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Expression, Epigenetic Patterns Predict Liver Cancer Response to Methylation-Inhibiting Drug

By Andrea Anderson

NEW YORK (GenomeWeb News) – Researchers from the National Cancer Institute reported online in Science Translational Medicine today that they have identified gene expression and epigenetic patterns that can help predict which liver cancers are most likely to respond to treatments targeting DNA methylation.

Through a series of experiments assessing gene expression and epigenetic patterns in liver cancer samples and cell lines, the team uncovered expression and epigenetic signatures linked to liver cancer cell response to a DNA methylation-inhibiting drug called zebularine.

By applying these findings to retrospective liver cancer patient data, the researchers found evidence that their signatures could stratify patients based on clinical outcomes. And, they say, results so far suggest this classification strategy may also be useful for finding individuals most likely to benefit from treatments that inhibit DNA methylation.

"Integration of the zebularine gene expression and demethylation response signatures allowed differentiation of patients with hepatocellular carcinoma according to their survival and disease recurrence," senior author Snorri Thorgeirsson, chief of NCI's laboratory of experimental carcinogenesis, and co-authors wrote.

"This integrated signature identified a sub-class of patients within the poor-survivor group that is likely to benefit from therapeutic agents that target the cancer epigenome," they added.

Less than a third of individuals diagnosed with hepatocellular carcinoma are eligible for liver transplantation, which is currently the only liver cancer cure, the researchers explained.

"Really, the curative option is transplantation. But that is only for a very small fraction of liver cancer," Thorgeirsson told GenomeWeb Daily News, explaining that he and his colleagues were interested in finding better treatment options and classification schemes for advanced liver cancer patients.

Because at least some liver cancers seem to be a consequence of excessive DNA methylation that silences key genes, the researchers decided to explore expression and methylation patterns in liver cancer samples — and the effects of treating such samples with the experimental drug zebularine, which curbs DNA methylation by inhibiting the DNA methyltransferase 1 enzyme.

"Epigenetic changes are pharmacologically reversible," they noted, "offering a promising multi-target translational strategy against cancer in which expression of a variety of silenced genes could be reactivated."

To do this, the team first assessed DNA methylation levels at 807 genes in 23 different primary hepatocellular carcinoma samples.

In general, they found that samples from a hepatocellular carcinoma subtype known to have higher recurrence rates and shorter survival times also tended to show enhanced CpG methylation, particularly at 32 of the genes tested.

Expression patterns at the same 32 genes could be used to classify another set of 53 hepatocellular carcinoma tumor samples as good or poor prognosis tumors, the team noted.

Because these genes included representatives from immune, cellular defense, cell signaling, and apoptosis-related pathways, they reasoned that "patients with advanced [hepatocellular carcinoma] and tumor hypermethylation may benefit from epigenetic therapy."

Experiments in 10 primary liver cancer cell lines, meanwhile, indicated that zebularine treatment alters the expression of 323 genes, including 308 with promoter CpG islands, consistent with the notion that drug-related expression changes might partly reflect altered methylation in these regions.

And although zebularine seems to effectively inhibit the DNA methyltransferase enzyme in both sensitive and resistant liver cancer lines, the team explained, comparisons between two drug-sensitive and two drug-resistant liver cancer lines revealed methylation differences at 133 genes. While the drug-sensitive lines grew more slowly and appeared to undergo apoptosis in response to zebularine, treating the resistant cell lines with the methylation-inhibiting drug actually made these cells grow faster.

When the team developed xenograft mouse models from zebularine-sensitive and -resistant cells, they found that mice that had drug sensitive liver cancer cells transplanted into their livers had fewer and smaller lung metastases following zebularine treatment than those transplanted with resistant liver cancer lines.

On the other hand, as in the cell line experiments, zebularine treatment actually seemed to ramp up tumor growth rate and metastasis frequency in mice transplanted with drug-resistant cells. Finally, the team demonstrated that the newly identified expression and epigenetic patterns could be used to retrospectively classify liver cancer patients.

For example, when they looked at a 70-gene expression signature in liver cancer samples from 57 patients, they found that they could predict clinical outcomes with between 84 and 96 percent accuracy.

Similarly, the researchers noted, their 133-gene demethylation signature could not only predict liver cancer survival with between 87 and 96 percent accuracy, but could also be used to sub-classify individuals within the poor prognosis group to find those expected to benefit from demethylation-based treatments.

Along with functional studies aimed at learning more about the mechanisms underlying these signatures, the researchers now hope to do prospective studies looking at whether it's beneficial to type liver cancer patients prior to treatment.

"Now we have to see, in a prospective way, whether this is as effective — or shows the same type of an effect — as we have seen in our experimental system," Thorgeirsson said. "The real test of this is now a prospective trial based on this signature classification of advanced liver cancer."

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