New study reveals cancer-promoting mutations in the ‘dark matter’ of genome.

International study led by University College Dublin and University of Bern researchers reveals new mechanism that tumours use to mutate and evolve. 

Tumours develop through cancer-promoting ('driver') mutations in the genome that enable cells to become fitter or more aggressive. Scientists in the field of cancer genomics want to understand which tumour mutations drive cell fitness, and how they manage to achieve this. Until now, most studies have focused on mutations affecting protein-coding regions of DNA. 

The Human Genome Project revealed that a mere 2% of our DNA codes for proteins. The remaining 98% was considered junk – nicknamed the ‘dark matter’ or ‘dark genome’. However, scientists now believe that the dark genome is fundamentally important in regulating the decoding process or gene expression. It does this by producing molecules called long noncoding RNAs (lncRNAs). These molecules are increasingly recognised as important cancer genes.

An international research team led by UCD Associate Professor Rory Johnson has shown, for the first time, that driver mutations can also occur in the dark genome. These mutations affect the activity of lncRNAs. This study provides one of the first catalogues of driver mutations in the dark genome. It will enable the future development of improved therapies targeting lncRNAs.

The team developed a software pipeline that trawls through millions of tumour mutations to identify statistical signals of driver mutations. They used this software to analyse mutations from 2583 primary and 3527 tumours that metastasised (spread) to other sites in the body.

The findings 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.

Dr Roberta Esposito, senior postdoctoral researcher at the Department of Medical Oncology, University Hospital of Bern, Switzerland said, “This work illustrates the power of genomics to understand disease. It was made possible thanks to interdisciplinary collaboration of researchers ranging from computational biologists to molecular biologists and clinical researchers. The project was based on data collected by the international collaboration (Pan-Cancer Analysis of Whole Genomes), and we should recognise the many thousands of patients and physicians who make such important projects possible.”

Drug discovery companies have traditionally focused on 20,000 proteins coded for by the 2% of DNA in the genome to treat diseases such as cancer. However, the lack of effective therapies has prompted them to extend their search into the dark genome. The recent success of the COVID-19 vaccination campaign has showcased the potential of such RNA therapeutics whose usefulness may extend to cancer.

Associate Professor Rory Johnson, from UCD School of Biology and Environmental Science and UCD Conway Institute said, “Searching for driver mutations is critical to understand how tumours form to develop more effective therapies and diagnostics. 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. This opens the exciting prospect of new therapies targeting these RNAs. In the coming years, my research group at UCD will continue to search for new driver RNA genes and develop drugs to target them.”

The findings of this study initiated with the international Pan Cancer Analysis of Whole Genomes project is published in the prestigious journal, Nature Communications and available online: https://www.nature.com/articles/s41467-023-39160-7.  

The study is funded through Science Foundation Ireland, EU Horizon 2020 MSC and the Swiss National Science Foundation.

Journal citation 

Esposito, R., Lanzós, A., Uroda, T. et al. Tumour mutations in long noncoding RNAs enhance cell fitness. Nat Commun 14, 3342 (2023). https://doi.org/10.1038/s41467-023-39160-7