Bowel cancer cells have the ability to regulate their growth using a genetic switch to maximise their chances of survival, a phenomenon observed for the first time by researchers at UCL and the University Medical Centre Utrecht.
Until now, it was thought that the number of genetic mutations in a cancer cell was purely random. But a new study, published in Nature Genetics, provides insights into how cancers manage to find an “evolutionary balance.”
Researchers have discovered that mutations in DNA repair genes can be created and repaired repeatedly, acting like “genetic switches” that either slow down a tumor’s growth or turn it back on, depending on what is most beneficial for the cancer’s development.
The researchers say these findings could potentially be used in personalized cancer medicine to assess how aggressive an individual’s cancer is in order to give them the most effective treatment.
Cancer is a genetic disease caused by mutations in our DNA. DNA damage occurs throughout life, both naturally and due to environmental factors. To cope, cells have developed strategies to protect the integrity of the genetic code, but if mutations accumulate in key cancer-related genes, tumors can develop.
Colorectal cancer is the fourth most common cancer in the UK, with around 42,900 cases each year. Although it is still a cancer that mainly affects older people, cases in the under-50s have increased in recent decades.
Disruption of DNA repair mechanisms is a major cause of increased cancer risk. About 20% of bowel cancers, called mismatch repair deficient (MMRd) cancers, are caused by mutations in DNA repair genes. But disruption of these repair mechanisms is not entirely beneficial for tumors. While they allow tumors to grow, each mutation increases the risk that the body’s immune system will be triggered to attack the tumor.
Dr Marnix Jansen, lead author of the study from the UCL Cancer Institute and UCLH, said: “Cancer cells need to acquire certain mutations to circumvent the mechanisms that preserve our genetic code. But if a cancer cell acquires too many mutations, it is more likely to attract the attention of the immune system because it is very different from a normal cell.
“We predicted that understanding how tumors exploit faulty DNA repair to drive tumor growth – while simultaneously avoiding immune detection – could help explain why the immune system sometimes fails to control cancer growth.”
In this study, UCL researchers analysed the complete genome sequences of 217 MMRd colorectal 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 a high overall volume of mutations.
The theory that these “flip-flop” mutations in DNA repair genes might control cancer mutation rates was then validated in complex cellular models, called organoids, grown in the laboratory from patient tumor samples.
Dr Suzanne van der Horst from the University Medical Center Utrecht said: “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 balance. On the one hand, these tumors play a game of dice by turning off DNA repair to evade the body’s defense mechanisms. While this uncontrolled mutation rate kills many cancer cells, it also produces a few ‘winners’ that fuel tumor growth.
“The really interesting result of our research is what happens next. It seems that the cancer reactivates the DNA repair mechanism to protect the parts of the genome that it also needs to survive and to avoid attracting the attention of the immune system. This is the first time we have observed a mutation that can be created and repaired infinitely, adding it to or removing it from the cancer’s genetic code as needed.”
The DNA repair mutations in question occur in repetitive segments of DNA found throughout the human genome, where an individual DNA letter (an A, T, C, or G) is repeated multiple times. Cells often make small copying errors in these repetitive segments during cell division, for example by changing eight Cs into seven Cs, which disrupts gene function.
Dr Hamzeh Kayhanian, lead author of the study from the UCL Cancer Institute and UCLH, said: “It was previously thought that the degree of genetic disorder in a cancer was due solely to the random accumulation of mutations over many years. Our work shows that cancer cells are secretly reusing these repetitive sequences in our DNA as evolutionary switches to fine-tune how quickly mutations accumulate in tumour cells.
“Interestingly, this evolutionary mechanism has been previously identified as a key driver of bacterial resistance to treatment in patients treated with antibiotics. Like cancer cells, bacteria have evolved genetic switches that increase mutational fuel when rapid evolution is essential, such as when confronted with antibiotics. Our work thus further highlights the similarities between the evolution of ancient bacteria and human tumor cells, a major area of active cancer research.”
The researchers say this knowledge could potentially be used to assess the characteristics of a patient’s tumor, which may require more intense treatment if DNA repair has been disabled and whether the tumor is likely to adapt more quickly to evade treatment – particularly immunotherapies, which are designed to target highly mutated tumors.
A follow-up study is already underway to find out what happens to these DNA repair switches in patients receiving cancer treatment.
Dr Hugo Snippert, lead author of the study from the University Medical Center Utrecht, said: “Overall, our research shows that the mutation rate is adaptable in tumors and facilitates their quest for optimal evolutionary fitness. New drugs could seek to turn off this switch to promote efficient immune recognition and hopefully produce better therapeutic outcomes for affected patients.”
This research was funded by grants from Cancer Research UK, the Rosetrees Trust and Bowel Research UK.
Georgia Sturt, Head of Research and Grants at Bowel Research UK, said: “Cancer’s ability to evade destruction by the immune system is a key part of its ability to grow and spread. Understanding exactly how bowel cancers do this is vital to optimising treatment for patients. Bowel Research UK is delighted that our funding has helped produce this exciting new data, and we look forward to seeing how these findings could change treatments for future patients.”
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