Previously considered “junk,” scientists learn that parts of DNA which don’t produce proteins are more important than first thought

It turns out that the long stretches of DNA in the human genome that are commonly called “junk DNA” or “dark DNA” may be doing important work. Researchers at the Ontario Institute for Cancer Research (OICR) recently published their findings about stretches of junk DNA that may have a role in how cancers develop.

This is an area where pathology and omics are making personalized medicine real. OICR’s researchers published their findings in the journal Molecular Cell. Titled “Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks,” the paper notes that scientists “have discovered new regions of non-coding DNA that, when altered, may lead to cancer growth and progression,” stated an OICR news release.

Is 98% of the Human Genome Unimportant?

Until very recently only about 2% of the human genome was considered important. Researchers were most interested in the portion of DNA that produces proteins, known as the coding region or CDS (coding sequence). The rest of the genome, 98% of it, was considered “junk” DNA. The OICR researchers found that all that DNA might not be junk after all, but instead plays a critical role in preventing cancer.

The OICR study included samples from more than 1,800 patients with different types of cancer. The researchers looked at more than 100,000 sections of each patient’s genome and examined mutation patterns within the large, non-coding parts of DNA. The researchers found that those non-coding areas can control how and when certain genes are activated.

“One of the 30 key regions discovered was predicted to have a significant role in regulating a known anti-tumor gene in cancer cells, despite being more than 250,000 base pairs away from the gene in the genome,” states the news release.

Viewing DNA in New Ways Brings Insights

Within just the last few years, researchers have begun to consider the architecture of DNA, and have begun to study it as a three-dimensional (3D) structure. What they’ve learned is that the twisting, turning way that DNA is packaged tightly into the nucleus of cells serves an important purpose. The structure of DNA allows areas of non-coding DNA to be in close proximity to other sections, as the OICR researchers discovered with the anti-tumor gene.

This discovery has revealed patterns that weren’t obvious when the DNA was examined as if it were stretched out in a flat line. Before scientists considered DNA in three dimensions, they were only able to identify certain mutations, such as BRCA, which are rare but indicate a higher cancer risk.

In looking at DNA as a whole, including the non-coding parts, researchers were able to identify specific Single Nucleotide Polymorphisms (SNPs) that when in particular positions can impact a person’s risk of cancer.

“Cancer-driver mutations are relatively rare in these large non-coding regions that often lie far from genes, presenting major challenges for systematic data analysis,” noted Jüri Reimand, PhD (above), molecular geneticist and principal investigator at OICR, Assistant Professor at the University of Toronto, and lead author of the OICR study. “Powered by novel statistical tools and whole genome sequencing data from more than 1,800 patients, we found evidence of new molecular mechanisms that may cause cancer and give rise to more-aggressive tumors.” (Photo copyright: University of Toronto.)

Another study conducted by scientist in England at Cancer Research UK and published in the British Journal of Cancer (BJC), titled, “Nongenic Cancer-Risk SNPs Affect Oncogenes, Tumour-Suppressor Genes, and Immune Function,” reached similar conclusions. The authors of that study wrote that “cancer-risk SNPs are associated with the expression levels of oncogenes [a gene with the potential to cause cancer] and tumor suppressor genes at a far greater rate than expected by chance. This indicates not only that mutations in these cancer genes are important, but also that genetic control of these genes by regulatory variants plays an important role.”

CRISPR and AI Bring New Discoveries

All of these genetic discoveries are a long way from being useful in developing diagnostics and treatments that can be used to help patients. However, researchers are using existing gene sequencing technologies such as CRISPR, along with artificial intelligence (AI), to speed up development.

The OICR researchers used CRISPR-Cas9 genome editing to explore the cancer-driving area of DNA they identified. And the researchers who conducted the BJC study plan to develop AI models based on their work that will better predict cancer risk.

“What we found surprised us, as it had never been reported before. Our results show that small genetic variations work collectively to subtly shift the activity of genes that drive cancer. We hope that this approach could one day save lives by helping to identify people at risk of cancer as well as other complex diseases,” said John Quackenbush, PhD, Professor, Computational Biology and Chair, Department of Biostatistics, Harvard T.H. Chan School of Public Health and lead author of the Cancer Research UK study, in a news release.

Clinical pathology may be on the cusp of change, driven in large part by the discoveries being made in the realms of omics. New cancer biomarkers coming out of these studies would be a boon to anatomic pathologists and clinical laboratory diagnostics. Increased development of precision medicine treatments based on these research findings could save many lives.

—Dava Stewart

Related Information:

Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks

Researchers Discover New Regions of Non-Coding DNA That May Lead to Cancer

Nongenic Cancer-Risk SNPs Affect Oncogenes, Tumour-Suppressor Genes, and Immune Function

‘Junk DNA’ Affects Inherited Cancer Risk