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

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

The researchers found five mutated genes in these patients, which also discovered a better 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

The research, published in Nature, was conducted by the Wellcome Sanger Institute, 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 observed in patients with type 2 diabetes.

The study shows that mutations acquired over a person’s lifetime could alter the liver’s ability to respond in a normal way to dietary sugars and fats.

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

The researchers analyzed 1,590 genomes from 34 liver samples from patients, including healthy livers and those with liver disease.

Multiple independent mutations in metabolism genes have been found. In some patients, mutations have collectively affected up to 15 to 25% of the entire liver.

The same metabolic gene was often mutated repeatedly in each patient.

But the pattern of mutations varied between different patients, suggesting that it may be possible to divide liver disease into defined subgroups and even develop and match new treatments to them.

Dr Stanley Ng, lead author and postdoctoral researcher at the Wellcome Sanger Institute, said: “Liver disease is a complex disease that is often at the center of other problems and conditions such as obesity and type 2 diabetes. However, the relationship between these diseases is poorly understood. While more studies are needed to understand the genetic links between these conditions and what the clinical consequences of mutations are for our patients, our research is leading to a fascinating new understanding of systemic diseases and how to diagnose, manage them. and process them.

Insulin signals liver cells to absorb, process, and store fat when consumed heavily. Over time, this burden can lead to liver disease and cirrhosis.

Cells that have the identified mutations do not respond to insulin signaling and therefore do not absorb fat.

This meant that they escaped damage from storing excess fat, so these mutated cells were able to survive and thrive. But while benefiting individual cells, it could also interfere with their ability to help the liver function.

Dr Peter Campbell, senior author and head of Cancer, Aging and Somatic Mutations, and lead group leader at the Wellcome Sanger Institute, and co-investigator of the Cancer Grand Challenges Mutographs team, said: “The 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. That’s the joy of science – we started this study in the hope of understanding how liver cancer emerges from chronic liver disease, but ended up coming up with an exciting new model in which the same genetic event is acquired multiple times independently in the liver, collectively representing a sizable fraction liver cells. Mutations could protect liver cells from toxicity, but only by allowing these cells to bypass their metabolic functions. “

Dr Matthew Hoare, senior author, advanced clinician scientist at Cancer Research UK Cambridge Institute and member of the early detection program at CRUK Cambridge Center, said: “Understanding the role of these and other mutations in liver disease could help identify those who are at higher risk for future complications, such as metabolic problems 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 can actually disrupt cells’ ability to meet these metabolic demands. This information can be useful in understanding the changes that liver cancer undergoes as it progresses 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 shows that the scope of this work goes beyond cancer, including helping us learn more about the role of mutations in other diseases, such as liver disease. “

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