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Exome sequencing found to assist in determining HCC therapy
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VIENNA — Exome sequencing of liver tumors was found to be effective in determining relationships between environmental exposures and mutation signatures, which may assist in determining therapy for patients with hepatocellular carcinoma in the future, according to data presented at a press conference at the 2015 International Liver Congress.
Jessica Zucman-Rossi, MD, PhD, professor of medicine at the Université René Descartes Pompidou in Paris, France, and head of the INSERM unit 1162, Functional Genomic of Solid Tumors, in Paris, and colleagues performed exome sequences of 243 liver tumors associated with cirrhosis (F4, n = 118), fibrosis (F2 and F3, n = 46), or non-fibrotic livers (F0 and F1, n = 79) surgically treated in Europe. The cirrhosis-associated tumors presented different stages along HCC progression: seven dysplastic macronodules, seven early, 17 small and progressed, 58 classic and 29 poor-prognosis HCC, according to the research. The tumors were divided based on specific risk factors: significant alcohol intake (41%), HCV (26%), nonalcoholic steatohepatitis (18%), HBV (14%), hemochromatosis (7%) and no known etiology (11%).
Jessica Zucman-Rossi
Eight mutational signatures were identified through the sequencing, of which six (signatures 1A, 1B, 4, 5, 6 and 16) were previously validated in a pan-cancer analysis. Signatures 23 and 24 were novel, according to the research. Hierarchical clustering, based on mutational signatures, revealed six groups (MSig1 to 6) and four singletons significantly associated with alcohol/tobacco consumption, aflatoxin B1 and other risk factors.
Researchers also identified 161 putative driver genes associated with 11 recurrent pathways. Associations of mutations defined three groups of genes centered on CTNNB1 (alcohol), TP53 (HBV), and AXIN1. Further analysis showed TERT promoter mutation as an early event in tumors, whereas FGF/CCND1 amplification, TP53 and CDKN2A alterations, began to surface at more advanced stages in aggressive tumors.
Overall, 28% of patients had at least one damaging alteration potentially targetable by an FDA-approved drug and 86% by a drug that has been studied in phase 1 to phase 3 clinical trials, according to the research.
“Sequencing has identified a huge number of genes,” Zucman-Rossi said during her presentation. “Twenty-eight percent of patients have genes that could be beneficial in terms of treatment of HCC. For patient care, genomic alterations identified in targetable genes will be useful to determine HCC patients that could potentially benefit from targeted treatment in future clinical trials.” – by Melinda Stevens
For More Information:
Schulze K. Abstract G05. Presented at: International Liver Congress; April 22-26, 2015; Vienna.
Schulze K, et al. Nat Genet. 2015;doi: 10.1038/ng.3252.
Disclosure: The researchers report no relevant financial disclosures.
Editor's note: This article has been updated to include the published reference.
Perspective
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Markus Peck-Radosavljevic, MD
Zucman-Rossi’s study is just a small spectrum of what she and her group and actually the whole consortium of researchers are trying to do. Cancer is a very complex disease and liver cancer is an even more complex disease due to all the factors that come in — the virus, inflammation, cirrhosis. I think it is very, very interesting data, but whether it will really be translated into successful or more successful treatments is something we will only see in the future.
The whole consortium, partly funded by the European Union, has done a tremendous job. I suspect we will need to wait a little longer until we really can see complete results.
In the end, these genetic drivers are important in hepato carcinogenesis, but whether they will really be then — once you have established cancer — will be a cure, I would doubt. But it could be another step and then we will see in the future probably also in liver cancer, interesting data on immunotherapy. Then, taking all this together, we might be able to improve the outcome in these patients.
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