Abstract More than 50% of the human genome consists of transposable elements (TE). However only certain classes of retrotransposons (ALU, SVA, ERV and L1) are believed to be active. They transpose using an RNA intermediate causing target-site duplications along with a poly-A tail. They can also insert into intronic regions and disrupt normal transcription of protein-coding genes. However, most TEs are repressed using various epigenetic mechanisms such as DNA methylation, histone modifications and RNA silencing. The piRNA pathway also plays an important role in retrotransposon silencing by establishing a repressive chromatin state. In this study, somatic and germline TE insertions in 77 TCGA breast cancer cases were characterized. These studies have revealed that somatic TEs can insert into intronic regions of tumor suppressor genes such as LRP1B, RAD51B and WNK2. Characterization of germline TE insertions, reveal insertions in intronic regions of predisposition genes such as CDH1 and BRCA2. Analysis of germline SNPs in high somatic TE patients reveals the presence of deleterious variants in genes such as NRDE2, RAD51C and DDX3X which are known to regulate TEs using RNA silencing via the piRNA pathway and other DNA-damage response mechanisms. Patients having high somatic TE insertions were found to have lower age of diagnosis suggesting a role in the early onset of cancer (median age of patients with high TE=43.37yrs; low TE=59.77yrs, Wilcoxan p=0.023). Further comparison of somatic TE insertion burden against somatic point-mutation burden revealed an inverse correlation suggesting analysis of TE insertions is indispensable to get the complete mutation profile of breast cancer genomes. Citation Format: Paul R, Solzak JP, Radovich M. Whole genome sequence analysis of 77 breast cancer patients reveal increased somatic transposable element insertions responsible for early onset of cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-05.