Concurrent L1 retrotransposition events promote reciprocal translocations in human tumorigenesis.
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| Title: | Concurrent L1 retrotransposition events promote reciprocal translocations in human tumorigenesis. |
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| Authors: | Zumalave, Sonia (AUTHOR), Santamarina, Martin (AUTHOR), P. Espasandín, Nuria (AUTHOR), Zamora, Jorge (AUTHOR), Garcia-Souto, Daniel (AUTHOR), Temes, Javier (AUTHOR), Baker, Toby M. (AUTHOR), Rodríguez-Castro, Jorge (AUTHOR), Otero, Paula (AUTHOR), Pequeño-Valtierra, Ana (AUTHOR), Otero, Iago (AUTHOR), Oitabén, Ana (AUTHOR), Álvarez, Eva G. (AUTHOR), Díaz-Arias, Iria (AUTHOR), Martínez-Fernández, Mónica (AUTHOR), Blanco, Miguel G. (AUTHOR), Van Loo, Peter (AUTHOR), Cristofari, Gael (AUTHOR), Rodriguez-Martin, Bernardo (AUTHOR), Tubio, Jose M. C. (AUTHOR) |
| Source: | Science. 4/2/2026, Vol. 392 Issue 6793, p1-22. 22p. |
| Subjects: | Chromosomal rearrangement, Gene rearrangement, Somatic mutation, Cancer genes, Nucleotide sequencing, Mutagenesis, Neoplastic cell transformation |
| Abstract: | LINE-1 (L1) retrotransposition generates somatic genomic variation in human cancer, but short-read sequencing has limited our understanding of its structural consequences and dynamics. Using long-read sequencing, we analyzed 10 tumors with exceptionally high retrotransposition activity, comprising more than 6000 somatic events. We reveal that L1-mediated reciprocal translocations occur frequently, typically driven by two concurrent L1 retrotransposition events on nonhomologous chromosomes. Using an independent tumor cohort spanning low to high L1 activity, we estimate that retrotransposon-mediated rearrangements arise at a frequency of one event per 60 somatic retrotranspositions. Molecular timing analyses indicate that these events arise early in tumorigenesis, establishing L1 activity as an early driver of chromosomal instability. Our findings demonstrate that L1 contributes substantially to cancer genome evolution in certain tumors. Editor's summary: LINE-1 retrotransposons are repetitive DNA elements present throughout the genome. Although most of them are truncated and incapable of transferring to new locations, a fraction of them remain active and capable of relocating to new regions of the genome through retrotransposition, a process that can disrupt other genes and sometimes drive tumorigenesis. Zumalave et al. used long-read sequencing to study 10 tumors with unusually high retrotransposition activity and examined the patterns of genetic changes and mechanisms involved in the process of tumor evolution resulting from retrotransposons (see the Perspective by Smits and Richardson). The authors then validated their findings in a lower-retrotransposition cohort, confirming their generalizability. —Yevgeniya Nusinovich INTRODUCTION: LINE-1 (L1) retrotransposons are abundant repetitive elements that make up ~17% of the human reference genome. These sequences behave as intragenomic parasites, propagating through a "copy-and-paste" mechanism known as retrotransposition. In this process, an active L1 locus is transcribed into an RNA intermediate, which is then reverse-transcribed and inserted at a new genomic site. Although most L1 copies are inactive, a handful of loci generate new insertions. Such mobilization can disrupt genome integrity, promote insertional mutagenesis, and occasionally contribute to human disease, including cancer. In certain tumors, somatic L1 activity becomes a prominent source of mutational burden. RATIONALE: Previous work revealed that aberrant somatic L1 retrotransposition can mediate diverse genomic rearrangements, with deletions representing the most frequent class (>95%). However, these analyses were largely hampered by the limitations of short-read sequencing, which obscures other forms of L1-driven chromosomal instability. In this work, we integrated multiplatform sequencing approaches, with an emphasis on long-read data, to investigate somatic retrotransposition in 10 human tumors selected for their high L1 activity. We developed a bioinformatics algorithm to uncover the patterns and mechanisms of retrotransposon-mediated rearrangements at nucleotide-level resolution. Furthermore, we implemented timing estimation approaches to characterize the tempo of these rearrangements during tumorigenesis. RESULTS: Across the 10 tumors, we identified 6418 somatic L1 retrotransposition events. Among