Changes in cancer epigenome implicated in chemotherapy resistance and lymphoma relapse

Genomic studies have illuminated the ways in which malfunctioning genes can drive cancer growth while stunting the therapeutic effects of chemotherapy and other treatments. However, new findings indicate that these genes are only partly to blame for why treatment that was effective ultimately fails in approximately 40% of patients with the most common form of non-Hodgkin lymphoma.

The study, published in Nature Communications (2015; doi:10.1038/ncomms7921), suggests that global changes in cancer cells' epigenome that turn normal genes on when they should be off, and vice versa, may be a powerful force in determining disease progression.

The investigators made this discovery by reviewing biopsies taken from patients with diffuse large B-cell lymphoma (DLBCL) before treatment and again after the treatment failed and cancer resurged. They compared the two samples and found that the epigenome in these patients' cancer cells had substantially changed after treatment.

They also found that the global epigenome of pretreatment biopsies was substantially different in patients whose disease did not recur compared to patients whose disease came back. The researchers found more cell-to-cell heterogeneity, that is, a greater variety of epigenetic patterns in patients who relapsed.

The epigenome, which surrounds genetic DNA like a bubble, is powerful; it can determine which genes are turned on or off, influencing the production of proteins. The epigenome can modify gene expression by adding or removing a chemical compound, known as a methyl group, to a specific place in a gene's DNA. Adding a methyl group to a gene turns the gene off, and removing a methyl group allows a gene to turn on when it should not.

This explains why the findings are so significant, investigators said, because drugs that disrupt the epigenetic machinery in cancer cells might reverse treatment resistance and help chemotherapy and other drugs to do their jobs.

"This is the first study I know of in cancer that looks at changes in the epigenome before and after treatment, and what we found could ultimately make traditional treatments much more effective," said senior author Olivier Elemento, PhD, an associate professor of physiology and biophysics and head of the Laboratory of Cancer Systems Biology in the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine at Weill Cornell Medical College in New York, New York.

To help uncover the role of epigenetic involvement, Elemento utilized biopsies banked by collaborators Giorgio Inghirami, MD, and Wayne Tam, MD, who are blood cancer pathology specialists and lymphoma researchers at Weill Cornell.

In each sample set, investigators looked at sites in the epigenome where a methyl group was added or removed after cancer recurred. They found a change in methylation that occurred between 39,808 and 1,035,960 specific methylation sites, depending on the cancer sample. In addition, they identified between 78 and 13,162 differently methylated regions in the epigenome in relapsed cancer.

"These are massive changes; given that the epigenome has 20 million methylation sites, our study shows that in some cases, up to one-twentieth of the entire epigenome is changed after treatment," Elemento said. "There are many more epigenetic changes than there are altered genes in DLBCL."

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