Genetic Mutation Tied to Rare Adolescent Liver Cancer

Researchers from Rockefeller University, Memorial Sloan Kettering Cancer Center and the New York Genome Center, all in New York, NY, have identified a genetic abnormality that may lead to better detection and treatment methods for a rare form of adolescent liver cancer—fibrolamellar hepatocellular carcinoma (FL-HCC).

“Prior to this research, we knew nothing about this disease, what caused it or even if it was one or many diseases,” says Sanford Simon, PhD, the study's senior author and head of Rockefeller University's laboratory of cellular biophysics. “These findings give us very specific directions to go diagnostically and therapeutically.”

In the study, recently published in Science, researchers sequenced DNA and RNA from the surgically resected tumors of 10 patients with FL-HCC and used computer algorithms to look for differences between the diseased samples and healthy liver tissue. The results predicted that the diseased samples contained a chimeric transcript encoding a fusion between DNAJB1 and PRKACA, the catalytic subunit of protein kinase A, resulting from a deletion on chromosome 19 that was not present in adjacent normal liver tissue.

Based on that prediction, the team looked at a total of 15 diseased tissue samples and found that they all contained the chimera. They also found that the encoded protein retained kinase activity that may drive progression of FL-HCC. The findings are especially significant, says Simon, because they demonstrate that the chimera is active even though chimeric proteins often are not functional.

“The fact that the same alteration was found in 15 out of 15 patient tumors but not in adjacent tissue, with almost no other mutations throughout the genome, is a very strong causal statement,” says Simon. “It suggests that the disease is probably due to one genetic glitch at one point and that if you can detect the mutation early enough, you may be able to resect the entire tumor.”

To follow up on the findings, Simon's team is testing how the chimera is expressed in human and mouse liver cells. By pinpointing a genetic cause of the disease, they hope to develop early detection methods and targeted therapy.

“Currently, the only way to diagnose FL-HCC is with a biopsy, and often that doesn't happen until the tumor has metastasized outside of the liver,” says Simon. “These findings suggest that we may be able to develop a simple diagnostic blood test to see if the mutated tumor cell is shedding this protein.”

“Early detection is especially important for patients with FL-HCC, who often complain of abdominal symptoms for years before a biopsy is performed,” says Elana Simon, a high school senior who initiated and coauthored the study with her father's team. She was diagnosed with the disease 6 years ago and underwent successful surgery to treat it.

“Doctors often attribute abdominal symptoms to lactose intolerance, stress, or appendicitis,” continues Sanford Simon. “Often patients don't get a biopsy until their symptoms are very severe, and once the tumor has metastasized there's no effective treatment.”

Researchers also suspect that the mutation found in FL-HCC tumors may be present in other types of cancer.

“It's quite possible that this mutation produces other cancers when it occurs in a different background,” says Sanford Simon. “Now that we know about this chimera, we can potentially screen for it in other types of tumors.”

Elana Simon's efforts to study FL-HCC and to advance cancer research in general have not gone unnoticed. On April 6, she received the American Association for Cancer Research's first Young Champion in Cancer Research Award at the organization's 2014 Annual Meeting in San Diego, CA. The award was created to recognize an individual for his or her early contributions to research on cancer and for enhancing public understanding of the disease.