Gems in the ‘junk’

SAN DIEGO—A recent study published in the journal Nature Genetics outlines the discovery of nearly 200 genetic mutations that may play a role in cancer and offer new avenues for precision therapies. As interest in cancer genomes has exploded over the last decade, the bulk of research has focused on the 2 percent of known genes that mutate to drive cancer development and growth. A team of researchers at the University of California, San Diego School of Medicine and Moores Cancer Center have broadened that view to include nearly 200 mutations that occur in DNA that do not encode genes, but still demonstrate the ability to change gene expression.

“Most cancer-related mutations occur in regions of the genome outside of genes, but there are so incredibly many of them that it’s hard to know which are actually relevant and which are merely noise,” said senior author Dr. Trey Ideker, professor at UC San Diego School of Medicine and Moores Cancer Center. “Here, for the first time, we found about 200 mutations in non-coding DNA that are functional in cancer—and that’s about 199 more than we knew before.”

The 98 percent of DNA known as non-coding was once considered “junk DNA,” without a clear purpose, but it is now recognized to have functional elements. Previous studies identified one non-coding gene, known as TERT, that when mutated was shown to be a tumor promoter by altering DNA replication sequences and allowing tumor cells to become functionally immortal through unregulated division and self-renewal. This recent discovery has added 192 new potential TERTs that may change gene expression downstream.

With nearly 200 mutations to explore for their therapeutic value, researchers will evaluate several factors, beginning with continued validation of their results. After an initial evaluation of 930 tumor samples, follow-up testing showed that nearly every tumor cell presented with at least one non-coding mutation, and that expression quantitative trait loci (eQTLs) were disrupted by non-encoding mutations in 88 percent of cases. They will also explore how many patients are affected by particular mutations, finding a few dozen mutations that seem to be the most prevalent tumor enhancers.

Scientists will then explore more functional validation of their research—engineering the mutation in the lab and watching the effects. One tumor promoter found in the initial study activated the DAAM1 gene, which then made the tumor cells more aggressive and better able to invade surrounding tissues. By functionally replicating the mutation in the lab, scientists could see the DAAM1 gene become more mobile in the dish, indicating its readiness to metastasize and benefit tumor formation.

In seeking precision therapies for cancer, research must center on the gene. Does a particular cancer serve as an oncogene, by dialing up gene function like in the case of DAAM1, allowing the tumor to grow? Or does it act as a gene suppressant, killing the protective mechanism of a gene, and thus requiring the activation of another gene to correct the suppression? And once that is discovered, which of those genes are able to be targeted with a drug? What is the combination necessary for synthetic lethality of a particular cancer?

The approach found in the paper was borrowed from non-cancer disease biology. Cancer is primarily caused by a genetic mutation, whereas many other diseases are inherited, stemming from germline mutations. Next, the researchers will try to combine these non-coding mutations with coding mutations and determine if there are subtypes, looking for particular mutation patterns that might provide diagnostic or prognostic clues. Studies into inherited breast cancer have shown that PARP inhibitors can be effective in killing the BRCA1 gene, a prime example of both coding and non-coding mutations.

“We know that cancer is heterogenous—each one is different. This is what makes the paper such a resource for other labs to continue their research,” says Ideker. “Even for scientists who don’t care about cancer, some of what we have found about gene mutation promotion downstream will be relevant in genetic mapping; we’ve found something nice.”