A Canadian-led research team’s discovery of a mutation in the “dark matter” of DNA that is linked to cancer could lead to new treatments for several deadly cancers, including chronic lymphocytic leukemia (CLL).

The distinctive mutation in the vast noncoding region of the human genome — once considered “junk DNA” — was first found in a rare pediatric brain cancer and then later, in CLL and in liver cancers, among others. Results of 2 related studies on mutations in the U1 genes, termed U1 small nuclear RNA (U1-snRNA) mutations, appeared in the journal Nature in October 2019.1, 2

“We haven’t connected all the dots as to how it causes cancer,” said Lincoln Stein, MD, PhD, head of adaptive oncology at the Ontario Institute for Cancer Research, Toronto, who is the coprincipal investigator on the studies. But, he added, his team is beginning to understand the effects of the mutations — a disruption in normal RNA splicing that causes faulty transcription of numerous cancer-driving genes.

The genetic error, a single “typo” in the DNA code, showed up in more than 90% of a rare subtype of brain cancers in children and in 10% to 15% of CLL cases and of liver cancers, respectively, according to Dr Stein. Overall, the researchers looked at 37 different cancers, analyzing nearly 2600 whole genomes derived from tumors.

“We didn’t find anything new initially, which was rather disappointing,” Dr Stein said. However, once his colleague, Michael Taylor, MD, a pediatric neurosurgeon and senior scientist at the Hospital for Sick Children in Toronto, identified the U1 error in tissue samples taken from patients with sonic hedgehog medulloblastoma, further analysis found the heavily conserved mutation in other cancers, as well. Dr Taylor, who is the Garron Family Chair in Childhood Cancer Research at the hospital, served as a second lead author on the Nature studies.

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“It’s the first example of a noncoding RNA where the mechanism is clear,” Dr Stein said.

 Also, he said, the mutation in the U1 gene occurs in difficult-to-treat cancers with the worst prognoses.

In CLL, for example, researchers identified the mutation in more primitive, poorly differentiated lymphocytes. Similarly, the mutation in liver cancers occurred in those cancers associated with heavy alcohol use, but not in liver cancers caused by the hepatitis virus — an unexpected finding, which is now under investigation.