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Exome Sequencing of Hepatocellular Carcinomas Reveals Disease Signature, Potential Treatment Targets

NEW YORK (GenomeWeb) – An international team of researchers has identified mutational signatures in hepatocellular carcinomas that are specific to certain risk factors like alcohol consumption, smoking, and hepatitis B infection.

The team led by INSERM's Jessica Zucman-Ross performed whole-exome sequencing on nearly 250 liver tumors from patients undergoing treatment in Europe. As they reported in Nature Genetics today, the team identified signatures linked with those risk factors as well as identified which mutations tended to occur early in tumor progression and which ones typically appeared at more advanced disease stages.

"Unraveling the patterns of genomic alterations in these heterogeneous tumors is pivotal in identifying targeted therapies that could improve patient care," Zucman-Ross and her colleagues wrote in their paper.

She and her colleagues collected liver tumor and matched normal samples as well as related risk factor information from 243 patients. They sequenced the tumors and matched normal samples to a mean 72-fold depth to uncover nearly 28,500 somatic mutations, though a sizable portion — about 6,200 — of them originated in a single tumor with a hypermutation phenotype.

By sifting through all these mutations using the Wellcome Trust Sanger Institute mutational signatures framework, the researchers uncovered four such signatures, two of which had previously been identified in a pan-cancer analysis and two of which were novel. They also examined the contribution of those and other previously uncovered mutational signatures, finding a role for eight signatures within their samples.

Hierarchical clustering of these signatures revealed six groups of tumors and a handful of singletons that were associated with certain demographic or molecular features.

For instance, the nine tumors in the group dubbed MSig1 were enriched for a signature of cytosine-to-adenine mutations as well as dinucleotide mutations, which have previously been associated with tobacco use. Seventy-five percent of the patients whose tumors fell into this category were smokers, the researchers noted.

Zucman-Ross and her colleagues also identified some 161 genes as putative driver genes based on their enrichment for deleterious mutations or copy number changes.

Mutations in these potential driver genes affected a variety of pathways, from telomerase expression to the WNT/beta-catenin pathway and to the PI3K-AKT-mTOR pathway.

There were, the researchers added, significant mutations linked to certain risk factors. HBV-related HCCs, for instance, were marked by TP53 mutations while alcohol-linked HCCs were enriched for mutations in CTNNB1, TERT, CDKN2A, SMARCA2, and HGF.

Certain changes tended to occur at particular stages of HCC progression. For instance, TERT promoter mutations were common early on in disease, while CTNNB1 and TP53 mutations tended to crop up later as the disease progressed. Additionally, independent of classical clinical and histological features, the researchers found that CDKN2A inactivation and FGF-CCND1 amplifications were associated with poor prognosis.

These mutations, Zucman-Ross and her colleagues added, represent possible therapeutic targets. Though each of the tumors accumulated a variety of mutations, they found three major clusters surrounding mutations in CTNNB1, which is linked to alcohol use; TP53, which is associated with HBV infection; and AXIN1.

More than a quarter of patients, the researchers said, had at least one damaging mutation that could be targeted by a US Food and Drug Administration-approved drug. And, when considering drugs currently in clinical trials, that number rose to 86 percent of patients.

They also noted that other mutations within the tumors could modulate tumor cells' sensitivity to drug treatment. Alterations to NQO1, for instance, increase sensitivity to the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin.

"For patient care, genomic alterations identified in targetable genes will be useful to identify patients with HCC who could potentially benefit from targeted treatment in future clinical trials," Zucman-Ross and her colleagues said.