Allelic Expression Imbalance Analysis Identified Amplification in p53- Dependent Osteosarcoma.

Osteosarcoma (OS) is a primary bone malignancy that mainly occurs during adolescent growth, suggesting that bone growth plays an important role in the aetiology of the disease. Genetic factors, such as heritable mutations of and are associated with an increased risk of OS. Identifying driver mutations for OS has been challenging due to the complexity of bone growth-related pathways and the extensive intra-tumoral heterogeneity of this cancer. We previously generated pigs carrying a mutated gene, which develop OS at high frequency. RNA sequencing and allele expression imbalance (AEI) analysis of OS and matched healthy control samples revealed a highly significant AEI ( = 2.14 × 10) for SNPs in the locus on pig chromosome 9. Analysis of copy number variation showed that amplification is associated with the AEI and the progression of OS. Accordingly, the inactivation of inhibits proliferation, migration, and invasion, and leads to the silencing of and reconstruction of expression in p53-deficient porcine OS cells. Increased mRNA expression correlated with lower methylation of its promoter. Altogether, our study provides molecular evidence for the role of amplification in the progression of p53-dependent OS.