A study published in the journal Science on the 27th revealed how a class of “jumping” DNA fragments in the human genome—the LINE-1 (L1) elements known as genetic “parasites”—became the main force in disrupting the stability of the cancer genome. Genome instability is precisely the breeding ground for cancer evolution, providing more opportunities for malignant cells to grow, adapt, and avoid treatment. This study challenged traditional views and discovered a key factor that has a comprehensive impact on the cancer genome.
A multinational team from the Barcelona Genome Regulation Center in Spain this time focused on the abnormally active L1 elements in tumors and adopted new long-read long-sequencing techniques, fully depicting for the first time the comprehensive impact of such “jumping genes” on the structure of the cancer genome. They found that L1 could not only destroy individual genes by inserting mutations, but could also drive large-scale and destructive genome structure rearrangements, such as deletions, translocations, and so on. In the 10 L1-highly active tumors analyzed, a total of 6,418 jumping events were observed, of which about every 40 jumps triggered a large-scale structural modification, three-quarters of which were difficult to detect with traditional short-read long-sequencing techniques.
Particularly important is that about 65% of L1 events occur in the early stages of tumor evolution, and most occur before the important event of “genome-wide doubling” (cancer cells replicating an entire set of chromosomes). This suggests that L1 activity is an important facilitator, rather than a result, of early genome remodeling in cancer formation. Moreover, the low methylation levels of L1 promoter regions in tumor tissue also align with the hypothesis that epigenetic changes may awaken these dormant elements.
This study, conducted in collaboration by multinational agencies, although the samples were concentrated on L1-activity-high cancer types, its findings provide new perspectives for understanding the root causes of cancer genome instability. This also highlights the potential value of long-read long-sequencing in cancer research, which is expected to point in new directions for future development of early intervention strategies.