Scientists at Rockefeller University have discovered a genetic mutation found in patients with fibrolamellar hepatocellular carcinoma (FL-HCC) as the driving force behind the rare and usually deadly liver cancer that targets adolescents and young adults.

Sanford Simon, head of Rockefeller University's Laboratory of Cellular Biophysics who conducted this research described the mutation as a "Chimeric Gene". A chimeric gene occurs when two genes that normally sit far apart fuse together due to the deletion of base pairs (building blocks of DNA) that normally sit between them.

How was this discovered?

Sanford Simon's laboratory previously found the chimeric mutation common in all of the hundreds of patients previously studied who have FL-HCC. Having found this common denominator in patients, Simon tried to uncover whether the mutation played a role in the development of FL-HCC and if so, what the nature of that role was. To do this, Simon teamed up with Scott Lowe, a cancer geneticist at the Memorial Sloan Kettering Cancer Center to form a mouse model to answer these questions. Most of the information provided below was provided by a report from Science Daily.

Using CRISPR gene editing to manipulate the DNA of the mice, Simon and Lowe were able to get these mice to produce the chimeric genetic mutation in their bodies by deleting the 400,000 base pairs that normally sat between the genes.

As discovered by Edward Kastenhuber, a graduate student in Lowe’s lab, the chimeric gene mutation produced in mice did cause tumors that mimic FL-HCC in humans. Another experiment on mice later confirmed that the fusion of the genes alone, even without the deletion of the base pairs between them, was sufficient to drive the disease in mice.

What do these findings mean?

The knowledge that the disease is specifically caused by the fusion of these genes means that better-targeted therapies can be developed.

One of the targets for these therapies being researched is a kinase protein. Kinases are enzymes that are often found to be mutated in cancers and according to Simon, are already being targeted in cancer therapies with great outcomes, citing Gleevec as an example.

The researchers have already been able to show that the disruption of kinase activity in mice who have the chimeric gene had in fact impaired tumor development, giving hope that kinase-targeted therapies would be effective in treating FL-HCC.

Additionally, the team is also studying the effects of targeting cellular mechanisms that speed the growth of tumors when overactive in FL-HCC patients, giving rise to other potential avenues of treatment. Mouse models will be used first to test the efficacy of these treatments before moving onto human trials.

How is FL-HCC currently treated?

At the moment, there are not many treatment options available for FL-HCC. In early stages of the disease, surgical removal can be an option as tumors would not have spread very far.

These treatments can be curative.But in most cases, diagnoses are made during advanced stages of the disease when it is more symptomatic. During these stages where there is a more distant spread of the disease, there are drugs that can slow the spread of tumors but their use is variable, as no standard regimen exists for treating advanced FL-HCC.
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