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DNA mutations impacting liver disease patients identified by Wellcome Sanger Institute and Cancer Research UK Cambridge Institute

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DNA mutations that impact metabolism and insulin sensitivity for patients with liver disease have been identified for the first time.

Five genes were found that are mutated in these patients by researchers, who also uncovered a deeper understanding of the role three of them play in the disordered fat metabolism seen in non-alcoholic fatty liver disease (NAFLD) and chronic alcohol consumption.

An illustration of a diseased liver
An illustration of a diseased liver

The research, published in Nature, was carried out by the Wellcome Sanger Institute, the Cancer Research UK Cambridge Institute and the Cancer Grand Challenges Mutographs team with collaborators.

It shows that these mutations reduce the sensitivity of liver cells to insulin. Resistance to insulin activity is found in type 2 diabetes patients.

The study demonstrates that mutations acquired during a person’s life could impair the liver’s ability to respond in a normal way to dietary sugars and fats.

The researchers say more studies are needed, but work could contribute to creating a new model for understanding how mutations in specific cell types contribute to systemic metabolic diseases, such as diabetes.

Researchers analysed 1,590 genomes from 34 patient liver samples, including healthy livers and those with liver disease.

Multiple independent mutations in metabolism genes were found. In some patients, mutations collectively impacted up to 15-25 per cent of the entire liver.

The same metabolism gene was often recurrently mutated within each patient.

But the pattern of mutations varied between different patients, suggesting it might be possible to split liver diseases into defined subgroups and even develop and match novel treatments to them.

Dr Stanley Ng, first author and postdoctoral fellow at the Wellcome Sanger Institute, said: “Liver disease is a complex disease that often sits at the centre of other issues and conditions such as obesity and type 2 diabetes. However, the relationship between these diseases is poorly understood. While further studies are needed to understand the genetic links between these conditions, and what the clinical consequences of the mutations are for our patients, our research leads to fascinating new understanding of systemic diseases and how to diagnose, manage, and treat them.”

Insulin signals to liver cells to take up, process and store fat if there is high consumption. Over time, the burden can lead to liver diseases and cirrhosis.

Cells that have the mutations identified do not react to insulin signalling and therefore do not take up the fats.

This meant they escaped the damage caused by storing excess fat, so these mutated cells were able to survive and grow. But while benefitting the individual cells, this could also impair their ability to contribute to the liver’s function.

Dr Peter Campbell, senior author and head of cancer, ageing and somatic mutation, and senior group leader at the Wellcome Sanger Institute, and co-investigator of the Cancer Grand Challenges Mutographs team, said: “Mutations acquired in specific cell types, such as liver cells, have not previously been suspected of contributing to the biology of conditions such as obesity and type 2 diabetes. This is the joy of science – we started this study hoping to understand how liver cancer emerges from chronic liver disease, but instead wind up proposing an exciting new model in which the same genetic event is acquired many times independently within the liver, collectively accounting for a considerable fraction of liver cells. The mutations might protect the liver cells from toxicity, but only by enabling those cells to shirk their metabolic duties.”

Dr Matthew Hoare, senior author, advanced clinician scientist at the Cancer Research UK Cambridge Institute and member of the CRUK Cambridge Centre early detection programme, said: “Understanding the role of these, and other, mutations in liver disease could help identify those who will be at higher risk of future complications, such as metabolic issues or liver cancer. Interestingly, none of the mutations in metabolism genes were linked to the development of liver cancer, possibly because cancer cells are hungry for nutrients and these mutations may actually disrupt the cells’ ability to meet those metabolic demands. This information may prove useful in understanding the changes experienced by a liver cancer as it evolves from a background of chronic liver disease.”

Dr David Scott, director of Cancer Grand Challenges at Cancer Research UK, said: “The Cancer Grand Challenges Mutographs team is helping to transform our understanding of the link between mutations and cancer. This study demonstrates that the breadth of that work goes beyond cancer, including helping us to learn more about the role of mutations in other diseases, like liver disease.”

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