Liver cancer can develop without DNA mutations in mice

Scientists focused on a group of liver tumors that lacked the usual cancer-driving DNA changes. They asked what was driving those tumors instead. Their hypothesis: a protein called YAP1, which regulates gene activity, might be responsible.

To test this, the researchers developed a mouse model in which they switched on YAP1 activity in a small subset of liver cells. Whole-exome sequencing confirmed that the tumors that formed contained no classic cancer-driving DNA mutations. What was present instead were widespread changes in DNA methylation, a process in which chemical groups are added to or removed from DNA without altering the underlying genetic sequence. This falls under epigenetic regulation: the control of gene activity without changing the genetic code itself. These changes caused multiple growth-promoting genes (oncogenes) to become active.

One gene proved central

The gene Tet1, which is involved in removing methyl groups from DNA, played a key role. Suppressing Tet1 reduced liver tumor formation in the mice. Spatial analysis of individual cells revealed a subpopulation of tumor cells with high Tet1 activity that interacted with other liver cell types.

The findings align with patterns seen in human tissue. Patients with a rare condition in which abnormal blood flow burdens the liver (Fontan-associated liver disease) more often develop liver cancer without classic DNA mutations. The same molecular patterns were found to be elevated in those patients.

An open question about aging

The study, published in Communications Biology, raises a broader question: to what extent does the accumulation of epigenetic changes during aging contribute to cancer? The authors frame this as an open scientific question. How the balance between DNA mutations and epigenetic shifts as cancer-driving factors varies likely differs by tissue type and cancer type.

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