Synonymous mutations that regulate translation speed might play a non-negligible role in liver cancer development

Abstract Background Synonymous mutations do not change the protein sequences. Automatically, they have been regarded as neutral events and are ignored in the mutation-based cancer studies. However, synonymous mutations will change the codon optimality, resulting in altered translational velocity. Methods We fully utilized the transcriptome and translatome of liver cancer and normal tissue from ten patients. We profiled the mutation spectrum and examined the effect of synonymous mutations on translational velocity. Results Synonymous mutations that increase the codon optimality significantly enhanced the translational velocity, and were enriched in oncogenes. Meanwhile, synonymous mutations decreasing codon optimality slowed down translation, and were enriched in tumor suppressor genes. These synonymous mutations significantly contributed to the translational changes in tumor samples compared to normal samples. Conclusions Synonymous mutations might play a role in liver cancer development by altering codon optimality and translational velocity. Synonymous mutations should no longer be ignored in the genome-wide studies.

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Genome-wide transcriptome and translatome analyses reveal the role of protein extension and domestication in liver cancer oncogenesis

10.1101/2021.02.10.430565 ◽

2021 ◽

Author(s):

Nima Wang ◽

Dalei Wang

Keyword(s):

Natural Selection ◽

Liver Cancer ◽

Stop Codon ◽

Protein Sequences ◽

Normal Tissues ◽

Genome Wide ◽

Cancer Field ◽

Tumor Tissues ◽

Translation Signals

ABSTRACTOne gene could be transcribed to different RNA isoforms, and then produce various forms of protein sequences. This mechanism largely diversifies the cellular pool and allows natural selection to select from a wider range of substrates. Most of the deleterious changes should be either purged or only be observed in patients with deficiencies or diseases. In the cancer field, the “intra-gene” changes between tumor and normal tissues such as the alternative splicing, stop codon read-through, or protein domestication could not be captured by differential expression analyses. In this work, we collected public transcriptome and translatome data from ten patients with liver cancer, and performed genome-wide comparison on the stop codon read-through and protein domestication events. Both events could diversify the proteome without changing the genome sequence. Surprisingly, we found that compared to normal tissues, the tumor tissues globally have significantly higher occurrence of stop codon read-through events. Similarly, the translation signals of non-coding repetitive elements (protein domestication) are elevated in tumor samples. These read-through and domestication events show limited overlapping across the ten patients, suggesting the randomness of the occurrence. It also indicates that these tumor-specific read-through and domestication events should be deleterious, and should be purged by natural selection if they are not collected timely. Our work manifests the role of protein extension and domestication in liver cancer oncogenesis, and adds new aspects to the cancer field.

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Faculty Opinions recommendation of Senescence surveillance of pre-malignant hepatocytes limits liver cancer development.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13371985.14870095 ◽

2012 ◽

Author(s):

Alberto Mantovani

Keyword(s):

Liver Cancer ◽

Cancer Development

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Faculty Opinions recommendation of Senescence surveillance of pre-malignant hepatocytes limits liver cancer development.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13371985.14742093 ◽

2011 ◽

Author(s):

Malcolm Alison

Keyword(s):

Liver Cancer ◽

Cancer Development

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P0075 Overexpression of niemann-pick type C2 protein inhibits cell proliferation and liver cancer development via modulating the ERK1/2 pathway

European Journal of Cancer ◽

10.1016/j.ejca.2015.06.049 ◽

2015 ◽

Vol 51 ◽

pp. e16

Author(s):

Y.J. Liao ◽

Y.H. Wang ◽

C.Y. Liao ◽

C.Y. Chen ◽

Y.M. Chen

Keyword(s):

Cell Proliferation ◽

Liver Cancer ◽

Cancer Development ◽

Niemann Pick

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Hepatic carboxylesterase 3 (Ces3/Tgh) is downregulated in the early stages of liver cancer development in the rat

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2016.08.006 ◽

2016 ◽

Vol 1862 (11) ◽

pp. 2043-2053 ◽

Cited By ~ 6

Author(s):

Ariel D. Quiroga ◽

María P. Ceballos ◽

Juan P. Parody ◽

Carla G. Comanzo ◽

Florencia Lorenzetti ◽

...

Keyword(s):

Liver Cancer ◽

Cancer Development ◽

Early Stages

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Association between expression of Carboxypeptidase 4 and stem cell markers and their clinical significance in liver cancer development

Journal of Cancer ◽

10.7150/jca.17060 ◽

2017 ◽

Vol 8 (1) ◽

pp. 111-116 ◽

Cited By ~ 4

Author(s):

Lichao Sun ◽

Chunguang Guo ◽

Joseph Burnett ◽

Jian Pan ◽

Zhihua Yang ◽

...