these, 152 insertions bridged genomic rearrangements. Although deletions remained the dominant category, translocations emerged as the second most frequent type, accounting for ~30% of these forms of structural variants. Notably, approximately half of the retrotransposon bridges mediating interchromosomal junctions participated in reciprocal translocations—balanced exchanges between nonhomologous chromosomes that were largely undetectable in earlier short-read studies. Long-read sequencing enabled reconstruction of the internal architecture of the insertions and revealed that these reciprocal translocations most commonly involve two distinct L1 molecules forming the junctions of the two derivative chromosomes. Notably, we found no evidence for postintegration homologous recombination between preexisting somatic L1 insertions. Instead, our data support a model in which two independent L1 insertions are resolved concurrently to generate the rearrangement. Similar principles also underlie the formation of reciprocal inversions and more complex structural variants, in which independent retrotransposition events mediate multiple junctions across concatenated rearrangements. Timing analyses revealed that ~65% of the L1 insertion events occurred early during tumor evolution. Comparative analyses in an independent set of tumors spanning lower retrotransposition rates confirmed associations between retrotransposition, TP53 alterations, and global DNA hypomethylation while further implicating disruption of the Fanconi anemia pathway in elevated rearrangement burdens. CONCLUSION: Together, our observations establish somatic L1 activity as a major contributor to tumor genome plasticity, extending its impact far beyond classical insertional mutagenesis. Approximately three-quarters of the retrotransposon-mediated rearrangements identified in this work would remain undetected or misclassified by short-read sequencing, which underscores how this class of structural variation has been largely overlooked. Collectively, our findings position L1 activity as an early driver of large-scale chromosomal instability in human cancer, with approximately one in every 40 to 60 somatic insertions giving rise to a genomic rearrangement. Proposed model of L1-driven chromosomal exchange.: Two independent, concurrent somatic L1 insertions bridge interchromosomal breakpoints to generate a reciprocal translocation in tumors with elevated retrotransposition activity. Each insertion initiates on one chromosome (chr), but second-strand synthesis is completed on a nonhomologous chromosome, mediated by short-sequence microhomologies. This process produces two L1 bridges that form the junctions of both derivative chromosomes from a reciprocal translocation. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | LINE-1 (L1) retrotransposition generates somatic genomic variation in human cancer, but short-read sequencing has limited our understanding of its structural consequences and dynamics. Using long-read sequencing, we analyzed 10 tumors with exceptionally high retrotransposition activity, comprising more than 6000 somatic events. We reveal that L1-mediated reciprocal translocations occur frequently, typically driven by two concurrent L1 retrotransposition events on nonhomologous chromosomes. Using an independent tumor cohort spanning low to high L1 activity, we estimate that retrotransposon-mediated rearrangements arise at a frequency of one event per 60 somatic retrotranspositions. Molecular timing analyses indicate that these events arise early in tumorigenesis, establishing L1 activity as an early driver of chromosomal instability. Our findings demonstrate that L1 contributes substantially to cancer genome evolution in certain tumors. Editor's summary: LINE-1 retrotransposons are repetitive DNA elements present throughout the genome. Although most of them are truncated and incapable of transferring to new locations, a fraction of them remain active and capable of relocating to new regions of the genome through retrotransposition, a process that can disrupt other genes and sometimes drive tumorigenesis. Zumalave et al. used long-read sequencing to study 10 tumors with unusually high retrotransposition activity and examined the patterns of genetic changes and mechanisms involved in the process of tumor evolution resulting from retrotransposons (see the Perspective by Smits and Richardson). The authors then validated their findings in a lower-retrotransposition