Allelic Expression Imbalance Analysis Identified YAP1 Amplification in p53- Dependent Osteosarcoma.

Guanglin Niu,Hubert Pausch,Melanie Nusselt,Angelika E Schnieke,Yue Zhang,Krzysztof Flisikowski,Tatiana Flisikowska,Agnieszka Bak

doi:10.3390/cancers13061364

Guanglin Niu, Hubert Pausch + Show 6 more

Open Access

https://doi.org/10.3390/cancers13061364

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Journal: Cancers	Publication Date: Mar 18, 2021
Citations: 4	License type: CC BY 4.0

Affiliation: Technical University of Munich, ETH Zurich

Abstract

Simple SummaryOsteosarcoma (OS) is a highly heterogenous cancer, making the identification of genetic driving factors difficult. Genetic factors, such as heritable mutations of Rb1 and TP53, are associated with an increased risk of OS. We previously generated pigs carrying a mutated TP53 gene, which develop OS at high frequency. RNA sequencing and allelic expression imbalance analysis identified an amplification of YAP1 involved in p53- dependent OS progression. The inactivation of YAP1 inhibits proliferation, migration, and invasion, and leads to the silencing of TP63 and reconstruction of p16 expression in p53-deficient porcine OS cells. This study confirms the importance of p53/YAP1 network in cancer.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 Rb1 and TP53, 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 TP53 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 (p = 2.14 × 10−39) for SNPs in the BIRC3-YAP1 locus on pig chromosome 9. Analysis of copy number variation showed that YAP1 amplification is associated with the AEI and the progression of OS. Accordingly, the inactivation of YAP1 inhibits proliferation, migration, and invasion, and leads to the silencing of TP63 and reconstruction of p16 expression in p53-deficient porcine OS cells. Increased p16 mRNA expression correlated with lower methylation of its promoter. Altogether, our study provides molecular evidence for the role of YAP1 amplification in the progression of p53-dependent OS.

Highlights

Osteosarcoma (OS) is the most common form of primary bone cancer, mainly found in young people with the second highest incidence group being over the age of 50 [1]
A total of 39 flTP53R167H/+ heterozygous and ten flTP53R167H/R167H homozygous pigs were examined by necropsy
We concluded that the high heterogeneity of OS limited the identification of differentially expressed genes (DEGs) and decided to perform allele expression imbalance (AEI) analysis

Summary

Introduction

Osteosarcoma (OS) is the most common form of primary bone cancer, mainly found in young people with the second highest incidence group being over the age of 50 [1]. OS is a highly aggressive cancer for which there have been no major therapeutic improvements over the last decades [2,3]. High heterogeneity of OS hinders the identification of driver mutations and therapeutic target genes. Genome-wide somatic alterations in OS include mutations and chromosomal lesions, such as structural and copy number variations in TP53 [9,10,11] and Rb1 [9,12], alternative lengthening of telomeres, and an aberrant epigenetic pattern [9,13,14,15,16,17,18]

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