes are replicated and passed down to progeny. Unlike the chromosomal genetic materials, these extra copies are randomly transferred to some but not all descendants. The unequal inheritance results in further diversification of the cells within the tumor. Cells with extra copies of cancer genes can proliferate and metastasize faster. Removing the extra DNA from the cells that have it reduces their survival ability.

Accumulation of neutral mutations

Cancer biologists distinguish between driver and passenger mutations. There is strong evidence of the role in cancer development for the former. They convey fitness to the cell that harbors them. The latter are mutations that accumulate in tumor cells with no causative role. The critical question is what the fraction of either is. Studies suggested that alterations in the genome of cancer cells occur early, and most mutations that occur afterward do not contribute to the phenotype. They are simply coming along for the ride. This is known as neutral evolution, and it simply happens because of genetic drift. Absent strong selection, mutations that do not impact the cell's fitness could eventually be fixed in the population even though they do not carry benefits either.

Non-inherited changes

Not all alterations of the cell behavior are a consequence of changes in the genomic sequence. Some changes, known as epigenetics, do not include altered sequences but modifications in how genes and proteins are expressed and translated. These quantitative differences often happen very fast in response to cues in the tumor microenvironment. Although not strictly heritable, they play a crucial role in developing phenotypes resistant to drugs. They could enable a tumor to persist for a long time despite therapeutic pressure.

The microenvironment

Healthy tissues often contain many of the same mutations that are mutagenic. Therefore the effect of mutations should also be determined by external factors. The age-dependence decline in tissue maintenance could be such a factor. Cells with the same mutations in young bodies would be less likely to evade immunity, establish themselves, and grow. This pattern is supported by the age-dependence incidence of cancer and the tissue specificity of oncogenic mutations.


  • Vendramin R, Litchfield K, Swanton C. Cancer evolution: Darwin and beyond. EMBO J. 2021 Sep 15;40(18):e108389. doi: 10.15252/embj.2021108389. Epub 2021 Aug 30. PMID: 34459009; PMCID: PMC8441388.