TY  - JOUR
AU  - Bayraktar, Recep
AU  - Tang, Yitao
AU  - Dragomir, Mihnea-Paul
AU  - Ivan, Cristina
AU  - Peng, Xinxin
AU  - Fabris, Linda
AU  - Zhang, Jianhua
AU  - Carugo, Alessandro
AU  - Aneli, Serena
AU  - Liu, Jintan
AU  - Chen, Mei-Ju M
AU  - Srinivasan, Sanjana
AU  - Sahnoune, Iman
AU  - Bayraktar, Emine
AU  - Akdemir, Kadir C
AU  - Chen, Meng
AU  - Narayanan, Pranav
AU  - Huang, Wilson
AU  - Ott, Leonie Florence
AU  - Eterovic, Agda Karina
AU  - Villarreal, Oscar Eduardo
AU  - Mohammad, Mohammad Moustaf
AU  - Peoples, Michael D
AU  - Walsh, Danielle M
AU  - Hernandez, Jon Andrew
AU  - Morgan, Margaret B
AU  - Shaw, Kenna R
AU  - Davis, Jennifer S
AU  - Menter, David
AU  - Tam, Constantine S
AU  - Yeh, Paul
AU  - Dawson, Sarah-Jane
AU  - Rassenti, Laura Z
AU  - Kipps, Thomas J
AU  - Kunej, Tanja
AU  - Estrov, Zeev
AU  - Joosse, Simon A
AU  - Pagani, Luca
AU  - Alix-Panabières, Catherine
AU  - Pantel, Klaus
AU  - Ferajoli, Alessandra
AU  - Futreal, Andrew
AU  - Wistuba, Ignacio I
AU  - Radovich, Milan
AU  - Kopetz, Scott
AU  - Keating, Michael J
AU  - Draetta, Giulio F
AU  - Mattick, John S
AU  - Liang, Han
AU  - Calin, George A
TI  - The mutational landscape and functional effects of noncoding ultraconserved elements in human cancers.
JO  - Science advances
VL  - 11
IS  - 8
SN  - 2375-2548
CY  - Washington, DC [u.a.]
PB  - Assoc.
M1  - DKFZ-2025-00401
SP  - eado2830
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Mutation
KW  - Neoplasms: genetics
KW  - Conserved Sequence
KW  - MicroRNAs: genetics
KW  - Cell Line, Tumor
KW  - Gene Expression Regulation, Neoplastic
KW  - RNA, Untranslated: genetics
KW  - Cell Proliferation: genetics
KW  - Animals
KW  - Mice
KW  - MicroRNAs (NLM Chemicals)
KW  - RNA, Untranslated (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39970212
DO  - DOI:10.1126/sciadv.ado2830
UR  - https://inrepo02.dkfz.de/record/298981
ER  -