A Tale of Two Genomes

27th April 2021

Efforts to elucidate how mutations in a cell's DNA cause cancer have overwhelmingly focused on the DNA within the nucleus, but a new study published Nature Metabolism highlights the exciting potential of also looking at the genome of the cell's energy factories: the mitochondrial genome.

Mitochondria shutterstock 396424405It's known that mitochondrial mutations can be found in cancer cells, but there has been little research into what they do or whether they have any effect on treatment response or how the cancer will progress.

To answer these questions, Dr Payam Gammage at the Beatson Institute collaborated with the Memorial Sloan Kettering Cancer Center in New York to collate and analyse the largest dataset so far of tumour samples that include mitochondrial genome data and the corresponding clinical outcomes of the patients.

By analysing this data from 344 patients with colorectal cancer, the researchers could match groups of mutations to the likelihood of survival. They found that, after controlling for other variables which affect cancer risk like age, the presence of mitochondrial mutations was associated with a 57 to 93% decreased risk of death from colorectal cancer, depending on the type of mitochondrial DNA mutation. The researchers hope that in the future, doctors could use this information to identify patients with more aggressive forms of bowel cancer so they can receive the most effective treatments.

The team also wanted to know how common mitochondrial mutations were in cancer more broadly. By looking at existing data from over 10,000 tumour samples across 23 cancer types to search for recurring mitochondrial mutations, they found that mitochondrial mutations were present in up to 60% of tumours, with 25 out of the 30 most commonly mutated genes across cancers being present in the mitochondrial genome.

These results indicate that mitochondrial mutations could play a role in survival beyond colorectal cancer. Further research is needed to understand the wider implications of mitochondrial mutations in different cancers, and to delve into the biological underpinnings behind it.

Gammage head 2020 067Payam, who co-led the study, said: "This new study shines a light on the impact of mitochondrial DNA mutations in cancer, which have been overlooked for decades. This discovery could have a huge impact on patient care, with potential for changes to suggested treatments and a patient's outlook based upon the mitochondrial DNA status of their cancer. However, further research will be necessary to move these discoveries from the lab to the clinic."

Dr Ed Reznik, co-lead author based at Memorial Sloan Kettering Cancer Center, said: "Using data hiding in plain sight, we have shown that a critical piece of the cell's machinery to make energy is quite often broken in cancers. It now begs the question of how these mutations within mitochondrial DNA might be exploited as drug targets."

Michelle Mitchell, chief executive of Cancer Research UK, said: "This work highlights just how much more there is to discover about the inner workings of cancer, and all those breakthroughs for people with cancer we have yet to unlock. An incredible amount of basic laboratory research like this is being carried out across our Centres and Institutes, which is so important for helping to drive forward these unchartered and pioneering areas of research."

The paper can be read here: Gorelick AN, Kim M, Chatila WK, La K, Hakimi AA, Berger MF, Taylor BS, Gammage PA, Reznik E. Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA. Nat Metab. 2021 Apr 8. doi: 10.1038/s42255-021-00378-8

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