Program > Browse abstracts by author > Majeed Safa

Background: Transposable elements (TEs) are dynamic repetitive regions which generate mutations and structural variants. TP53 plays a crucial role in suppressing TE movement to maintain genomic stability. The relationship between TP53 and TEs has been extensively studied in tumours, but not the germline. Individuals with germline TP53 pathogenic variants have Li-Fraumeni Syndrome (LFS), a cancer predisposition syndrome with a high lifetime risk of cancer in various tissues. This study aims to characterize the TE landscape in individuals with Li-Fraumeni Syndrome and determine how this may contribute to increased cancer risk.

Methods: MELT and xTea were used to identify TEs in young adults with (n=64) or without (n=79) a germline TP53 variant. TE calls were merged with SURVIVOR and variants were annotated with AnnotSV. To assess the influence of TP53 on TE location, we quantified TEs across genomic windows and identified the top 200 significantly different regions with the Mann-Whitney U test, adjusting for multiple comparisons. We used these regions to develop a gradient-boosted tree model with 5-fold cross-validation to predict TP53 status.

Results: Individuals with germline TP53 variants harboured significantly fewer ALU and LINE1 elements in their germline genome compared to the control dataset (p<0.001). The phenomenon was consistent across chromosomes and significant in chromosomes 5 and 11 (FDR<0.05). A gradient-boosted tree model was able to differentiate patients with and without a germline TP53 variant with an AUC of 0.7 on the unseen test set.

Conclusion: Germline TP53 variants may effect the frequency and location of TE insertions, which may influence nearby genomic variations and lead to cancer development. Analyzing TEs in individuals with LFS will enhance our understanding of accelerated cancer development in these patients, informing future research for diagnostic and therapeutic approaches.