Mobile Element Insertions and Associated Structural Variants in Longitudinal Breast Cancer Samples

Abstract

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. In addition to insertion events, mobile elements have also been found to mediate many structural variation events in the genome. Here, to better understand the timing and impact of mobile element insertions and structural variants involving existing mobile elements in cancer, we examined their activity in longitudinal samples of four metastatic breast cancer patients. With whole-genome sequencing data from multiple timepoints through tumor progression, we used mobile element detection software followed by visual confirmation of the insertions. We identified 11 mobile element insertions or structural variants involving existing elements and found that the majority of these occurred early in tumor progression. Two of the identified insertions were SVA elements, which have rarely been found in previous cancer studies. Most of the variants appear to 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. The high variant allele fraction of the MAP2K4 translocation, the loss of the other copy of MAP2K4, the recurrent loss-of-function mutations found in this gene in other human cancers, and the important function of MAP2K4 indicate that this translocation is potentially a driver mutation. 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.