The mutational landscape and functional effects of noncoding ultraconserved elements in human cancers
Recep Bayraktar, Yitao Tang, Mihnea P. Dragomir, Cristina Ivan, Xinxin Peng, Linda Fabris, Jianhua Zhang, Alessandro Carugo, Serena Aneli, Jintan Liu, Mei-Ju M. Chen, Sanjana Srinivasan, Iman Sahnoune, Emine Bayraktar, Kadir C. Akdemir, Meng Chen, Pranav Narayanan, Wilson Huang, Leonie Florence Ott, Agda Karina Eterovic, Oscar Eduardo Villarreal, Mohammad Moustaf Mohammad, Michael D. Peoples, Danielle M. Walsh, Jon Andrew Hernandez, Margaret B. Morgan, Kenna R. Shaw, Jennifer S. Davis, David Menter, Constantine S. Tam, Paul Yeh, Sarah-Jane Dawson, Laura Z. Rassenti, Thomas J. Kipps, Tanja Kunej, Zeev Estrov, Simon A. Joosse, Luca Pagani, Catherine Alix-Panabières, Klaus Pantel, Alessandra Ferajoli, Andrew Futreal, Ignacio I. Wistuba, Milan Radovich, Scott Kopetz, Michael J. Keating, Giulio F. Draetta, John S. Mattick, Han Liang, George A. CalinThe 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 more than 3000 patients with cancer of 13,736 UCEs and demonstrate that ncUCE somatic alterations are common. Using a multiplexed CRISPR knockout screen in colorectal cancer cells, we show that the loss of several altered ncUCEs significantly affects 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 miRNAs, resulting in the down-regulation of the mature transcript. These results provide systematic evidence that specific ncUCEs play diverse regulatory roles in cancer.