Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer
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 (uA...
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MDPI AG
2021-05-01
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| Online Access: | https://www.mdpi.com/2227-9059/9/6/618 |
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| author | Lara Jürgens Felix Manske Elvira Hubert Tabea Kischka Lea Flötotto Oliver Klaas Victoria Shabardina Christoph Schliemann Wojciech Makalowski Klaus Wethmar |
| author_facet | Lara Jürgens Felix Manske Elvira Hubert Tabea Kischka Lea Flötotto Oliver Klaas Victoria Shabardina Christoph Schliemann Wojciech Makalowski Klaus Wethmar |
| author_sort | Lara Jürgens |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T10:53:33Z |
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| language | English |
| last_indexed | 2024-03-10T10:53:33Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-51576d248f9c4c60b0ae57c9e59e687b2023-11-21T22:03:02ZengMDPI AGBiomedicines2227-90592021-05-019661810.3390/biomedicines9060618Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human CancerLara Jürgens0Felix Manske1Elvira Hubert2Tabea Kischka3Lea Flötotto4Oliver Klaas5Victoria Shabardina6Christoph Schliemann7Wojciech Makalowski8Klaus Wethmar9Department of Medicine A, Hematology, Oncology, Hemostaseology and Pneumology, University Hospital Münster, 48149 Münster, GermanyFaculty of Medicine, Institute of Bioinformatics, University of Münster, 48149 Münster, GermanyDepartment of Medicine A, Hematology, Oncology, Hemostaseology and Pneumology, University Hospital Münster, 48149 Münster, GermanyFaculty of Medicine, Institute of Bioinformatics, University of Münster, 48149 Münster, GermanyDepartment of Medicine A, Hematology, Oncology, Hemostaseology and Pneumology, University Hospital Münster, 48149 Münster, GermanyDepartment of Medicine A, Hematology, Oncology, Hemostaseology and Pneumology, University Hospital Münster, 48149 Münster, GermanyInstitute of Evolutionary Biology, CSIC-Unversitat Pompeu Frabra, 08002 Barcelona, SpainDepartment of Medicine A, Hematology, Oncology, Hemostaseology and Pneumology, University Hospital Münster, 48149 Münster, GermanyFaculty of Medicine, Institute of Bioinformatics, University of Münster, 48149 Münster, GermanyDepartment of Medicine A, Hematology, Oncology, Hemostaseology and Pneumology, University Hospital Münster, 48149 Münster, GermanyUpstream 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.https://www.mdpi.com/2227-9059/9/6/618gene expression regulationupstream open reading framecancerwhole-exome-sequencingtranslational control |
| spellingShingle | Lara Jürgens Felix Manske Elvira Hubert Tabea Kischka Lea Flötotto Oliver Klaas Victoria Shabardina Christoph Schliemann Wojciech Makalowski Klaus Wethmar Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer Biomedicines gene expression regulation upstream open reading frame cancer whole-exome-sequencing translational control |
| title | Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer |
| title_full | Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer |
| title_fullStr | Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer |
| title_full_unstemmed | Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer |
| title_short | Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer |
| title_sort | somatic functional deletions of upstream open reading frame associated initiation and termination codons in human cancer |
| topic | gene expression regulation upstream open reading frame cancer whole-exome-sequencing translational control |
| url | https://www.mdpi.com/2227-9059/9/6/618 |
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