Abstract 3148: Mapping mobile DNAs in human cancer cell lines.

Abstract

Abstract Genomic instability represented by genetic and epigenetic changes is a hallmark of oncogenesis and tumor progression. The study of genomic instability using conventional methods has necessarily been restricted to regions of unique DNA and excludes repetitive DNA sequences. Repeat elements derived from mobile DNAs comprise a large portion of the human genome and are known sources of genetic variation in humans. Active transposable elements (TE) have recently been shown to cause genetic heterogeneity in tumors through somatic insertions. The functional impact of inherited and somatically acquired TE in cancer development and progression remains unproven. To begin to understand the roles of these mobile DNA elements in transformed cells, we used a novel genomic method to map TEs in a panel of well-characterized human cancer cell lines. Using transposon insertion profiling (TIP)-chip we discover transposition competent families of L1 and Alu TEs. This technique recovered many known reference and polymorphic insertions, novel polymorphisms shared by unrelated tumor cell lines, as well as unique, potentially tumor-specific insertions. Insertions were discovered in several important oncogenes such as KRAS, ALK and BRAF. Most insertions discovered were intronic or intergenic, however 16 TEs were putative exonic. Analysis of the novel and polymorphic insertions revealed a relative enrichment of L1 and Alu insertions in cancer gene loci that are mutated in human cancers or implicated in tumor development in forward genetic screens (p=7.74e-10). We also report associations of individual insertion sites with cellular phenotypes, including DNA methylation status, RNA and protein expression, and drug sensitivities. Epigenetic, gene expression and gene pathway associations were evaluated to delineate local (cis) from pathway (trans) effects. We identified several examples of cis effects of TEs on gene structure as well as nearly 250 curated proliferation pathways affected by a TE insertion. These data suggest that TE insertions may function locally to alter genomic structure or act more globally in concert with other genetic mechanisms to promote the development and progression of several common tumor types. Citation Format: John G. Zampella, Wan Rho Yang, Nemanja Rodric, Cheng Ran Lisa Huang, Jane Welch, Veena P. Gnanakkan, Toby C. Cornish, Jef D. Boeke, Kathleen H. Burns. Mapping mobile DNAs in human cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3148. doi:10.1158/1538-7445.AM2013-3148