The role of germline transposable element insertions in pediatric cancer predisposition

Vollständiger Abstract

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Abstract At least 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 (TEs) 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 for detection. We characterized the germline TE insertion landscape using non-tumor whole genome sequencing data from 2,334 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. While 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-seq data revealed transcriptional impact for a subset of insertions. Notably, a 3′ UTR L1 insertion in the tumor suppressor 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.