Abstract P3-04-10: Analysis of somatic transposable element insertions in a breast cancer genome
Authors: Paul R , Solzak JP , Chen Y-H , Hancock BA , Radovich M 
Published: February 2018

Abstract
Introduction: More than 50% of the human genome consists of transposable elements (TE). However most TEs are inactive and remain relatively stable among different human populations. However, some classes of retrotransposons consisting of Alu, SVA, ERV and L1s are active and believe to be involved in cancer. Commonly used bioinformatics pipelines of whole genome sequencing (WGS) data do not currently analyze for somatic TE insertions, and maybe missing an important class of somatic mutations. As a proof-of-concept, we analyzed the HCC1143 triple-negative breast cancer cell line along with a matched normal control to analyze for the presence of somatic TEs.
Methods: WGS data of the HCC1143 cell line along with the matched lymphoblastoid control cell line, HCC1143BL, were downloaded from the NCI GDC Commons. We used discordant read-pair (only one paired-end read matches to the reference genome) and split-read (part of a read matches to the reference) analysis to detect novel somatic TE insertion sites in genes known to play important roles in cancer proliferation.
Results: Most TE insertions are heterogenous in nature such that they insert only in a small subset of the cells. Therefore by comparing the number of split reads and discordant reads to the total number of reads the heterogenity of the insertion can be inserted. The discordant and split read analysis revealed about 30 high confidence hits. A subset of the high confidence hits were validated experimentally using PCR amplification and gel electrophoresis. About 85% of the hits were successfully validated. A subset of the validated hits known to be relevant to breast cancer have been shown in Table 1.
Table 1 - Validated somatic TE insertion locations in HCC1143 cell lineGeneFunctionChromosome numberStart positionStop position% heterogeneity in tumor line = (split_reads + discordant_reads)*2 / total_reads% heterogeneity in blood line = (split_reads + discordant_reads)*2 / total_readsPBRM1Chromatin remodeling352662648526635501001.1GLIS3Overexpressed in TNBC/involved in Wnt pathway942369794237291402.5XPR1Receptor of murine leukemia viruses1180857399180857714253.2CSMD1Tumor suppressor gene84452610445304323.520TMEM181Involved in tamoxifen response61590532671590538254.710
Discussion: Using the approach described above, we were able to detect somatic TEs within several genes known to be involved in cancer. PBRM1, a gene involved in chromatin remodeling, was found to have several exons replaced with a TE insert. Other genes such as CSMD1 is a known tumor suppressor gene, and TMEM181 which is involved in tamoxifen response. These results suggest that TE insertions may be involved in cancer biology. Therefore, TE insert prediction can serve as useful biomarkers for early detection and have precision medicine implications in the treatment of breast cancer. Analyses in additional breast cancer patient genomes is currently underway.
Citation Format: Paul R, Solzak JP, Chen Y-H, Hancock BA, Radovich M. Analysis of somatic transposable element insertions in a breast cancer genome [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-04-10.