Epigenomic abnormalities predict survival of patients with non-Hodgkin lymphoma

In cancer, not only can genes themselves go bad, but abnormal epigenetic changes can unfortunately change the expression of these genes. Researchers hope to control the harmful epigenomic changes to turn down cancer itself or perhaps sensitize cancers to existing drugs.

The primary tool of the epigenome, and by far its easiest to study, is methylation. Methyl groups are attached to DNA sequences near the genes to silence or promote their expression.

”Not only do we see more abnormal methylation in non-Hodgkin lymphoma patients than in healthy B-cell populations, but there are three distinct subtypes of the disease in the clinic, each more aggressive than the next. These three clinical trajectories of non-Hodgkin lymphoma were distinctly marked by their levels of abnormal methylation,” said Subhajyoti De, PhD, University of Colorado Cancer Center investigator and assistant professor at the CU School of Medicine.

Methylation patterns predict patient survival. DNA should be methylated in a consistent way, so a certain, standardized amount of methyl “residue” is attached to genes, which is the case in healthy B cells. Subhajyoti and colleagues have shown that in cancerous B cells, the level of DNA methylation varies wildly from cell to cell. The more wildly the level of DNA methylation varies, the more aggressive the cancer is. When methylation occurs “willy-nilly,” abnormal cells like cancer are promoted.

Abnormal methylation is correlated with not only cancer, but also with the aggressive behavior of cancer subtypes. What is the functional role of methylation? ”We think that in addition to genetic mutations that cause cancer, epigenetic changes probably play a subtle role that allows the cancer to thrive within our body,” Subhajyoti said.

Some drugs affect the epigenome's ability to methylate and so control genes. Some increase or decrease the amount of methylation across the board, and some affect the amount of methylation on certain genetic products. Subhajyoti hopes to find out which of these drugs may hold the key to muting cancer.

”For the last 50 years, the scientific community pushed to identify the genetic drivers of cancer, but now in the past 5 or 6 years we've expanded the search into the epigenome as well,” Subhajyoti said. ”We now expect to find that both genetic and epigenetic abnormalities are important for initiation and maintenance of cancer.”

This study was published in PLoS Genetics (2013; doi:10.1371/journal.pgen.1003137).

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