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

被引：0

作者：

Bayraktar, Recep ^{[1
,2
]}

Tang, Yitao ^{[2
,3
]}

Dragomir, Mihnea P. ^{[4
,5
,6
,7
,8
,9
]}

Ivan, Cristina ^{[4
,10
,11
]}

Peng, Xinxin ^{[3
]}

Fabris, Linda ^{[1
]}

Zhang, Jianhua ^{[12
]}

Carugo, Alessandro ^{[13
]}

Aneli, Serena ^{[14
,15
]}

Liu, Jintan ^{[2
,12
]}

Chen, Mei-Ju M. ^{[3
]}

Srinivasan, Sanjana ^{[12
]}

Sahnoune, Iman ^{[1
]}

Bayraktar, Emine ^{[2
,10
,16
]}

Akdemir, Kadir C. ^{[12
,17
]}

Chen, Meng ^{[1
]}

Narayanan, Pranav ^{[1
,18
]}

Huang, Wilson ^{[1
,19
,20
]}

Ott, Leonie Florence ^{[4
,21
]}

Eterovic, Agda Karina ^{[22
,23
]}

Villarreal, Oscar Eduardo ^{[24
]}

Mohammad, Mohammad Moustaf ^{[22
]}

Peoples, Michael D. ^{[12
,13
]}

Walsh, Danielle M. ^{[25
]}

Hernandez, Jon Andrew ^{[25
]}

Morgan, Margaret B. ^{[22
]}

Shaw, Kenna R. ^{[22
]}

Davis, Jennifer S. ^{[26
]}

Menter, David ^{[24
]}

Tam, Constantine S. ^{[27
,28
,36
,37
]}

Yeh, Paul ^{[27
,28
,38
,39
]}

Dawson, Sarah-Jane ^{[27
,28
]}

Rassenti, Laura Z. ^{[29
]}

Kipps, Thomas J. ^{[29
]}

Kunej, Tanja ^{[30
]}

Estrov, Zeev ^{[25
]}

Joosse, Simon A. ^{[21
,31
]}

Pagani, Luca ^{[14
]}

Alix-Panabieres, Catherine ^{[32
]}

Pantel, Klaus ^{[21
]}

Ferajoli, Alessandra ^{[25
]}

Futreal, Andrew ^{[12
]}

Wistuba, Ignacio I. ^{[1
]}

Radovich, Milan ^{[11
,33
]}

Kopetz, Scott ^{[24
]}

Keating, Michael J. ^{[25
]}

Draetta, Giulio F. ^{[12
]}

Mattick, John S. ^{[34
]}

Liang, Han ^{[3
,35
]}

Calin, George A. ^{[1
,4
,10
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[2] MD Anderson Canc Ctr, UTHlth Grad Sch Biomed Sci Houston, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA

[5] Charite Univ Med Berlin, Inst Pathol, Charitepl 1, D-12203 Berlin, Germany

[6] Free Univ Berlin, Charitepl 1, D-10117 Berlin, Germany

[7] Humboldt Univ, CCM, Charitepl 1, D-10117 Berlin, Germany

[8] Charite, Berlin Inst Hlth, Charitepl 1, D-10117 Berlin, Germany

[9] Heidelberg & German Canc Consortium DKTK, German Canc Res Ctr DKFZ, Partner Site, Berlin, Germany

[10] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNAs, Houston, TX 77030 USA

[11] Caris Life Sci, Irving, TX 75039 USA

[12] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[13] Univ Texas MD Anderson Canc Ctr, TRACT Platform, Houston, TX 77030 USA

[14] Univ Padua, DEPT BIOL, I-35131 Padua, Italy

[15] Univ Turin, Dept Publ Hlth Sci & Pediat, I-10126 Turin, Italy

[16] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77030 USA

[17] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA

[18] Rice Univ, Dept BioSci, Houston, TX 77005 USA

[19] Johns Hopkins Univ, Johns Hopkins Phys Sci Oncol Ctr, 3400 N Charles St, Baltimore, MD 21218 USA

[20] Johns Hopkins Univ, Inst NanoBioTechnol, 3400 N Charles St, Baltimore, MD 21218 USA

[21] Univ Med Ctr Hamburg Eppendorf, Dept Tumor Biol, Hamburg, Germany

[22] Univ Texas MD Anderson Canc Ctr, Inst Personalized Canc Therapy, Houston, TX 77030 USA

[23] Viracor Eurofins Clin Diagnost, Lees Summit, MO 64086 USA

[24] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA

[25] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[26] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[27] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[28] Univ Melbourne, Melbourne, Vic, Australia

[29] Univ Calif San Diego, Ctr Novel Therapeut, Moores Canc Ctr, La Jolla, CA 92037 USA

[30] Univ Ljubljana, Biotech Fac, Dept Anim Sci, Groblje 3, SI-1230 Domzale, Slovenia

[31] Univ Med Ctr Hamburg Eppendorf, Mildred Scheel Canc Career Ctr HaTriCS4, Hamburg, Germany

[32] Univ Med Ctr Montpellier, Lab Rare Human Circulating Cells & Liquid Biopsy, Montpellier, France

[33] Indiana Univ Sch Med, Dept Surg, Div Gen Surg, Indianapolis, IN 46202 USA

[34] UNSW Sydney, Sch Biotechnol & Biomol Sci, Kensington, NSW 2052, Australia

[35] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[36] Alfred Hosp, Melbourne, Vic, Australia

[37] Monash Univ, Melbourne, Vic, Australia

[38] Monash Hlth, Monash Haematol, Clayton, Vic, Australia

[39] Monash Univ, Sch Clin Sci, Dept Med, Monash Hlth, Clayton, Vic, Australia

来源：

SCIENCE ADVANCES | 2025年 / 11卷 / 08期

关键词：

SOMATIC MUTATIONS; SIGNATURES; ENHANCERS; VARIANTS; DATABASE; CATALOG; PROTEIN; DRIVER; CELLS; SNP;

D O I：

10.1126/sciadv.ado2830

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：17

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