cohort, confirming their generalizability. —Yevgeniya Nusinovich INTRODUCTION: LINE-1 (L1) retrotransposons are abundant repetitive elements that make up ~17% of the human reference genome. These sequences behave as intragenomic parasites, propagating through a "copy-and-paste" mechanism known as retrotransposition. In this process, an active L1 locus is transcribed into an RNA intermediate, which is then reverse-transcribed and inserted at a new genomic site. Although most L1 copies are inactive, a handful of loci generate new insertions. Such mobilization can disrupt genome integrity, promote insertional mutagenesis, and occasionally contribute to human disease, including cancer. In certain tumors, somatic L1 activity becomes a prominent source of mutational burden. RATIONALE: Previous work revealed that aberrant somatic L1 retrotransposition can mediate diverse genomic rearrangements, with deletions representing the most frequent class (>95%). However, these analyses were largely hampered by the limitations of short-read sequencing, which obscures other forms of L1-driven chromosomal instability. In this work, we integrated multiplatform sequencing approaches, with an emphasis on long-read data, to investigate somatic retrotransposition in 10 human tumors selected for their high L1 activity. We developed a bioinformatics algorithm to uncover the patterns and mechanisms of retrotransposon-mediated rearrangements at nucleotide-level resolution. Furthermore, we implemented timing estimation approaches to characterize the tempo of these rearrangements during tumorigenesis. RESULTS: Across the 10 tumors, we identified 6418 somatic L1 retrotransposition events. Among these, 152 insertions bridged genomic rearrangements. Although deletions remained the dominant category, translocations emerged as the second most frequent type, accounting for ~30% of these forms of structural variants. Notably, approximately half of the retrotransposon bridges mediating interchromosomal junctions participated in reciprocal translocations—balanced exchanges between nonhomologous chromosomes that were largely undetectable in earlier short-read studies. Long-read sequencing enabled reconstruction of the internal architecture of the insertions and revealed that these reciprocal translocations most commonly involve two distinct L1 molecules forming the junctions of the two derivative chromosomes. Notably, we found no evidence for postintegration homologous recombination between preexisting somatic L1 insertions. Instead, our data support a model in which two independent L1 insertions are resolved concurrently to generate the rearrangement. Similar principles also underlie the formation of reciprocal inversions and more complex structural variants, in which independent retrotransposition events mediate multiple junctions across concatenated rearrangements. Timing analyses revealed that ~65% of the L1 insertion events occurred early during tumor evolution. Comparative analyses in an independent set of tumors spanning lower retrotransposition rates confirmed associations between retrotransposition, TP53 alterations, and global DNA hypomethylation while further implicating disruption of the Fanconi anemia pathway in elevated rearrangement burdens. CONCLUSION: Together, our observations establish somatic L1 activity as a major contributor to tumor genome plasticity, extending its impact far beyond classical insertional mutagenesis. Approximately three-quarters of the retrotransposon-mediated rearrangements identified in this work would remain undetected or misclassified by short-read sequencing, which underscores how this class of structural variation has been largely overlooked. Collectively, our findings position L1 activity as an early driver of large-scale chromosomal instability in human cancer, with approximately one in every 40 to 60 somatic insertions giving rise to a genomic rearrangement. Proposed model of L1-driven chromosomal exchange.: Two independent, concurrent somatic L1 insertions bridge interchromosomal breakpoints to generate a reciprocal translocation in tumors with elevated retrotransposition activity. Each insertion initiates on one chromosome (chr), but second-strand synthesis is completed on a nonhomologous chromosome, mediated by short-sequence microhomologies. This process produces two L1 bridges that form the junctions of both derivative chromosomes from a reciprocal translocation. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.aee4513 |
