Scientists have spent much time and energy mapping the many DNA misspellings that can transform healthy cells into cancerous ones. But recently it has become increasingly clear that changes to the DNA sequence itself are not the only culprits. Cancer can also be driven by epigenetic changes to DNA—modifications to chemical marks on the genome don’t alter the sequence of the DNA molecule, but act to influence gene activity. A prime example of this can been seen in glioblastoma, a rare and deadly form of brain cancer that strikes about 12,000 Americans each year.
In fact, an NIH-funded research team recently published in Nature Communications the most complete portrait to date of the epigenetic patterns characteristic of the glioblastoma genome . Among their findings were patterns associated with how long patients survived after the cancer was detected. While far more research is needed, the findings highlight the potential of epigenetic information to help doctors devise more precise ways of diagnosing, treating, and perhaps even preventing glioblastoma and many other forms of cancer.
Earlier studies had suggested that glioblastoma comes with widespread epigenetic changes to DNA. However, the picture was far from complete, focusing only on the most common and well-studied DNA modification, known as 5-methylcytosine (5-mC). The new study, led by Kevin Johnson and Brock Christensen at the Geisel School of Medicine at Dartmouth College, Lebanon, NH, broke new ground by applying laboratory  and statistical approaches  that now make it possible to distinguish between 5-mC and another chemical mark called 5-hydroxymethylcytosine (5-hmC) to tumor samples.
The 5-hmC mark is a modified form of 5-mC. It seems more associated with activation of nearby genes, while 5-mC is more commonly involved with repression. Because 5-hmC was already known to be more common in the brain than in other parts of the body, Johnson, Christensen, and colleagues wondered whether it might also play a role in brain cancer.
Using these new laboratory and statistical approaches, the researchers painstakingly analyzed frozen glioblastoma samples from 30 adults who had died from the cancer. Those analyses showed that the tumor DNA had widespread losses of 5-hmC compared to healthy brain cells, suggesting a link between changes in the epigenetic patterns and glioblastoma.
But the finding came with an unexpected twist. Despite the overall loss of 5-hmC in these tumor cells, select regions of the glioblastoma genome retained high levels of this chemical mark. Indeed, 5-hmC popped up more frequently on genes with important roles in immunity and in stem cell biology. It also was more common in places where transcription factor proteins bind to switch on genes, including some with known links to cancer.
Taken together, the evidence suggests that 5-hmC marks might help to launch the genetic programs that drive glioblastoma. In fact, the researchers found further evidence to support this idea in a comparison of their epigenetic data to gene activity data for glioblastoma in the NIH-funded Cancer Genome Atlas. The comparison revealed a significant enrichment of 5-hmC marks on genes that show increased activity in glioblastoma cells.
How might this information help doctors provide a more accurate prognosis for their patients? It’s too early to say. But the total levels of 5-hmC varied considerably from one tumor to another, and those differences appear to be critical. The researchers showed that patients with less 5-hmC present on select parts of their tumor DNA had a worse prognosis. In fact, people with low amounts of this chemical mark often lived little more than two months compared to over a year for those with higher 5-hmC.
Today, even with surgery, radiation, and chemotherapy, people diagnosed with glioblastoma have a median survival of only about 18 months. That’s why this kind of information could ultimately prove valuable for patients and their doctors in making difficult treatment and end-of-life care decisions. That’s also why Johnson and Christensen say they’ll continue to work to learn more about how these epigenetic patterns and other molecular level changes drive glioblastoma and other cancers.
 5-Hydroxymethylcytosine localizes to enhancer elements and is associated with survival in glioblastoma patients. Johnson KC, Houseman EA, King JE, von Herrmann KM, Fadul CE, Christensen BC. Nat Commun. 2016 Nov 25;7:13177.
 Accurate measurement of 5-methylcytosine and 5-hydroxymethylcytosine in human cerebellum DNA by oxidative bisulfite on an array (OxBS-array). Field SF, Beraldi D, Bachman M, Stewart SK, Beck S, Balasubramanian S. PLoS One. 2015 Feb 23;10(2):e0118202.
 OxyBS: estimation of 5-methylcytosine and 5-hydroxymethylcytosine from tandem-treated oxidative bisulfite and bisulfite DNA. Houseman EA, Johnson KC, Christensen BC. Bioinformatics. 2016 Aug 15;32(16):2505-2507.
Brain Cancer (National Cancer Institute/NIH)
The Cancer Genome Atlas (NIH)
Christensen Lab (Geisel School of Medicine at Dartmouth, Lebanon, NH)
NIH Support: National Institute of Dental and Craniofacial Research; National Institute of Mental Health; National Institute of General Medical Sciences