Scientists find the cause of the accumulation of genetic mutations in certain regions of the genome of melanomas and lung cancers

Genetic mutations are changes in the DNA sequence that can cause errors in cell function, and in the worst case, their accumulation leads to serious diseases such as cancer. To avoid this, cells have mechanisms thatare continuously detecting and repairing these changes, but which sometimes fail, resulting in the accumulation of mutations and the emergence of tumours . A scientific team led by Núria López-Bigas, ICREA researcher at the Department of Experimental and Health Sciences (DCEXS) of Pompeu Fabra University (UPF), has found, for the first time, the reason why mutations specifically accumulate in certain regions of the genome in cells of melanoma and lung cancer (adenocarcinoma and lung squamous cell carcinomas), two which are highly prevalent in the population. The results of this research appear published in the latest edition of journal Nature.

The team of López-Bigas has shown that the number of mutations is higher than expected in regions of the DNA to which the so-called transcription factors, proteins that regulate the activity of different genes, are bound. The results of the study indicate that the binding of these proteins to the DNA hinders access to the DNA’s repair machinery, which ultimately causes the accumulation of genetic mutations in these areas. Specifically, the analysis of the genomes of 38 melanomas sequenced by The Cancer Genome Atlas consortium, in which the team of Núria López-Bigas is taking part, shows that the mutation rate in these regions is approximately five times higher than in neighboring regions of the genome.

Melanoma, one of the most aggressive types of skin cancer, has its origin on many occasions in DNA damage that ultraviolet (UV) rays cause in skin cells. This damage is repaired by a specific cellular mechanism called Nucleotide Excision Repair. The same mechanism is responsible for the repair of the damage caused by tobacco smoke and that lead to some types of lung cancer. For this reason, the researchers decided to test whether this phenomenon could also be observed in these other types of tumours. The results were reproduced, observing that the areas where transcription factors were bound in lung cells also had a much higher mutation rate than their neighboring regions of the genome.

Unraveling the genetic origin of cancer is crucial to have a better understanding of the disease and to develop better tools to fight it. As the authors note, the methods currently used to identify key mutations in tumour development must take into account the influence of the proteins bound to the DNA in the occurrence of these alterations, and this discovery will have a major impact on the study of the mechanisms that cause the disease to appear and develop. The results described in this press release are elaborated on in an article signed by five members of the group from Pompeu Fabra University, published on 14 April in the journal Nature.

Reference work: Radhakrishnan Sabarinathan, Loris Mularoni, Jordi Deu-Pons, Abel González-Pérez, Núria López-Bigas. Nucleotide excision repair is impaired by binding of transcription factors to DNA. Nature, April 2016. DOI: 10.1038/nature17661

Image 1 (made by Iris Joval): The exposure to UV light causes specific lesions in DNA. These alterations are recognized and repaired by nucleotide excision repair (NER). Non-repaired lesions can lead to mutations in DNA. Skin tumours like melanomas accumulate a large amount of mutations caused by these unrepaired DNA lesions. López-Bigas’s study shows that in DNA regions that are bound to proteins like transcription factors, the activity of NER is strongly reduced causing an accumulation of mutations in these genome regions.