Cancer element driver#

Since this initial discovery, mobile element insertions have been found to be associated with more than 130 disease cases 10. Mobile element activity in human disease became a subject of interest after two hemophilia A patients were found to have de novo L1 insertions in the F8 gene 9. The majority of these insertions seem to have no adverse impact however, some insertions have been found to cause disease 8. With only a small fraction of these elements retaining the ability to retrotranspose, recent work has shown that germline mobile element insertions in humans are quite rare 7. These three mobile element families compose nearly one-third of the human genome 2, 6. While most of these elements have become transcriptionally inactive over time 4, 5, three mobile element families remain active in humans, including LINE-1 (L1), Alu elements, and SVA. In humans, retrotransposons represent a class of active mobile elements, inserting new elements through a “copy and paste” mechanism 3. These elements compose a significant portion of the human genome, with estimates ranging from nearly 50 to 66% 1, 2. Mobile elements, or transposable elements, are segments of DNA that are capable of mobilizing from one genomic location to another. Overall, using a unique longitudinal dataset, we find that most variants are likely passenger mutations in the four patients we examined, but some variants impact tumor progression.

Cancer element driver#

The high variant allele fraction of the translocation, the loss of the other copy of MAP2K4, the recurrent loss-of-function mutations found in this gene in other cancers, and the important function of MAP2K4 indicate that this translocation is potentially a driver mutation. Most of the variants impact intergenic regions however, we identified a translocation interrupting MAP2K4 involving Alu elements and a deletion in YTHDF2 involving mobile elements that likely inactivate reported tumor suppressor genes. We identified 11 mobile element insertions or associated structural variants and found that the majority of these occurred early in tumor progression. Here, to better understand the timing and impact of mobile element insertions and associated structural variants in cancer, we examined their activity in longitudinal samples of four metastatic breast cancer patients. In addition to insertion events, mobile elements have also been found to mediate many structural variation events in the genome.

While mobile elements are largely inactive in healthy somatic tissues, increased activity has been found in cancer tissues, with significant variation among different cancer types.