The mutational landscape and functional effects of noncoding ultraconserved elements in human cancers

Bayraktar, R; Tang, Y; Dragomir, MP; Ivan, C; Peng, X; Fabris, L; Zhang, J; Carugo, A; Aneli, S; Liu, J; Chen, MM; Srinivasan, S; Sahnoune, I; Bayraktar, E; Akdemir, KC; Chen, M; Narayanan, P; Huang, W; Ott, LF; Eterovic, AK; Villarreal, OE; Mohammad, MM; Peoples, MD; Walsh, DM; Hernandez, JA; Morgan, MB; Shaw, KR; Davis, JS; Menter, D; Tam, CS; Yeh, P; Dawson, SJ; Rassenti, LZ; Kipps, TJ; Kunej, T; Estrov, Z; Joosse, SA; Pagani, L; Alix-Panabi&#232;res, C; Pantel, K; Ferajoli, A; Futreal, A; Wistuba, II; Radovich, M; Kopetz, S; Keating, MJ; Draetta, GF; Mattick, JS; Liang, H; Calin, GA

Author(s): Bayraktar, R; Tang, Y; Dragomir, MP; Ivan, C; Peng, X; Fabris, L; Zhang, J; Carugo, A; Aneli, S; Liu, J; Chen, MM; Srinivasan, S; Sahnoune, I; Bayraktar, E; Akdemir, KC; Chen, M; Narayanan, P; Huang, W; Ott, LF; Eterovic, AK; Villarreal, OE; Mohammad, MM; Peoples, MD; Walsh, DM; Hernandez, JA; Morgan, MB; Shaw, KR; Davis, JS; Menter, D; Tam, CS; Yeh, P; Dawson, SJ; Rassenti, LZ; Kipps, TJ; Kunej, T; Estrov, Z; Joosse, SA; Pagani, L; Alix-Panabières, C; Pantel, K; Ferajoli, A; Futreal, A; Wistuba, II; Radovich, M; Kopetz, S; Keating, MJ; Draetta, GF; Mattick, JS; Liang, H; Calin, GA;
Details: Publication Year 2025-02-21,Volume 11,Issue #8,Page eado2830
Journal Title: Science Advances
Publication Type: Research article
Abstract: 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 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.
Keywords: Humans; *Mutation; *Neoplasms/genetics; *Conserved Sequence; *MicroRNAs/genetics; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; RNA, Untranslated/genetics; Cell Proliferation/genetics; Animals; Mice
Department(s): Haematology; Medical Oncology; Laboratory Research
Publisher's Version: https://doi.org/10.1126/sciadv.ado2830
Open Access at Publisher's Site: https://doi.org/10.1126/sciadv.ado2830
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-03-14 07:06:21

Last Modified: 2025-03-14 07:08:56