Jumping "DNA Parasites” Linked to Early Tumor Development

Transposable elements, particularly long interspersed nuclear element-1 (LINE-1), have been implicated in this instability, but their timing and impact have remained uncertain. Clarifying these mechanisms could inform which genomic analyses best capture the alterations shaping tumor evolution. New findings demonstrate that LINE-1 activity can trigger early, large-scale genome remodeling in tumors.

Investigators used long-read sequencing to resolve how LINE-1 (L1) retrotransposition restructures cancer genomes. Long-read sequencing enabled reconstruction of complex structural variation that short-read technologies struggle to assemble, revealing the full spectrum of L1-induced changes. L1 elements copy and insert themselves into new genomic loci, a process that can produce simple insertions as well as deletions, translocations, and other architectural rearrangements.

The team analyzed ten tumors with high L1 activity—five head and neck squamous carcinomas, four lung squamous carcinomas, and one colorectal adenoma—performing in-depth sequencing and variant interpretation. A total of 6,418 retrotransposition events were identified, the vast majority being insertions that extended genomic length, often as truncated copies. Crucially, 152 events produced large-scale structural rearrangements, with an estimated incidence of one in 40 among high-activity tumors and one in 60 in lower-activity tumors, underscoring their potential to drive oncogenesis.

The researchers report that two in three (65%) L1 events occurred during early tumor evolution. Whole genome doubling occurred a median of 4.77 years before diagnosis in this cohort, and most L1 activity preceded this milestone, indicating that retrotransposition can represent an early mutational process. They also observed that L1 promoters were typically less methylated in tumors than in nearby non-tumor tissue, consistent with epigenetic activation. Among the structural mechanisms, the group describes a previously unrecognized, balanced DNA exchange between chromosomes—termed a reciprocal translocation—likely arising from near-concurrent L1 events.

According to the report, these findings strengthen arguments for long-read sequencing in cases where standard tests cannot explain a tumor’s behavior, because short-read approaches may miss the underlying mechanism. The study was published in Science on February 6 and was carried out by CiMUS at the Universidade de Santiago de Compostela in collaboration with the Center for Genomic Regulation (CRG), Université Côte d'Azur, the Francis Crick Institute, and the University of Texas MD Anderson Cancer Center. The authors note that the cohort was deliberately seleted for extreme L1 activity, which may limit generalizability.

“Cancer genomes are more influenced by these jumping fragments of DNA parasites than we previously thought,” said Professor José Tubio, researcher at the Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CiMUS) at the Universidade de Santiago de Compostela (USC) and coordinator of the study.

“The next focus should be understanding when and where L1 activity tips the balance and how to target that therapeutically,” said Dr. Bernardo Rodriguez-Martin, Independent Fellow at the Center for Genomic Regulation in Barcelona and one of the main authors of the study.

Related Links
Center for Genomic Regulation (CRG)
CiMUS at the Universidade de Santiago de Compostela