A single-hit trigger of genomic chaos

It was postulated that the favorite route towards cancer initiation involves two-hits, disrupting both copies of a genome guardian gene. This idea has prevailed over the last 60 years. Now, using experimental evolution, the authors demonstrated that a single-hit suffices to cause genetic instability, and discovered genes that mutate to trigger instability in yeast and human cells, which belong to non-canonical functional classes. This means that cells are more likely to become genetically unstable than previously thought.

HFSP Long-Term Fellow Miguel Coelho and colleagues
authored on Mon, 11 March 2019

Cells are able to copy themselves, helping embryos develop into adult bodies, maintain tissues and recover from injury. During cellular division mistakes called mutations accumulate. Sometimes these mutations occur in genes that control the process of cellular division, causing cells to proliferate uncontrollably, which can lead to cancer. Therefore, to decrease the chance of altering cancer guardian genes, it is in a cell’s best interest to maintain the rate at which mutations occur low. The principle is similar to throwing darts at a target while blind-folded: randomly throwing more darts increases the likelihood to hit an important target. Now, Miguel Coelho, an HFSP Long-term Fellow, and collaborators have discovered how genetic instability, defined as the heritable increase in the rate at which mutations accumulate, starts1. A hallmark of cancer is that instability accelerates the rate at which cancer genes mutate and compromises cancer treatment. The main limitation so far has been the inaccessibility of the original event that triggers the expansion of a tumor founding cell, since the heterogeneity and high number of mutations in tumor samples makes it hard to distinguish the temporal order and causality.

The image represents yeast cells evolving, and on the right side the blue and orange dots represent mutations and genetic instability. 

HFSP funding was crucial to support an unconventional project combining yeast evolution and genomic analysis to address a very challenging question: how does genetic instability start? The authors decided to mimic cancer progression by selecting for the ability to inactivate tumor guardian genes more frequently. In the cells that survived selection, a common feature evolved: accelerated rates of mutation (genetic instability). Surprisingly, a single-hit generating a heterozygous mutation sufficed to cause genetic instability, challenging a 60 year-old dogma stating that two-hits are required for cancer to start2,3. By allowing the process to evolve, it was discovered that the genes involved were not only the classical DNA maintenance genes, but also genes involved in protein quality control, cytoskeleton and cellular metabolism – which caused genetic instability also when homolog genes were inactivated in human cells.

Future studies will continue to look into what sets the cellular speed of mutations (setting the pace of the evolutionary clock) and explore how different types of genetic instability accelerate the progression of different cancer types. Hopefully, the basic findings will develop into translational tools to diagnose and combat genetic instability in order to block treatment resistance and slow-down more aggressive forms of cancer. In this context, Miguel Coelho met Daniel Schramek, an HFSP CDA awardee, during the 2017 HFSP Awardees Meeting in Lisbon, and the lunch conversation led to a collaborative project, where both researchers are deciphering how genetic instability is selected during tumor evolution using in vivo mouse models. Miguel aims to start his own research lab in Europe, where he is currently interviewing for group leader positions.

References

[1] Heterozygous mutations cause genetic instability in a yeast model of cancer evolution. Coelho, M. C., Pinto, R. M. & Murray, A. W.  Nature 566, 275-278, doi:10.1038/s41586-019-0887-y (2019).

[2] Mutation and cancer: statistical study of retinoblastoma. Knudson, A. G., Jr.  Proc Natl Acad Sci U S A 68, 820-823 (1971). 

[3] A new theory on cancer-inducing mechanism. Nordling, C. O.  Br J Cancer 7, 68-72 (1953).

Link to article [1]

PubMed link [1]

Scientific American: A new idea about how cancer begins