Leaping DNA Sequences Drive Early Tumor Development

Long-read sequencing unmasked thousands of L1 retrotransposon-mediated mutations that previously flew under the radar of standard genomic analysis.

Where there’s a bountiful host, there are parasites ready to take advantage of the resources. This holds true even at microscopic levels. Lying within human DNA are repetitive elements called LINE-1 (L1) retrotransposons that promote their own propagation at the cost of the host organism’s health.¹ These genetic parasites create copies of themselves that then get inserted at new locations within the genome. Until recently, scientists thought that the activity of L1s mostly resulted in local alterations to genes.

Now, in a new study published in Science, researchers have demonstrated that L1s can trigger dramatic structural changes in DNA, resulting in cancer-causing mutations.² These findings, which shed light on the intricate relationship between cancer evolution and the genome, could lead to improved diagnostic and therapeutic strategies for different cancers.

“Cancer genomes are more influenced by these jumping fragments of DNA parasites than we previously thought,” said José Tubio, a molecular biologist at the University of Santiago de Compostela, in a statement.

Approximately 500,000 L1s are scattered across the human genome, making up 17 percent of DNA. However, not all sequences are capable of copy-pasting themselves. Only a small subset of 150–200 L1s possess this retrotransposition ability. Even among those, some “hot L1s” show an exceptionally high frequency of jumping around, leading to mutagenesis and unstable genomes seen in cancer.^3,4

Scientists and clinicians have observed L1 insertions in 35 percent of all human tumors, especially those invading tissues in the head, neck, lungs, and intestines.⁵ Yet, due to sequencing limitations, analysis of potential structural genomic changes and dynamics due to L1s has been lacking.

To bridge this gap, Tubio and his team analyzed L1 insertions and their consequences in ten human tumors with high levels of L1 retrotransposition. Using long-read sequencing and a custom algorithm to detect and classify L1 events, the researchers identified 6,418 retrotransposition events in the tumor cells. Contrary to previous assumptions that L1 activity was simply a feature of the unstable genetic environment in cancers and ramped up in later stages, 65 percent of the L1 retrotranspositions occurred in the early stages of tumor formation. Among the thousands of L1 events, 152 caused large-scale structural alterations to the genome.

“On paper, 152 might not sound like a huge number. But when you’re looking at just ten tumours, that’s extraordinarily high,” said Bernardo Rodriguez-Martin, a computational biologist at the Centre for Genomic Regulation, in the statement.

The team estimated that one in every 40 insertions in tumors with high L1 activity caused architectural changes to the genome, compared to one in every 60 insertions in tumors with low activity. The researchers also noted that most L1 events preceded whole-genome duplication, which is a key driver of tumor formation.

“Three quarters of these large-scale rearrangements would have flown under the radar of short-read sequencing technologies,” Rodriguez-Martin said. “The next focus should be understanding when and where L1 activity tips the balance and how to target that therapeutically.”