Comprehensive genomic profiling of patients with favorable prognosis in osteosarcoma

e22501 Background: Osteosarcoma (OS) is characterized by complex genetic features and mysterious biological behavior. Genomic technologies are starting to give more insights. However, recent investigations have focused on patients with the advanced or metastatic disease. This study intended to evaluate the genetic landscape and identify new prognostic biomarkers in OS pts with good prognosis. Methods: This study conducted in-depth genomic profiling in a cohort of 21 patients (MSTS stage II) with long-term follow-up. Whole exome sequencing of primary tumors with matched normal tissues were performed. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (Indels), copy number variations (CNV) and chromosomal rearrangements and their prevalence was compared to the pts with metastatic disease reported before (Wang et al, 2018). Tumor mutation burden (TMB) and microsatellite instability (MSI) was analyzed, with additional analysis for mutational signatures. The endpoint was disease free survival (DFS). Results: 21 participants were enrolled between July. 23th, 2008 and Aug. 19th, 2013. 21 pts (M/F 13/8), median age 17y (5-33). Median DFS was 88.4 (95% CI 61.27–111.77) months. The top ranked altered genes were MUC4 (67%), FRG1 (62%), TXNDC2 (62%), ZNF717 (62%), ANKRD20A4 (57%), IGSF3 (52%), MUC16 (52%), NBPF10 (52%), MUC12 (48%) and ARID1A (43%). TMB was evaluated as lower level with a median value of 1.11 muts/MB (range from 0.78 to 3.58), relative to the other solid tumors. None pathogenic and likely pathogenic germline mutations were detected. Mutation signature 5 and 6 were most prevalent. CNV were frequently happened in stage II OS with an incidence of 80.9% (17/21). Among these, The co-occurrence of copy number gain (CNG) and copy number loss (CNL) significantly correlated with DFS (p = 0.0164), comparing with pts of either CNG or CNL . While CNV of driver genes in stage II OS were different from those of stage III published before (Wang et al, 2018), TP53 (0% vs 30% ), RB1 (4.5% vs 60%), CDKN2A (0% vs 30% ), MYC (0% vs 60%) and MDM2 (0% vs 60%). Conclusions: Stage II OS with favorable prognosis has unique genetic characterizes relative to metastatic OS. This study indicates that MUC family could be one of prognostic indicators. Genes with CNV, and the state which CNV occurs could provide clinical significance for the discovery of prognostic markers, which need to be validated by prospective prognostic data.