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Chronic Liver Disease Genome Sequences Point to Recurrent Mutations in Metabolic Genes

NEW YORK – A UK-led research team has tracked down somatic alterations linked to forms of chronic liver disease that are related to alcohol use or obesity. The genetic changes included clonal liver mutations that converged on key metabolic or insulin-related pathways without apparent ties to liver cancer.

"[W]e 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," co-senior and co-corresponding author Peter Campbell, head of the Wellcome Sanger Institute's Cancer, Ageing, and Somatic Mutation group, said in a statement.

For a study published in Nature on Wednesday, members of the Cancer Research UK-funded Cancer Grand Challenges Mutographs team brought together 1,108 new and 482 previously published genome sequences derived from laser-capture microdissected samples from 34 individuals. The participants included five healthy individuals, 10 individuals with alcohol-related liver disease (ARLD), and 19 individuals with non-alcoholic fatty liver disease (NAFLD), a condition that often overlaps with insulin resistance or type 2 diabetes.

The sample set included nine microdissected samples from individuals with both cirrhosis and hepatocellular carcinoma, the team noted, as well as eight liver samples from cirrhosis-free individuals with HCC. The group also considered mutation data spanning some 1,670 HCC samples that were previously profiled for the International Cancer Genome Consortium effort.

The team saw a liver disease-linked uptick in somatic mutations in half a dozen genes, including several genes that did not seem to be significantly altered in HCC. Among them were a gene called CIDEB that regulates lipid droplet metabolism in liver cells and the GPAM gene, which codes for a mitochondrial enzyme involved in triacylglycerol synthesis. The researchers also unearthed hotspot mutations affecting the insulin signaling-related transcription factor FOXO1 in seven of the 29 liver disease patients.

"We only see these mutations in chronic liver disease, not in normal liver and not in liver cancers, arguing that they are specific to the disease process," Campbell said in an email. "The mutations are all predicted, in their various ways, to protect hepatocytes from the burden of storing lipids, largely by abrogating insulin signaling in the hepatocytes."

The researchers noted that liver disease-associated mutations in given driver gene candidates often turned up in multiple clones from the same individual, affecting anywhere from one to 14 liver clones per person. Together, these clones appeared to impact up to around one quarter of the liver, they noted, hinting that such alterations may alter broader liver activity and function.

"[I]t’s tempting to speculate that such a large volume of hepatocytes with these mutations could feasibly contribute to the defects in glucose and lipid handling that are common in these diseases," Campbell noted, though he cautioned that this question remains unexplored.

The team noted that the recurrent gene mutation set may further help in finding individuals at risk of liver disease and damage related to so-called "fatty liver disease" — excess fat accumulation in hepatocyte cells — in response to processes such as alcohol consumption or diabetes-related insulin signaling.

"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," co-senior and co-corresponding author Matthew Hoare, an advanced clinician scientist with Cancer Research UK's Cambridge Institute, said in a statement, noting that the insights "may prove useful in understanding the changes experienced by a liver cancer as it evolves from a background of chronic liver disease."

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