Results of single-cell genotyping suggest the evolution of acute myeloid leukemia (AML) is more complex than we thought.
In screening for mutations in 2 genes, researchers identified at least 9 distinct clonal populations, each harboring unique mutational patterns.
Some mutations seemed to arise not sequentially, but independently and at different points in time.
These results suggest single-cell analysis may be more effective than bulk-tumor analysis for assessing cancer evolution.
Carlo Maley, PhD, of Arizona State University in Tempe, and his colleagues recounted the results in Science Translational Medicine.
The researchers set out to provide a more accurate picture of what takes place at the genetic level when an AML patient experiences relapse or metastasis. So they examined individual cells, screening them for mutations in FLT3 and NPM1.
The results suggested the same mutation was occurring multiple times within an AML patient. The team examined individual cells from 6 AML patients, and the results showed all combinations of homozygous and heterozygous mutations of FLT3 and NPM1.
“There’s no way to explain that with each mutation only happening once,” Dr Maley said. “That’s scary because it means that these cancers have access to many mutations and can find the same mutation over and over.”
Dr Maley noted that the process of convergent evolution, in which separate lineages develop similar features, appears to account for some of the observed diversity. And influences from the environment may drive convergent evolution, but identical mutations can also arise through pure coincidence, simply by virtue of the enormous numbers involved.
For example, a 1 cm3 AML tumor may contain a billion cells, each containing some 3 billion base pairs in its genome. Mutations are estimated to occur at a rate of 1 mutation in every billion base pairs.
“That means every time the population of cells in a 1 cm3 tumor undergoes 1 generation, which we think takes just a couple days, every possible mutation of the genome is happening somewhere in that tumor,” Dr Maley said.
This alone would lead to the same mutation likely occurring independently multiple times.
Curbing cancer’s lethality
Given AML’s near-limitless capacity for creating novel variants, what can clinicians do to halt the disease’s advance? According to Dr Maley, one approach would be to use cancer’s ability to evolve to our advantage, rather than attempt to fight it head on.
This paradigm draws on a branch of ecology known as life history theory. The idea is to carefully study the environmental factors that may lead organisms to favor either a fast or slow reproducing strategy to maximize their ability to survive.
According to the theory, fast reproduction tends to occur in environments with high extrinsic mortality. Aggressive cancer treatment creates just such an environment, favoring those cells able to reproduce quickly, producing large numbers of daughter cells, with a few evading extrinsic mortality to repopulate the tumor.
On the other hand, a very stable environment often favors slow reproduction, because organisms reach a carrying capacity of their surrounding environment. In this case, the limiting factor becomes competition between like organisms. Here, a slow reproducing strategy favoring greater investment in maintenance and survivability wins the competition.
“This approach would say, ‘Let’s keep tumors as stable as possible and keep their resources limited,’” Dr Maley said. “If we are able to keep the tumor cells contained and let them fight it out, we would expect to see more competitively fit cells that are growing very slowly.”
