ArticleScience advances2025
The mutational landscape and functional effects of noncoding ultraconserved elements in human cancers.
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Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8citing papers in PubMed
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Who cites it
8 citing papers in PubMed.
- Characterizing highly conserved fragments in 3'UTRs via statistical and transfer learning approaches.NAR genomics and bioinformatics · 2026Article
- ARID1B damaging variants from more than one million genomes, cause human diseases by impairing protein-protein interactions, stability, and regulation.bioRxiv : the preprint server for biology · 2026Article
- Splicing of ultraconserved poison exons controls mitotic fidelity and stem cell viability.bioRxiv : the preprint server for biology · 2026Article
- Genomic context of mutations in MIR142 in blood cancers: summary and integrative analysis.Cellular & molecular biology letters · 2026Review
- MicroRNAs in oncology: a translational perspective in the era of AI.Nature reviews. Clinical oncology · 2026Review
- miRNA gene mutations commonly disrupt the proper functioning of miRNA genes.Science advances · 2026Article
- Preliminary examination of noncoding mutations of esophageal squamous cell carcinoma in African Americans.Frontiers in genetics · 2026Article
- DNA methylation profile to aid in the diagnosis of pancreatic ductal adenocarcinoma and its role in disease progression.Epigenomics · 2025Review
Corrections and comments
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Authors and funding
50 authors.
Recep BayraktarDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-8227-2055
Yitao TangMD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Houston, Houston, TX 77030, USA.ORCID 0000-0002-5340-1890
Mihnea P DragomirDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-5550-3516
Cristina IvanDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-4848-0168
Xinxin PengDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-1503-5404
Linda FabrisDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jianhua ZhangDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0001-5412-9860
Alessandro CarugoTRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0001-5182-3320
Serena AneliDepartment of Biology, University of Padova, Padova, Italy.ORCID 0000-0003-4303-2507
Jintan LiuMD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Houston, Houston, TX 77030, USA.ORCID 0000-0001-6609-9777
Mei-Ju M ChenDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-8721-0304
Sanjana SrinivasanDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-1439-1052
Iman SahnouneDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Emine BayraktarMD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Houston, Houston, TX 77030, USA.ORCID 0000-0002-5189-1507
Kadir C AkdemirDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Meng ChenDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-2449-5904
Pranav NarayananDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0009-0009-5045-4856
Wilson HuangDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Leonie Florence OttDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-6308-0242
Agda Karina EterovicInstitute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Oscar Eduardo VillarrealDepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-4138-2696
Mohammad Moustaf MohammadInstitute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Michael D PeoplesDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0001-5233-2603
Danielle M WalshDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0001-8141-1685
Jon Andrew HernandezDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0009-0009-5557-1226
Margaret B MorganInstitute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-0579-0975
Kenna R ShawInstitute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jennifer S DavisDepartment of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0001-9456-1682
David MenterDepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Constantine S TamPeter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia.
Paul YehPeter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia.ORCID 0000-0002-4172-3614
Sarah-Jane DawsonPeter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia.ORCID 0000-0002-8276-0374
Laura Z RassentiCenter for Novel Therapeutics, Moores Cancer Center, University of California San Diego, La Jolla, CA 92037, USA.
Thomas J KippsCenter for Novel Therapeutics, Moores Cancer Center, University of California San Diego, La Jolla, CA 92037, USA.ORCID 0000-0002-0064-4549
Tanja KunejDepartment of Animal Science, Biotechnical Faculty, University of Ljubljana, Groblje 3, SI-1230 Domzale, Slovenia.ORCID 0000-0002-0465-1762
Zeev EstrovDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-1623-3613
Simon A JoosseDepartment of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.ORCID 0000-0002-4296-5615
Luca PaganiDepartment of Biology, University of Padova, Padova, Italy.ORCID 0000-0002-6639-524X
Catherine Alix-PanabièresThe Laboratory Rare Human Circulating Cells and Liquid Biopsy, The University Medical Center of Montpellier, Montpellier, France.ORCID 0000-0002-6401-2903
Klaus PantelDepartment of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Alessandra FerajoliDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0001-9547-4193
Andrew FutrealDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0001-8663-2671
Ignacio I WistubaDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0003-3365-6340
Milan RadovichCaris Life Science, Irving, TX 75039, USA.
