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Molecules in the lesser-researched ‘dark genome’ of human DNA could be instrumental for cancer cell growth, new research finds.
Scientists from University College Dublin, with partners in the University of Bern, have published research that shows that cancer-promoting cell mutations, also known as driver mutations, are coded in the ‘dark genome’ of human DNA. The findings could pave the way for improved understanding of tumour growth and lead to better cancer treatments.
‘Driver mutation’ is a term used to describe changes in the DNA sequence of genes that causes cells to become cancer cells and to grow and spread in the body. The discovery of these mutations is significant because until recently, many scientists believed the dark genome, which makes up 98pc of our DNA, was “junk”.
The Human Genome Project, a landmark international study of human DNA, revealed that only 2pc of our DNA codes for proteins (meaning that only 2pc corresponds to genes). As a result, the remaining 98pc, referred to as the ‘dark genome’ or ‘dark matter’, was considered to be useless.
However, the dark genome produces molecules called long noncoding RNAs (lncRNAs) and scientists have started to consider these molecules to be fundamental in regulating and translating gene expression and responding to environmental influences.
The UCD research is the first to show that driver mutations occur in the dark genome and affect the activity of lncRNAs.
Tumours develop because of driver mutations in the genome that enable cells to become fitter and more aggressive. Traditionally, scientists researching cancer genomics have mostly looked at the protein-coding (2pc) regions of DNA to understand how these driver mutations operate.
However, this study looked at driver mutations in the dark genome with the goal of enabling the development of improved cancer therapies targeting lncRNAs.
Using data collected by the Pan-Cancer Analysis of Whole Genomes project, the interdisciplinary research team analysed mutations from 2,583 primary tumours and 3,527 tumours that had spread. The results revealed 54 driver lncRNAs, many of which promote tumour cell growth. The team tested the accuracy of these predictions using laboratory experiments with cancer cells.
“While most studies have focused on protein-coding genes, this study is the first to demonstrate that mutations in non-protein-coding RNAs contribute to the fitness of tumour cells,” explained Dr Rory Johnson, associate professor in UCD’s School of Biology and Environmental Science. “This opens the exciting prospect of new therapies targeting these RNAs.”
Dr Roberta Esposito, from the Department of Medical Oncology, University Hospital of Bern, wanted to “recognise the many thousands of patients and physicians who make such important projects possible”. Esposito stressed the significance of this research for illustrating “the power of genomics to understand disease”.
According to Johnson, the team in UCD will build on this research by continuing “to search for new driver RNA genes and develop[ing] drugs to target them”.
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