儿童泛癌中转座元件的表征及其受种系TP53变异的调控

Transposable elements (TEs) are dynamic repetitive genomic regions that are silenced through epigenetic repression. Although TE activation is a well-recognized feature of embryonic development and adult cancers, their role in pediatric malignancies is poorly understood. Approximately 15-18% of pediatric cancers arise in the context of hereditary cancer predisposition syndromes, such as Li-Fraumeni Syndrome, caused by germline TP53 (g TP53 ) variants. TP53 binds to LINE1 elements to suppress their transcription, and adult tumors with somatic TP53 mutations exhibit elevated TE activity. These findings suggest that g TP53 variants may disrupt TE regulation during development, predisposing tissues to malignant transformation. To investigate this, we characterized the germline and tumor TE landscape across a pediatric pan-cancer cohort and evaluated the impact of g TP53 variants. We identified TEs in 456 germline and 380 tumor samples. Germline ALU, LINE1, SVA elements were called using MELT, xTEA, and INSurVeyor, while tumor LINE1 elements were called with xTEA and TotalReCall. We excluded 96% of germline and 23% of tumor TEs classified as common (>3% of gnomAD or our additional cancer-free cohort (n=166)). We observed no difference in germline TE burden between g TP53 carriers and non-carriers, prompting us to examine insertion-site patterns. Motivated by prior findings of global germline methylation differences in g TP53 carriers, we tested if g TP53 variants alter germline insertion location. A support vector machine trained on TE distribution predicted g TP53 status with an AUPRC of 0.74, suggesting g TP53 variants influence the position of germline insertions. Germline TEs in cancer-free individuals affected regulatory regions governing cell cycle and mitotic pathways whereas germline TEs in the cancer cohort disrupted immune-related regulatory elements (FDR < 0.05). Preliminary evidence suggests immune pathways are altered in germline blood and fibroblast DNA, indicating a systemic effect. Half of tumors harboured at least one insertion, with epithelial-origin cancers containing more TEs, reflecting adults-onset cancers. As TEs are active in brain development, we analyzed an additional 102 medulloblastoma samples and found 97% contained no insertions. Unlike adult tumors, somatic or germline TP53 variants did not increase LINE1 insertion burden. Regulatory regions linked to metabolic pathways were affected in g TP53 carriers (FDR < 0.05). Overall, we found g TP53 variants do not increase germline or tumor TE burden but strongly influence the positional distribution of germline insertions. Tumors in the context of g TP53 variants contain TEs that affect metabolic regulatory regions , highlighting consequences of this altered germline architecture. This work enhances our understanding of tumour susceptibility and TP53 -associated cancers to guide future therapeutics.