The Mutational Landscape and Functional Effects of Noncoding Ultraconserved Elements in Human Cancers
The mutational landscape of phylogenetically ultraconserved elements (UCEs), especially those in noncoding DNAs (ncUCEs), and their functional relevance in cancers remain poorly characterized. Here we perform a systematic analysis of whole-genome and in-house targeted UCE sequencing datasets from over 3000 patients of 13,736 UCEs and demonstrate that ncUCE somatic alterations are pervasive. Using a multiplexed CRISPR knockout screen in colorectal cancer cells, we show that the loss of several altered ncUCEs significantly impacts cell proliferation. In-depth functional studies in vitro and in vivo further reveal that specific ncUCEs can be enhancers of tumor suppressors (such as ARID1B) and silencers of oncogenic proteins (such as RPS13). Moreover, several miRNAs located in ncUCEs are recurrently mutated: mutations in miR-142 locus can affect the Drosha-mediated processing of precursor-(pre)-miRNAs, resulting in the downregulation of the mature transcript. These results provide the first systematic evidence that specific ncUCEs play important regulatory roles in cancer.