Oncogenic Enhancers from Small Genomic Insertions

The noncoding regions of tumor cell genomes harbor a considerable fraction of total variation, but the functional contribution of such variants to tumorigenesis is ill-defined. Among these noncoding variants, somatic insertions are among the least well-characterized due to challenges with interpreting short-read DNA sequences. To address this, we have identified enhancer-associated small insertion variants across a spectrum of tumor cells by using ChIP-seq to enrich and sequence enhancer DNA, and a computational approach with multiple alignment procedures to identify small insertions. Among the 82 tumor genomes studied here, small insertions were frequently observed in enhancer DNA sequences located near known oncogenes. Further study of one such insertion, found in primary leukemia tumor genomes, revealed that it nucleates formation of an active enhancer that drives expression of the LMO2 oncogene. The catalogue of enhancer-associated small insertion variants described here provides a foundation for further investigating the functions of this class of variants across a range of human cancers. ChIP-Seq for H3K27ac in cancer cell lines