Editors' ChoiceCirrhosis

Somatic mutations are improving their bad rap

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Science Translational Medicine  01 May 2019:
Vol. 11, Issue 490, eaax4871
DOI: 10.1126/scitranslmed.aax4871

Abstract

Recurrent somatic mutations could help protect the liver from injury.

Somatic mutations have mostly been studied in the context of carcinogenesis, but in recent years, sensitive new sequencing approaches have provided an improved lens for observing somatic evolution in normal tissues as well. It is now clear that mutant clones populate many, if not all, normal tissues, with their size and mutation burden modulated by age and lifestyle factors. Typically, such clones have been viewed with suspicion as potential incipient “cancers to be,” particularly if they contain recurrent somatic mutations. Now, a new study shows that somatic mutations found in the cirrhotic liver can actually be beneficial, protecting the liver against injury and facilitating regeneration.

To understand the mutational changes occurring during chronic liver disease, a common condition associated with hepatitis and alcoholism, Zhu and colleagues performed exome and ultra-deep targeted sequencing of 82 cirrhotic liver samples. They found abundant clonal expansions whose mutation burden and size generally increased with the degree of tissue damage. Furthermore, they identified numerous genes that were recurrently mutated in the diseased liver. Given that cirrhosis is a major risk factor for hepatocellular carcinoma development, one might expect these genes to match known liver cancer drivers. Surprisingly, however, the majority of the mutated genes—among them PPARGC1B and PKD1—have not been implicated in hepatocellular carcinoma genesis. Through an in vivo pooled CRISPR screen, Zhu et al. discovered that several of the gene losses identified in the human setting conferred a selective advantage in mice, facilitating survival and regrowth of normal hepatocytes after liver injury. For example, follow-up analysis showed that PKD1-mutant liver was protected against carbon tetrachloride–induced cell death and subsequent fibrosis.

These findings may begin to erode the prevalent notion that recurrent somatic mutations in nonmalignant tissues are “bad players” or stepping stones toward transformation. As sequencing capabilities continue to improve, and new early detection assays proliferate, these findings are a powerful reminder that we still know very little about somatic evolution and the selection of gene variants throughout life. These results furthermore open the exciting possibility of a new class of drugs that protect the liver through transient suppression of genes that normally mediate hepatocyte death and limit regeneration.

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