The Role of Germline Transposable Element Insertions in Pediatric Cancer Predisposition

Abstract

Abstract At least 10 to 15% of children with cancer have a pathogenic germline variant in a cancer predisposition gene. Studies of germline cancer predisposition, however, have focused primarily on single-nucleotide and copy-number variants, leaving other classes such as transposable elements (TE) largely unexplored. Although rare pathogenic TE insertions have been implicated in inherited cancer, their contribution to pediatric cancer predisposition remains unknown, partly because these repetitive sequences often require whole-genome sequencing (WGS) for detection. We characterized the germline TE insertion landscape using nontumor WGS data from 2,334 patients with pediatric cancer and 3,447 controls. Across 5,781 genomes, we identified 96,484 TE insertions, most of which were rare and located in intergenic or intronic regions. Whereas global TE burden did not differ between cases and controls, rare TE insertions were significantly enriched in cancer genes in patients with solid tumors, particularly within 3′ untranslated regions (P < 0.02). Gene–phenotype concordance analysis identified 19 insertions in genes with established dominant cancer predisposition, representing ∼0.8% of cases. Integration of RNA sequencing data revealed transcriptional impact for a subset of insertions. Notably, a 3′ untranslated region LINE-1 insertion in the tumor-suppressor gene PTEN disrupted alternative polyadenylation, whereas an SVA insertion in a STIM1 intron induced exonization, generating a novel transcript containing SVA sequence. These findings demonstrate that rare germline TE insertions in cancer predisposition genes can have functional consequences at the RNA level. Incorporating TE detection into genomic workflows may improve identification of cancer predisposition syndromes and expand understanding of noncoding contributions to pediatric cancer susceptibility. Significance: At least 10 to 15% of children with cancer have a germline predisposition; however, the true prevalence is likely higher. This study demonstrates that TE insertions can disrupt cancer predisposition genes and have functional consequences. Incorporating TE detection can identify cancer predisposition in children for whom standard testing is uninformative.