Gene mutation associated with development of fibrolamellar hepatocellular carcinoma

February 28, 2014, Rockefeller University
Researchers discover unusual genetic mutation linked to adolescent liver cancer
Images taken with a fluorescent microscope show the activity of a kinase (green) in tumor cells (bottom) compared to normal cells (top).

In the race for better treatments and possible cures, rare diseases are often left behind. In a collaboration of researchers at The Rockefeller University, Memorial Sloan Kettering Cancer Center and the New York Genome Center (NYGC), an unusual mutation has been found that is strongly linked to one such disease: a rare liver cancer that affects teens and young adults. The results, published this week in Science, suggest that the mutation plays a key role in the development of the disease, called fibrolamellar hepatocellular carcinoma, and may also underlie more common cancers as well.

With only about 200 people diagnosed each year with fibrolamellar, the disease is as rare as it is mysterious—there are no known causes and it's difficult to both detect and treat. By the time doctors discover a growing tumor it is often too late, and the cancer has spread.

"We reasoned that it would be easier to identify genetic mutations in the tumors of young patients than in older ones, because in older people, the genome has been altered by years of aging and environmental factors," says Elana Simon, a co-first author on the study and a member of the Rockefeller team. "Both the person as a whole and the tumor itself will have had less time to accumulate mutations, so those that we do find are more likely to be relevant."

The researchers sequenced DNA and RNA at NYGC from tumors that had been surgically removed from 15 people with fibrolamellar. NYGC computational biologists and members of the Simon Laboratory at The Rockefeller University discussed the possibility of using a series of computer algorithms to search for sequence differences between the tumor samples and samples of healthy liver tissue. One abnormality that really stood out, and it was present in all 15 patients: a piece of DNA that had been broken and rejoined, creating a mutated gene that had the potential to wreak havoc in the bodies of individuals with the gene.

Researchers discover unusual genetic mutation linked to adolescent liver cancer
Elana Simon in the Rockefeller University lab where she conducted research on fibrolamellar cancer, the same type she was diagnosed with six years ago.

"We discovered chimeric RNAs in the tumor samples—made when DNA deletions create unnatural products that can drive cancer," says Nicolas Robine, co-first author and NYGC Computational Biologist.  "This chimera had never been seen before, so we believe it will help drive the work of our Rockefeller colleagues and Elana's future.  It is the NYGC's mission to undertake such collaborative genomic studies that will accelerate medical advances."

"Because of the deletion and then rejoining of the DNA, a new gene that was a mixture of two previous genes was created, called a chimera," says Elana Simon. "A number of other types of tumors have been shown to be driven by chimeras, but this one is unique—it codes for a kinase, an enzyme that modifies other proteins, that has not been identified in cancers." Furthermore, the researchers found that the kinase was made only in the tumor cells, and that it was constantly active. They believe that overproduction of this kinase may explain the uncontrolled growth of the tumor.

"These results were extremely encouraging," says Sanford Simon, the study's senior author and head of Rockefeller's Laboratory of Cellular Biophysics. "It is uncommon for a genetic screen for a cancer to turn up such a strong candidate mutation, and for the mutation to be present in every single patient tested."

For Elana Simon, who is finishing her senior year in high school and did the work after school and during breaks, the results are not only a scientific success, but also a profoundly personal one: her interest in studying the disease developed after she herself was diagnosed with fibrolamellar six years ago. The study was conducted in collaboration with the surgeon who removed her in 2008, Michael P. LaQuaglia, chief of the Pediatric Surgical Service at Memorial Sloan Kettering Cancer Center, and her father, Sanford Simon, as well as the NYGC team.

The research is also unusual in that it was funded not by a federal grant, but largely with private gifts from the Fibrolamellar Cancer Foundation and several individual donors whose lives have been touched by the disease. Additional support was also provided by the Howard Hughes Medical Institute, the New York Genome Center, The Rockefeller University Center for Clinical and Translational Science and by a gift to The Rockefeller University by an anonymous donor.

The Simon lab is now working on testing the effects of the chimera on human liver cells and in mouse livers, to further elucidate its role in the disease. If they can understand what's causing the tumors to develop, the scientists can work on not only treating them—using a genetic target to halt the cancer's growth—but also catching them before they even appear.

"The hope is that we'd be able to screen the blood for the presence of this chimera, and patients wouldn't have to wait until the tumors are present, until it might be too late, to do something about it," says Sanford Simon.

The work may also have implications for other cancers. "Genomics is allowing us to classify cancers based not on the organ they originate in, but on the molecular changes they trigger," says Sanford Simon. "Now that we know about this new chimera kinase, we can look for it in other cancers and work to develop new tools that will someday radically improve our ability to fight disease."

Explore further: Teen helps scientists study her own rare disease

Related Stories

Teen helps scientists study her own rare disease

February 27, 2014
(AP)—First the American teenager survived a rare cancer. Then she wanted to study it, spurring a study that helped scientists find a weird gene flaw that might play a role in how the tumor strikes.

Recurrent but rare mutations might underlie cancer growth

February 26, 2014
A potential new gene mutation that might drive lung cancer development and growth has been identified by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard ...

Gene sequencing project discovers common driver of a childhood brain tumor

February 19, 2014
The St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project has identified the most common genetic alteration ever reported in the brain tumor ependymoma and evidence that the alteration ...

Multiple myeloma study uncovers genetic diversity within tumors

January 13, 2014
The most comprehensive genetic study to date of the blood cancer multiple myeloma has revealed that the genetic landscape of the disease may be more complicated than previously thought. Through results published in Cancer ...

Scientists map gene changes driving tumors in common pediatric soft-tissue cancer

January 23, 2014
(Medical Xpress)—Scientists have mapped the genetic changes that drive tumors in rhabdomyosarcoma, a pediatric soft-tissue cancer, and found that the disease is characterized by two distinct genotypes. The genetic alterations ...

Research suggests a blood test to locate gene defects associated with cancer may not be far off

January 8, 2014
Some surprising research findings from scientists at The University of Texas MD Anderson Cancer Center suggest it's possible a simple blood test could be developed to determine whether gene mutations associated with pancreatic ...

Recommended for you

Scientists zoom in to watch DNA code being read

January 17, 2018
Scientists have unveiled incredible images of how the DNA code is read and interpreted—revealing new detail about one of the fundamental processes of life.

T-cells engineered to outsmart tumors induce clinical responses in relapsed Hodgkin lymphoma

January 16, 2018
WASHINGTON-(Jan. 16, 2018)-Tumors have come up with ingenious strategies that enable them to evade detection and destruction by the immune system. So, a research team that includes Children's National Health System clinician-researchers ...

Researchers identify new treatment target for melanoma

January 16, 2018
Researchers in the Perelman School of Medicine at the University of Pennsylvania have identified a new therapeutic target for the treatment of melanoma. For decades, research has associated female sex and a history of previous ...

More evidence of link between severe gum disease and cancer risk

January 16, 2018
Data collected during a long-term health study provides additional evidence for a link between increased risk of cancer in individuals with advanced gum disease, according to a new collaborative study led by epidemiologists ...

Researchers develop a remote-controlled cancer immunotherapy system

January 15, 2018
A team of researchers has developed an ultrasound-based system that can non-invasively and remotely control genetic processes in live immune T cells so that they recognize and kill cancer cells.

Dietary fat, changes in fat metabolism may promote prostate cancer metastasis

January 15, 2018
Prostate tumors tend to be what scientists call "indolent" - so slow-growing and self-contained that many affected men die with prostate cancer, not of it. But for the percentage of men whose prostate tumors metastasize, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.