A consortium of researchers coordinated from CiMUS at USC discovers how “mobile fragments” of DNA can alter the genome architecture of human tumours
- The study, published in the prestigious journal Science, shows that these mobile elements (L1) are key players that can act as an early drivers of chromosomal instability, a hallmark associated with many human tumours.
- The discovery of this genetic mutation mechanism opens the door to future research avenues aimed at developing new therapies.
An international team led by Oportunius researcher Jose Tubío at the Center for Research in Molecular Medicine and Chronic Diseases (CiMUS) of the Universidade de Santiago de Compostela (USC) has discovered a previously unknown mechanism by which certain mobile pieces of human DNA can cause major chromosomal rearrangements in tumour cells. The study confirms that mobile elements are relevant actors capable of generating mutations and contributing to the origin and progression of human cancer, opening new avenues of research for future treatments.
The study is published today in Science, one of the world’s highest-impact scientific journals.
The research, conducted in collaboration with several national institutions, including the Centre for Genomic Regulation (CRG), and international institutions (Université Côte d’Azur in France, The Francis Crick Institute in the United Kingdom, and the MD Anderson Cancer Center in the United States), focuses on elements known as LINE-1 (L1), mobile sequences that make up 17% of the human genome. Although most are inactive, some copies retain the ability to jump from one place to another within the genome, copying themselves and inserting into new locations through a process called retrotransposition.
“Jumping genes,” responsible for a new cancer architecture
In certain types of human cancer, this activity can profoundly alter the genome architecture of a tumour, producing structural variants. “These genetic variants include losses of genetic material, duplications, inversions, and translocations, meaning the exchange of genetic material between two chromosomes,” explains Jose Tubío, lead author of the article. About one in every 40–60 L1 jumps in a tumour genome can result in a structural variant.
Genomics in the service of science
Using advanced genomic sequencing technologies, the team analyzed ten human tumours with high L1 activity, identifying more than 6,400 jumps of these elements that occurred during tumour development. “Of these, 152 generated structural variants in the genome of cancer cells, a number never previously observed,” says Bernardo Rodríguez-Martín, collaborator on the study and researcher at the CRG.
Reciprocal translocation
One of the most significant findings is the identification of a molecular mechanism in which the simultaneous, though independent, jumping of two L1 elements occurring on two different chromosomes generates reciprocal exchanges between them, giving rise to a type of structural rearrangement known as reciprocal translocation. “It is as if two different pages of a book break at the same time and swap fragments with each other, and the L1 element acts as glue between both pages,” explains Sonia Zumalave, first author of the study. This type of rearrangement—often highly relevant in the emergence and development of certain human tumours—had gone unnoticed in previous studies.
The results show that approximately 65% of these events occur in early phases of tumour evolution, suggesting that L1 activity may act as an early driver of the chromosomal instability that characterizes many human tumours.
This research was supported by the Spanish Association Against Cancer (AECC), the “la Caixa” Foundation, the Ministry of Science, Innovation and Universities, and the Xunta de Galicia.
The research was carried out at CiMUS, a center supported by competitive structural funding, including the María de Maeztu accreditation (CEX2024-001463-M), funded by MICIU/AEI/10.13039/501100011033; the support of the Consellería de Educación, Ciencia, Universidades e Formación Profesional of the Xunta de Galicia through the CIGUS Network of Research Centers (ED431G/2023/02); and co-financing by the European Union through the European Regional Development Fund (ERDF).
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