'DNA spellchecker' errors cause cancer

Scientists at the Centre of Genomic Regulation (CRG) have identified important processes that create cancer-causing mutations by studying the genomes of more than 1000 tumours.

Cancer is mostly caused by changes in the DNA of our cells that occur during our lifetime, rather than those that we inherit from our parents. Identifying the causes of these ‘mutations’ is a difficult challenge because many processes can result in an identical DNA sequence change in a genome. The researchers at CRG have identified one of the important mechanisms that causes these mutations as mistakes made by a DNA ‘spellchecker’ that repairs damage in our genomes.

“Clustered mutations are likely to be generated at the same moment in time, so by looking at several neighbouring mutations at once, we can have a better understanding of what has damaged the DNA,” said Fran Supek, CRG alumnus and first author of the study. 

By studying clusters, the scientists identified nine mutational signatures that were evident in more than 1000 genomes of tumours from various organs. Their results, published in Cell, revealed new major mutation-causing processes, including an unusual case of DNA repair which should normally safeguard the genome from damage but is sometimes subverted and starts introducing clustered mutations.

“Our work provides information about new biological mechanisms underlying some types of cancers. For example, the main oncogenes involved in melanoma are well known, but it is not known what causes the exact mutations that activate these genes to cause cancer. While many mutations in melanoma are recognised to be a direct consequence of UV radiation, the origin of mutations affecting the most important oncogenes is still a mystery. We identified a mechanism that has the capacity to cause these oncogenic, cancer-driving mutations in melanoma,” said Supek.

One of these new mutational processes is highly unusual and it is most evident in active genes. These regions are usually protected by DNA repair mechanisms; ­in other words, DNA repair is directed towards the places where it is needed most.

“Our results suggest that exposure to carcinogens, such as high amounts of alcohol, can shift the balance of the DNA repair machinery from a high-fidelity mode to an error-prone mode, causing the mutation rates to shoot up in the most important bits of the genome,” said Ben Lehner, ICREA research professor at the EMBL-CRG Systems Biology Research Unit and principal investigator of the study. “This error-prone repair generates a large number of mutations overall and is likely to be a major mutation source in human cells.”

DNA repair is extremely important because our bodies are constantly renewing their cells — which involves copying more than two metres of DNA — and errors inevitably get introduced. Moreover, mutagens in the environment like sunlight and tobacco smoke damage DNA and this damage has to be corrected. DNA repair is normally exquisitely accurate, but some types of damage can only be corrected using lower-fidelity ‘spellcheckers’. It is the mistakes made by one of these less accurate spellcheckers that cause many of the mutations seen in different types of tumours, including liver, colon, stomach, oesophagus and lung cancer.  

As another part of the study, the CRG scientists found that cigarette smoking is associated with several different kinds of clustered mutations.

Alcohol is a well-known contributor to many types of cancer, but the reasons for this are surprisingly unclear. Supek and Lehner’s work suggests that alcohol, when consumed in large amounts, can increase the use of low-fidelity DNA repair, thereby increasing the mutation rate in the most important regions of the genome. This finding provides a first glimpse into one mechanism by which alcohol may contribute to cancer risk. High exposure to sunlight seems to have a similar consequence.