New research published in The Cell from researchers at UC San Diego School of Medicine and Case Western Reserve School of Medicine shows non-coding DNA—often referred to as ‘junk’ DNA because it does not encode for any known function—can contribute to cancer development.

The mechanism identified suggests that when an oncogene is activated and begins to replicate itself in an uncontrolled fashion, creating multiple copies of itself within the genome (and beginning the process of turning a normal cell into a cancerous one), non-coding DNA material is included in the replication sequence.  Previously, it was unknown if the additional DNA was involved in the cancer development or if it was simply a byproduct of unregulated DNA replication.

Using human glioblastoma brain tumor samples, researchers determined that all the ‘extra’ DNA is critical for maintaining oncogene activation, and ultimately supporting a cancer cell’s ability to survive.  When the results from these findings were used to analyze a public database of patient tumor genetics, it was discovered that if two different tumor types are driven by the same cancer-causing gene, the extra DNA may differ.  This may explain why certain anti-cancer drugs will often work for some cancer types but not others.

“We’ve been targeting the cancer-causing gene for therapy, but it turns out we should [have] also [been thinking] about targeting the switches that are carried along with it,” said Peter Scacheri, Ph.D., professor of oncology at Case Western Reserve.

When the human genome was first sequenced, many people were surprised it contained far fewer genes—segments of DNA that encode proteins — than expected. It turns out that the remainder of human DNA in the genome, the non-coding regions, play important roles in regulating and enhancing the protein-coding genes—turning them “on” and “off,” for example.

In this study, the researchers focused on one example cancer-causing gene, EGFR, which is particularly active in aggressive cancers, such as glioblastoma. When copies of EGFR build up in the genome of cancer cells, they tend to be in the form of circular DNA, separate from the chromosome.

“In 2004, I was the lead on the first clinical trial to test a small molecule inhibitor of EGFR in glioblastoma,” said co-senior author Jeremy Rich, M.D., professor of medicine at UC San Diego School of Medicine and director of the Neuro-oncology and Brain Tumor Institute at UC San Diego. “But it didn’t work. And here we are, 15 years later, still trying to understand why brain tumors don’t respond to inhibitors of what seems to be one of the most important genes to make this cancer grow.”

The team took a closer look at the extra DNA surrounding EGFR circles in 9 of 44 different glioblastoma tumor samples donated by patients undergoing surgery. They discovered that the circles contained between 20 to 50 gene enhancers and other regulatory elements. Some of the regulatory elements had been adjacent to EGFR in the genome, but others were pulled in from other regions.

To determine the role each regulatory element plays, the researchers silenced them one at a time. They concluded that nearly every single regulatory element contributed to tumor growth.

“It looks like the cancer-causing gene grabs as many switches it can get its hands on … co-opting their normal activity to maximize its own expression,” Scacheri said.

First author Andrew Morton, a graduate student in Scacheri’s lab, then searched a public database of patient tumor genetic information — more than 4,500 records covering nine different cancer types. He found that the team’s observation was not limited to EGFR and glioblastoma.

Enhancers were amplified alongside cancer-causing genes in many tumors, most notably the MYC gene in medulloblastoma and MYCN in neuroblastoma and Wilms’ tumors.

“People thought that the high copy number alone explained the high activity levels of cancer-causing genes, but that’s because people weren’t really looking at the enhancers,” Morton said. “The field has been really gene-centric up to this point, and now we’re taking a broader view.”

Next, the researchers want to know if the diversity in regulatory elements across cancer types could also be helping tumors evolve and resist chemotherapy. They want to find a class of therapeutic drugs to inhibit these regulatory elements, providing another way to put the brakes on oncogenes.

“This isn’t just a laboratory phenomenon, it’s information I need to better treat my patients,” said Rich.