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

ABSTRACT One 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.