The role of germline transposable element insertions in pediatric cancer predisposition

Rare germline transposable element insertions in cancer predisposition genes with transcriptional consequences: a 3' UTR L1 insertion in PTEN disrupts alternative polyadenylation, and an intronic SVA insertion in STIM1 induces exonization generating a novel transcript.

Studies of germline cancer predisposition have focused on single nucleotide and copy number variants, leaving transposable elements largely unexplored. The authors characterised the germline transposable element insertion landscape in non-tumour whole genome sequencing from 2,334 children with cancer and 3,447 controls, identifying 96,484 insertions across 5,781 genomes, mostly rare and intergenic or intronic. Global burden did not differ between cases and controls, but rare insertions were significantly enriched in cancer genes among patients with solid tumours, particularly within 3' untranslated regions (p < 0.02). Gene-phenotype concordance analysis identified 19 insertions in genes with established dominant cancer predisposition, about 0.8% of cases, and RNA-seq integration documented transcriptional impact for a subset.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

0.8% of cases is a small figure on its own, but it is the order of magnitude of an additional diagnostic yield obtained with no new sample, on genomes already sequenced: the question is not adding a technique but adding a variant caller to the existing pipeline. The two functional examples — alternative polyadenylation of PTEN, exonization in STIM1 — mainly show that these insertions escape standard interpretation rules, which have no way of scoring a 3' untranslated region event. The p < 0.02 enrichment threshold and the absence of family segregation, however, preclude any insertion-by-insertion causal conclusion.

Analysis by Dr Thibaut Benquey