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Deep Dive into Liver Tumor Genome Points to Plan of Attack

Susman, Ed

doi: 10.1097/01.COT.0000466411.17428.3c
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VIENNA, Austria—A genomic analysis of liver tumors may point to an attack plan for treatment—with at least a quarter of the cancers indicating that the lesions are sensitive to drugs that have already been approved, according to data reported here at the International Liver Congress.

Jessica Zucman-Rossi, MD, PhD, Professor and Director of the Functional Genomics of Solid Tumors Laboratory at the University of Paris Descartes, explained that using exome sequencing—a technique for sequencing all the protein-coding genes in a genome—she and her colleagues identified relationships between environmental exposures, such as tobacco smoke and alcohol use, and mutational patterns in hepatocellular carcinoma.

Still, she emphasized, the initial results, while intriguing, are too early yet to use clinically. “We don't want to overemphasize out results,” she said in an interview after reporting the findings at a European Association for the Study of the Liver (EASL) news conference. “This is the first step to develop more personalized care of patients with hepatocellular carcinoma. We think what we have shown is important knowledge for the design of future clinical trials.

“Mutational signatures help with understanding the biological history of a cancer and can enable differentiation between ongoing mutational processes and historical ones,” she continued. “This helps identify potential new targets for anticancer therapies. We think this study will also be helpful in designing drugs for these targets. To defeat hepatocellular cancer, we are going to need smart drugs. We think we may need a panel of drugs. This will take time.”

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Study Details

She and her colleagues performed exome sequencing on 236 liver cancers, sequencing the whole coding region of the genome—about 20,000 genes. The team identified 28,478 somatic gene mutations. The tumors ranged from having one mutation to having 6,184 mutations, she said.

JESSICA ZUCMAN-ROSSI, MD, PHD

JESSICA ZUCMAN-ROSSI, MD, PHD

“We identified a mean of more than 60 mutations per tumor. Each tumor is, in fact, a result of a unique combination of genetic mutations.” She said the analysis has also identified 161 genes that are drivers of hepatocellular cancer formation.

MARKUS PECK-RADOSAVLJEVIC, MD

MARKUS PECK-RADOSAVLJEVIC, MD

“Most patients had at least one damaging alteration that could potentially be treated with either an FDA-approved drug—28 percent of patients—or an investigational drug—86 percent of patients—that has been studied in Phase I to Phase III clinical trials.”

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‘Small Spectrum of Work’

The moderator of the news conference, Markus Peck-Radosavljevic, MD, Secretary General of the EASL, explained that hepatocarcinogenesis is a multistep process in which precancerous lesions can ultimately transform into liver cancer.

“Genomic analyses, such as exome sequencing, allow us to better understand the mutational processes involved in the development of cancers. This detailed knowledge then helps us to unravel the mutagenic processes and to optimize personalized patient care,” he said.

“What has been presented here is just a small spectrum of work done by a consortium of researchers,” he told OT. “The whole consortium funded by the European Union has done a tremendous job. Cancer is a very complex disease and liver cancer is even more complex, due to the variety of risk factors—virus, cirrhosis, and others—that result in the disease.

“This is very interesting data, but whether it will really be translated into more successful treatments is something that we will only see in the future,” said Peck-Radosavlijevic, who is also Associate Professor of Medicine and Vice Chairman of the Department of Gastroenterology and Hepatology at Medical University of Vienna.

“Genetic drivers appear to be important in carcinogenesis but once you have established cancer, I would doubt that their attack would result in a cure. If we take into account immunotherapy and put this together, we might be able to improve the outcome for these patients. We will have to wait a bit longer before we can see concrete results.”

Zucman-Rossi noted that more than half of hepatocellular carcinoma worldwide is related to alcohol, hepatitis B virus infection, hepatitis C virus infection, or metabolic syndrome. “Hepatocellular cancer is really a genetic disease, so the aim of our work is to understand the genomic diversity in hepatocellular carcinoma and to translate it to genomic biomarkers in order to improve clinical care of patients and identify new biomarkers to treat the disease, as well as to be able to offer prognosis and treatment performance information.”

In her laboratory, researchers have collected tumors from the first appearance of liver nodules to the manifestation of liver cancer. Zucman-Rossi said that by looking at different stages in the tumor development continuum, the researchers have identified some genes that occur very early in cancer development along with tumors that appear later in the process that may be important in predicting outcomes.

She also said her laboratory has determined that hepatocellular cancers that arise from alcoholic caused-cirrhosis have different genetics than, say, tumors that arise from hepatitis B virus infection. In fact, she said there were eight genetic signatures that differentiated various tumor sequences—including specific signatures that involved tobacco, age, afloxin B1, factor related to DNA repair, and others.

“This is like doing archeology of the tumor,” Zucman-Rossi said. “We can analyze the genetic profile of the tumor and from that, determine the cause of the tumor.”

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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