A study led by Weill Cornell Medicine researchers found that certain gliomas become more aggressive as cancer cells lose DNA methylation and shift toward an immature, stem-like state.
The findings, published June 22 in Nature Genetics, are based on an analysis of 36 tumor samples collected over time from patients whose isocitrate dehydrogenase-mutant gliomas progressed from lower to higher grades.
Researchers used single-cell methods to examine genetic activity, DNA changes and methylation patterns within the tumors. They found that progression was consistently associated with widespread hypomethylation, or reduced chemical marking of DNA, across cancer cells.
The hypomethylated cells showed greater flexibility and invasive behavior and activated genes normally associated with neural stem cells. Researchers said that shift may help explain how the tumors evolve and become harder to treat.
The findings could also help explain why drugs that inhibit mutant isocitrate dehydrogenase benefit some patients more than others. Tumors that do not respond may contain more cells that have already moved into the hypomethylated, stem-like state, though further research is needed.
The study brought together researchers from Weill Cornell Medicine, the New York Genome Center, Harvard Medical School and Massachusetts General Hospital. Senior authors included Dan Landau and Mario Suva, while Masashi Nomura, Ramya Raviram and Joshua Schiffman were co-first authors.
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