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Article

Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer

1
Department of Medicine A, Hematology, Oncology, Hemostaseology and Pneumology, University Hospital Münster, 48149 Münster, Germany
2
Faculty of Medicine, Institute of Bioinformatics, University of Münster, 48149 Münster, Germany
3
Institute of Evolutionary Biology, CSIC-Unversitat Pompeu Frabra, 08002 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Luísa Romão
Biomedicines 2021, 9(6), 618; https://doi.org/10.3390/biomedicines9060618
Received: 18 April 2021 / Revised: 22 May 2021 / Accepted: 27 May 2021 / Published: 29 May 2021
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
Upstream open reading frame (uORF)-mediated translational control has emerged as an important regulatory mechanism in human health and disease. However, a systematic search for cancer-associated somatic uORF mutations has not been performed. Here, we analyzed the genetic variability at canonical (uAUG) and alternative translational initiation sites (aTISs), as well as the associated upstream termination codons (uStops) in 3394 whole-exome-sequencing datasets from patient samples of breast, colon, lung, prostate, and skin cancer and of acute myeloid leukemia, provided by The Cancer Genome Atlas research network. We found that 66.5% of patient samples were affected by at least one of 5277 recurrent uORF-associated somatic single nucleotide variants altering 446 uAUG, 347 uStop, and 4733 aTIS codons. While twelve uORF variants were detected in all entities, 17 variants occurred in all five types of solid cancer analyzed here. Highest frequencies of individual somatic variants in the TLSs of NBPF20 and CHCHD2 reached 10.1% among LAML and 8.1% among skin cancer patients, respectively. Functional evaluation by dual luciferase reporter assays identified 19 uORF variants causing significant translational deregulation of the associated main coding sequence, ranging from 1.73-fold induction for an AUG.1 > UUG variant in SETD4 to 0.006-fold repression for a CUG.6 > GUG variant in HLA-DRB1. These data suggest that somatic uORF mutations are highly prevalent in human malignancies and that defective translational regulation of protein expression may contribute to the onset or progression of cancer. View Full-Text
Keywords: gene expression regulation; upstream open reading frame; cancer; whole-exome-sequencing; translational control gene expression regulation; upstream open reading frame; cancer; whole-exome-sequencing; translational control
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MDPI and ACS Style

Jürgens, L.; Manske, F.; Hubert, E.; Kischka, T.; Flötotto, L.; Klaas, O.; Shabardina, V.; Schliemann, C.; Makalowski, W.; Wethmar, K. Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer. Biomedicines 2021, 9, 618. https://doi.org/10.3390/biomedicines9060618

AMA Style

Jürgens L, Manske F, Hubert E, Kischka T, Flötotto L, Klaas O, Shabardina V, Schliemann C, Makalowski W, Wethmar K. Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer. Biomedicines. 2021; 9(6):618. https://doi.org/10.3390/biomedicines9060618

Chicago/Turabian Style

Jürgens, Lara, Felix Manske, Elvira Hubert, Tabea Kischka, Lea Flötotto, Oliver Klaas, Victoria Shabardina, Christoph Schliemann, Wojciech Makalowski, and Klaus Wethmar. 2021. "Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer" Biomedicines 9, no. 6: 618. https://doi.org/10.3390/biomedicines9060618

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