Scott KopetzDepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0001-9647-3416
Michael J KeatingDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-9121-6450
Giulio F DraettaDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0001-5225-9610
John S MattickSchool of Biotechnology and Biomolecular Sciences, UNSW Sydney, Kensington, New South Wales 2052, Australia.
Han LiangDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0001-7633-286X
George A CalinDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-7427-0578
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Fabien Delerue · 1985 to 2026
$290.8MTropism Enhanced Oncolytic Adenovirus for the Treatment of Brain TumorsP50CA127001 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Juan Fueyo · 2008 to 2026
$41.2MUPR/MDACC Partnership for Excellence in Cancer Research(Parent Grant U54 CA096297)U54CA096297 · NCI · UNIVERSITY OF PUERTO RICO MED SCIENCES · PI SHARON Hermes GIORDANO, REYNOLD Eugenio LOPEZ-ENRIQUEZ · 2002 to 2026
$36.9MUPR/MDACC Partnership for Excellence in Cancer Research (Luis Segarra supplement)U54CA096300 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI SHARON Hermes GIORDANO · 2002 to 2026
$23.8MThe University of Texas MD Anderson Cancer Center SPORE in Ovarian CancerP50CA281701 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI ROBERT C BAST, ANIL K SOOD · 2023 to 2026
$11.5MThe University of Texas MD Anderson Cancer Center SPORE in MelanomaP50CA221703 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI DAVIES, MICHAEL · 2019 to 2023
$10.3MThe Cancer Proteome Atlas: an Integrated Bioinformatics Resource for Functional Cancer Proteomic DataU24CA264128 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Rehan Akbani, Han Liang · 2022 to 2026
$3.9MSystematic Characterization and Targeting of Neomorphic Drivers in CancerU01CA281902 · NCI · OREGON HEALTH & SCIENCE UNIVERSITY · PI Benjamin Deneen, Han Liang · 2023 to 2026
$3.5MHarnessing the nervous system to overcome resistance to immunotherapy in oral cancerR01DE032018 · NIDCR · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Moran Amit, George A. Calin · 2022 to 2026
$3.5MProtein-coding and non-coding RNA biomarkers for early detection of CLLR01CA182905 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI ABRUZZO, LYNNE V., CALIN, GEORGE A. · 2014 to 2018
$2.9MCharacterization and modeling of m6A RNA methylation in cancerR01CA251150 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI LIANG, HAN · 2020 to 2024
$2.7MMechanistic maps of adaptive responses to therapeutic stress to optimize combination therapies.U01CA253472 · NCI · OREGON HEALTH & SCIENCE UNIVERSITY · PI KORKUT, ANIL, LIANG, HAN · 2021 to 2025
$2.6MNCI NIH HHS P30 CA016672NCI NIH HHS P50 CA127001NCI NIH HHS P50 CA221703NCI NIH HHS P50 CA281701NCI NIH HHS R01 CA182905NCI NIH HHS R01 CA222007NCI NIH HHS R01 CA251150NCI NIH HHS U01 CA253472NCI NIH HHS U01 CA281902NCI NIH HHS U24 CA264128NCI NIH HHS U54 CA096297NCI NIH HHS U54 CA096300NIDCR NIH HHS R01 DE032018NIGMS NIH HHS R01 GM122775
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.
Indexed as
Conserved SequenceDNA, IntergenicMutationNeoplasmsAnimalsCell Line, TumorCell ProliferationGene Expression Regulation, NeoplasticHumansMiceMicroRNAsDNA, IntergenicMicroRNAs
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