Just one mutation in the ‘Dark DNA’ of the genome could drive the progression of a range of cancers.

Dark DNA is the 98% of the genome that does not code for any proteins. Laxmi Parida, a Dark DNA researcher, describes it as ‘the part of the DNA that we – the scientific community – know nothing about. Dark DNA are not genes, they are not transcription factors and they are not binding sites; they are nothing that we know about. There are no descriptions about this type of DNA across the entire research community.’

Dark DNA is therefore very difficult to study, and although its role in cancer development was suspected, this was challenging to prove.

For this study, data was sourced from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project, which contained more than 2,800 cancer whole genomes from the International Cancer Genetic Consortium (ICGC). It was analysed by researchers at Ontario Institute of Cancer Research to determine if mutations in the Dark DNA could be linked to different types of cancers.

It was discovered that a recurring single letter change in the Dark DNA could drive the progression of a range of cancers, including those of the brain, liver and blood. The mutation, known as U1-snRNA, was found to interfere with RNA splicing, the process where a newly made precursor messenger RNA is converted into the mature form of mRNA. Disrupting splicing can therefore disrupt the transcription of multiple cancer regulatory genes.

U1-snRNA was found in ~50% of Sonic Hedgehog medulloblastomas but was not present in other types of medulloblastoma. The mutation was also found in chronic lymphocytic leukaemia, the most common type of adult blood cancer and hepatocellular carcinoma, the most common type of liver cancer. All of these cancers are difficult to treat, but this discovery could lead to the development of new drugs or gene therapies to directly target the mutation and the possibility for existing drugs and immunotherapies to be used to target the mutant proteins created by the RNA splicing errors.

To find out more about Dark DNA, read our recent interview with Laxmi Parida, IBM. She discusses her AI algorithm that can distinguish blood cancer subtypes from dark matter DNA.