A-to-I RNA editing shows dramatic up-regulation in osteosarcoma and broadly regulates tumor-related genes by altering microRNA target regions.

A-to-I RNA editing is a prevalent type of RNA modification in animals. The dysregulation of RNA editing has led to multiple human cancers. However, the role of RNA editing has never been studied in osteosarcoma, a complex bone cancer with unknown molecular basis. We retrieved the RNA-sequencing data from 24 primary osteosarcoma patients and 3 healthy controls. We systematically profiled the RNA editomes in these samples and quantitatively identified reliable differential editing sites (DES) between osteosarcoma and normal samples. RNA editing efficiency is dramatically increased in osteosarcoma, presumably due to the significant up-regulation of editing enzymes ADAR1 and ADAR2. Up-regulated DES in osteosarcoma are enriched in 3'UTRs. Strikingly, such 3'UTR sites are further enriched in microRNA binding regions of gene EMP2 and other oncogenes, abolishing the microRNA suppression on target genes. Accordingly, the expression of these tumor-promoting genes is elevated in osteosarcoma. There might be an RNA editing-dependent pathway leading to osteosarcoma. We expanded our knowledge on the potential roles of RNA editing in oncogenesis. Based on these molecular features, our work is valuable for future prognosis and diagnosis of osteosarcoma.

An evolutionarily conserved mechanism that amplifies the effect of deleterious mutations in osteosarcoma.

Illustrating the molecular consequence of deleterious mutations is essential for bridging the gap between genotype and phenotype. In the cancer field, differential expression of the two alleles on heterozygous sites could directly reflect the effect of a mutation under certain trans environment. We retrieved transcriptomes of osteosarcoma and normal tissues in human and mouse. We defined tumor-specific heterozygous mutations with stringent criteria by considering sequencing depth and ancestral state. We calculated the relative expression of mutated alleles and normal alleles on the missense mutation sites in osteosarcoma. There is a conserved pattern that the mutated alleles have globally higher expression levels than the normal alleles in tumors. In the shared genes with missense mutations in both human and mouse, the relative expression of mutated alleles is highly correlated. Moreover, shared genes are functionally more important than unshared genes, and are enriched in oncogenes. The oncogenic role of mutations in oncogene KMT2A is experimentally verified. We systematically illustrate the deleterious effects of missense mutations by showing the over-expression of mutated alleles. We partially bridge the gap between genotype and phenotype by surmising that the over-expression of the mutated alleles might break the cellular equilibrium and lead to tumorigenesis.