Researchers from University College London (UCL) and University Medical Center Utrecht discovered that bowel cancer cells have the ability to regulate their growth using a genetic on-off switch to maximize their chances of survival.
The number of genetic mutations in a cancer cell was previously thought to be purely down to chance. But a new study “Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer,” published in Nature Genetics, has provided insights into how cancers navigate an evolutionary balancing act.
The scientists found that mutations in DNA repair genes can be repeatedly created and repaired, acting as genetic switches that take the brakes off a tumor’s growth or put the brakes back on, depending on what would be most beneficial for the cancer to develop.
The team believes the findings could potentially be used in personalized cancer medicine to gauge how aggressive an individual’s cancer is so that they can be given the most effective treatment.
DNA repair mechanisms
Disruption of DNA repair mechanisms is a major cause of increased cancer risk. About 20% of bowel cancers, known as mismatch repair deficient (MMRd) cancers, are caused by mutations in DNA repair genes. But disrupting these repair mechanisms is not entirely beneficial to tumors. Though they do allow tumors to develop, each mutation increases the risk that the body’s immune system will be triggered to attack the tumor.
“Cancer cells need to acquire certain mutations to circumvent mechanisms that preserve our genetic code,” says Marnix Jansen, senior author of the study. “But if a cancer cell acquires too many mutations, it is more likely to attract the attention of the immune system, because it’s so different from a normal cell.
“We predicted that understanding how tumors exploit faulty DNA repair to drive tumor growth, while simultaneously avoiding immune detection, might help explain why the immune system sometimes fails to control cancer development.”
In this study, researchers from UCL analyzed whole genome sequences from 217 MMRd bowel cancer samples in the 100,000 Genomes Project database. They looked for links between the total number of mutations and genetic changes in key DNA repair genes.
The team identified a strong correlation between DNA repair mutations in the MSH3 and MSH6 genes, and an overall high volume of mutations.
The theory that these “flip-flop” mutations in DNA repair genes might control cancer mutation rates was then validated in complex cell models, called organoids, grown in the lab from patient tumor samples.
“Our study reveals that DNA repair mutations in the MSH3 and MSH6 genes act as a genetic switch that cancers exploit to navigate an evolutionary balancing act,” notes Suzanne van der Horst from University Medical Center Utrecht.” On one hand, these tumors roll the dice by turning off DNA repair to escape the body’s defense mechanisms. While this unrestrained mutation rate kills many cancer cells, it also produces a few ‘winners’ that fuel tumor development.
“The really interesting finding from our research is what happens afterwards. It seems the cancer turns the DNA repair switch back on to protect the parts of the genome that they too need to survive and to avoid attracting the attention of the immune system. This is the first time that we’ve seen a mutation that can be created and repaired over and over again, adding it or deleting it from the cancer’s genetic code as required.”
The researchers say that this knowledge could potentially be used to gauge the characteristics of a patient’s tumor, which may require more intense treatment if DNA repair has been switched off and there is potential for the tumor to adapt more quickly to evade treatment, particularly to immunotherapies, which are designed to target heavily mutated tumors.
A follow-up study is already underway to find out what happens to these DNA repair switches in patients who receive cancer treatment.
