Clone evolution and genomic alteration analysis of osteosarcoma and matched lung metastasis.

Abstract

11032 Background: Lung metastasis (LM), as the most common metastatic site, is the main reason resulting in treatment failure and death of osteosarcoma (OS). But there was no report about the clone evolution and genomic alteration in the process of LM of OS. Methods: Multiregion whole-genome sequencing and whole-exome sequencing were performed on ten patients with primary OS and matched lung metastatic tumors. A set of high confident somatic nucleotide variants (SNV), small insertion and deletion (indel) and copy number variation (CNV) in each sample were identified, then the n-dimensional Bayesian Dirichlet process was applied to define the constituent mutation clusters as clone or subclone. Neoantigen prediction and HLA typing were performed using NetMHC3.0 and POLYSOLVER algorithm, respectively. Results: There were diversified metastatic progression during lung metastasis of OS including linear evolution (7/10) and parallel evolution (3/10), and metastasis-to-metastasis spread was also found in a patient with multiple metastasis; Mutation accumulative effect during the metastasis of OS was evident, LM had much higher mutation load (fold change = 4.1, P-value < 0.01) and neoantigen burden (fold change = 4.5, P-value < 0.001) than the primary tumor; DNA mismatch repair (MMR) genes relevant deleterious mutation events were found in germline in 8/10 metastatic OS cases and MMR genes mutation were much more in LM than primary cancer; The genome instability of LM was prevalently much more significant than primary tumor, with higher copy number variation frequency (fold change = 7.01, P-value < 0.01). Conclusions: The evolution of OS during LM was very complex with diversified metastatic progression. For the LM of OS, the novel therapy should be considering the much higher mutation load, especially those causing tumor neoantigens, higher genomic instability which were associated with tumor immune therapy. Furthermore, the findings of germline MMR genes mutation in primary OS which had occurred LM and more MMR genes mutation in LM of OS indicated potential clinical benefit on immune checkpoint inhibitor therapy and other small molecular drugs for MMR genes.