Ancient Gene Stress Mutation Gives Clues To Cancer Resistance

Cancer as a biological phenomenon with very deep evolutionary roots is highlighted in an unusual research collaboration between physicists and a leading geneticist.

Paul Davies, Ph.D., Arizona State University Professor, and physicist Charles Lineweaver, Ph.D. of Australian National University teamed up with geneticist Kimberly Bussey, Ph.D. and biophysicist Luis Cisneros, Ph.D. of NantOmics, LLC to trace the evolutionary history of cancer genes back to the dawn of multicellularity, over one billion years ago.

Asking why these cancer genes evolved and what their functionality might be, the researchers hit on an astonishing link.

Cancer cells deploy an ancient mechanism used by single-celled organisms to elevate their mutation rate in response to stress. The discovery explains one of the best-known hallmarks of cancer – its high mutation rate, which contributes to the rapid evolution of drug resistance.

Sweeping Therapeutic Implications

The research involves looking anew at the genetic control switches that allow complex life to flourish. Should such regulation become corrupted, cells may lose their cooperative properties and regress to the single-celled behavior common to much more ancient organisms.

Such reversion to ancestral evolutionary traits is known as atavism.

Davies explains:

“Lineweaver and I have long argued that cancer is a type of throwback to a more primitive ancestral form but we lacked the hard evidence. Now Kim Bussey and Luis Cisneros, with the help of students Adam Orr and Milica Milicavic, have painstakingly analyzed the evolutionary origins of a large collection of cancer genes and confirmed that one of cancer’s most distinctive and troublesome hallmarks is indeed extremely ancient and deep-rooted. It has sweeping implications for therapy.”

The work finds that mutational bursts surrounding double-stranded breaks in DNA are commonly seen in cancer. Further, such bursts are similar to those seen in single-celled organisms engaged in stress-induced mutation.

cancer stress mutation genetics

For each human gene, the expected number of mutations is obtained based on the normal mutation pattern: frequency of normal mutations times the total number of cancer mutations recorded in the data set.
Credit: Luis Cisneros, et al./PLOS One

In the case of cancer, the mutations appear to be spread across the genome, including older genes that are evolutionarily conserved and normally off limits to mutational events. The effect is to allow somatic cells to search ancient genome space for solutions to the stress-induced pressures they are experiencing.

Maladaptive Stress Response

As corresponding author Kimberly J. Bussey, Ph.D., Principal Scientist with NantOmics and Adjunct Faculty in the Department of Biomedical Informatics at Arizona State University, explains, a stress response that evolved to protect single-celled organisms from extinction may prove hazardous to a multicellular creature, should some event suddenly resuscitate it.

“If you’re dealing with a unicellular organism and the population experiences some stress that it can’t deal with using the current toolbox of responses, for the population to survive—for the species to survive—it has to evolve. When a somatic cell in a multicellular organism evolves, cancer can occur.”

The results suggest that in cases of rapid resistance to chemotherapy, the ability to generate regulated bursts of mutation may be at the core of this deadly disease.

“On the clinical side, I think this is really going to make us rethink what we mean by curing cancer. Maybe the goal isn’t curing but controlling,” Bussey says. “If this is a burst response, maybe there is a level of therapy with which we can impact the viability of the tumor cells but not actually induce the stress response.”

Such approaches have already made some inroads into clinical use.

So-called metronomic therapy applies more frequent rounds of lower-dose treatment, while adaptive therapy seeks to pulse cancer treatments in order to stabilize rather than eradicate a tumor. These and other evolutionary approaches to treating cancer offer new hope in the war against a cunning and profoundly versatile foe.

The study was supported by NIH and NantOmics.

Cisneros L, Bussey KJ, Orr AJ, Miočević M, Lineweaver CH, Davies P (2017)
Ancient genes establish stress-induced mutation as a hallmark of cancer
PLoS ONE 12(4): e0176258. https://doi.org/10.1371/journal.pone.0176258

Top Image: Jason Drees for the Biodesign Institute

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