Keyword(s):

Stem Cell ◽

Liver Cancer ◽

Clinical Significance ◽

Cancer Development ◽

Stem Cell Markers ◽

Cell Markers

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Genome-Wide Screening of Genes Regulated by DNA Methylation in Colon Cancer Development

PLoS ONE ◽

10.1371/journal.pone.0046215 ◽

2012 ◽

Vol 7 (10) ◽

pp. e46215 ◽

Cited By ~ 25

Author(s):

Sándor Spisák ◽

Alexandra Kalmár ◽

Orsolya Galamb ◽

Barna Wichmann ◽

Ferenc Sipos ◽

...

Keyword(s):

Dna Methylation ◽

Colon Cancer ◽

Cancer Development ◽

Genome Wide

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Molecular genetics of meningiomas: a systematic review of the current literature and potential basis for future treatment paradigms

Neurosurgical FOCUS ◽

10.3171/2011.2.focus1117 ◽

2011 ◽

Vol 30 (5) ◽

pp. E7 ◽

Cited By ~ 35

Author(s):

Martin H. Pham ◽

Gabriel Zada ◽

Gina M. Mosich ◽

Thomas C. Chen ◽

Steven L. Giannotta ◽

...

Keyword(s):

Current Literature ◽

Tumor Suppressor Genes ◽

Association Studies ◽

Treatment Strategies ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Genetic Abnormalities ◽

Molecular Therapies ◽

Potential Basis ◽

Skull Base Meningiomas

Although a majority of meningiomas are benign neoplasms, those occurring at the cranial base may be challenging tumors to treat because of extensive tissue invasion, an inability to achieve gross-total microscopic resection, and local tumor recurrence and/or progression. A more comprehensive understanding of the genetic abnormalities associated with meningioma tumorigenesis, growth, and invasion may provide novel targets for grading assessments and individualizing molecular therapies for skull base meningiomas. The authors performed a review of the current literature to identify genes that have been associated with the formation and/or progression of meningiomas. Mutations in the NF2 gene have been most commonly implicated in the formation of the majority of meningiomas. Inactivation of other tumor suppressor genes, including DAL-1 and various tissue inhibitors of matrix metalloproteinases, upregulation of several oncogenes including c-sis and STAT3, and signaling dysregulation of pathways such as the Wnt pathway, have each been found to play important, and perhaps, complementary roles in meningioma development, progression, and recurrence. Identification of these genetic factors using genome-wide association studies and high-throughput genomics may provide data for future individualized treatment strategies.

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Comparative Analysis of Whole-Genome and Methylome Profiles of a Smooth and a Rough Mycobacterium abscessus Clinical Strain

G3 Genes|Genome|Genetics ◽

10.1534/g3.119.400737 ◽

2019 ◽

Vol 10 (1) ◽

pp. 13-22 ◽

Cited By ~ 2

Author(s):

Chiranjibi Chhotaray ◽

Shuai Wang ◽

Yaoju Tan ◽

Amjad Ali ◽

Muhammad Shehroz ◽

...

Keyword(s):

Single Molecule ◽

Gene Clusters ◽

Mycobacterium Abscessus ◽

Clinical Strain ◽

Comparative Genomic ◽

Illumina Hiseq ◽

Clinical Strains ◽

Synonymous Mutations ◽

Pan Genome ◽

Genome Wide

Mycobacterium abscessus is a fast growing Mycobacterium species mainly causing skin and respiratory infections in human. M. abscessus is resistant to numerous drugs, which is a major challenge for the treatment. In this study, we have sequenced the genomes of two clinical M. abscessus strains having rough and smooth morphology, using the single molecule real-time and Illumina HiSeq sequencing technology. In addition, we reported the first comparative methylome profiles of a rough and a smooth M. abscessus clinical strains. The number of N4-methylcytosine (4mC) and N6-methyladenine (6mA) modified bases obtained from smooth phenotype were two-fold and 1.6 fold respectively higher than that of rough phenotype. We have also identified 4 distinct novel motifs in two clinical strains and genes encoding antibiotic-modifying/targeting enzymes and genes associated with intracellular survivability having different methylation patterns. To our knowledge, this is the first report about genome-wide methylation profiles of M. abscessus strains and identification of a natural linear plasmid (15 kb) in this critical pathogen harboring methylated bases. The pan-genome analysis of 25 M. abscessus strains including two clinical strains revealed an open pan genome comprises of 7596 gene clusters. Likewise, structural variation analysis revealed that the genome of rough phenotype strain contains more insertions and deletions than the smooth phenotype and that of the reference strain. A total of 391 single nucleotide variations responsible for the non-synonymous mutations were detected in clinical strains compared to the reference genome. The comparative genomic analysis elucidates the genome plasticity in this emerging pathogen. Furthermore, the detection of genome-wide methylation profiles of M. abscessus clinical strains may provide insight into the significant role of DNA methylation in pathogenicity and drug resistance in this opportunistic pathogen.

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