Abstract
Mutation is the major cause of phenotypic innovations. Apart from DNA mutations, the alteration on RNA such as the ADAR-mediated A-to-I RNA editing could also shape the phenotype. These two layers of variations have not been systematically combined to study their collective roles in cancers. We collected the high-quality transcriptomes of ten hepatocellular carcinoma (HCC) and the matched control samples. We systematically identified HCC-specific mutations in the exonic regions and profiled the A-to-I RNA editome in each sample. All ten HCC samples had mutations in the CDS of ADAR2 gene (dsRNA-binding domain or catalytic domain). The consequence of these mutations converged to the elevation of ADAR2 efficiency as reflected by the global increase of RNA editing levels in HCC. The up-regulated editing sites (UES) were enriched in the CDS and UTR of oncogenes and tumor suppressor genes (TSG), indicating the possible roles of these target genes in HCC oncogenesis. We present the mutation-ADAR2-UES-oncogene/TSG-HCC axis that explains how mutations at different layers would finally lead to abnormal phenotype. In the light of central dogma, our work provides novel insights into how to fully take advantage of the transcriptome data to decipher the consequence of mutations.
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Data availability
We downloaded the human reference genome from the Ensembl website (http://ensemblgenomes.org/) (hg38, GRCh38.87). RNA sequencing data (RNA-Seq, transcriptome) of normal/tumor tissues from ten patients were retrieved from NCBI with accession number GSE112705 (Zou et al. 2019). The ten patients suffered from a particular type of liver cancer termed hepatocellular carcinoma (HCC). The matched normal tissue of each individual refers to the adjacent normal liver tissues. The list of oncogenes and TSG was retrieved from cancer gene census website (https://www.sanger.ac.uk/data/cancer-gene-census/). Totally 240 oncogenes and 242 TSG were downloaded.
Abbreviations
- ADAR:
-
Adenosine deaminase acting on RNA
- AA:
-
Amino acid
- dsRNA:
-
Double-stranded RNA
- DRBM:
-
DsRNA-binding domain
- HCC:
-
Hepatocellular carcinoma
- CDS:
-
Coding sequence
- UTR:
-
Untranslated region
- UES:
-
Up-regulated editing site
- SNP:
-
Single nucleotide polymorphism
- RPKM:
-
Reads per kilobase per million mapped reads
- TSG:
-
Tumor suppressor gene
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We thank the lab members for their previous suggestions to this project.
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Conception and design: Wengui Xu. Collection and assembly of data: Jian Li, Chaowei Li. Data analysis and interpretation: Jian Li, Chaowei Li. Manuscript writing: Jian Li, Chaowei Li, Wengui Xu. Final approval of manuscript: Jian Li, Chaowei Li, Wengui Xu.
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Li, J., Li, C. & Xu, W. Liver cancer-specific mutations in functional domains of ADAR2 lead to the elevation of coding and non-coding RNA editing in multiple tumor-related genes. Mol Genet Genomics 299, 1 (2024). https://doi.org/10.1007/s00438-023-02091-5
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DOI: https://doi.org/10.1007/s00438-023-02091-5