Identifying Genetic Signatures Associated with Oncogene-Induced Replication Stress in Osteosarcoma and Screening for Potential Targeted Drugs.

Abstract

Osteosarcoma is the most common type of primary malignant bone tumor. Due to the lack of selectivity and sensitivity of chemotherapy drugs to tumor cells, coupled with the use of large doses, chemotherapy drugs often have systemic toxicity. The use of modern sequencing technology to screen tumor markers in a large number of tumor samples is a common method for screening highly specific and selective anti-tumor drugs. This study aims to identify potential biomarkers using the latest reported gene expression signatures of oncogene-induced replication stress (ORS) in aggressive cancers, and potential anti-osteosarcoma drugs were screened in different drug databases. In this study, we obtained 89 osteosarcoma-related samples in the TARGET database, all of which included survival information. According to the median expression of each of six reported ORS gene markers (NAT10/DDX27/ZNF48/C8ORF33/MOCS3/MPP6), we divided 89 osteosarcoma gene expression datasets into a high expression group and a low expression group and then performed a differentially expressed gene (DEG) analysis. The coexisting genes of 6 groups of DEGs were used as replication stress-related genes (RSGs) of osteosarcoma. Then, key RSGs were screened using LASSO regression, a Cox risk proportional regression prognostic model and a tenfold cross-validation test. GSE21257 datasets collected from the Gene Expression Omnibus (GEO) database were used to verify the prognostic model. The final key RSGs selected were used in the L1000PWD and DGIdb databases to mine potential drugs. After further validation by the prognostic model, we identified seven genes associated with ORS in osteosarcoma as key RSGs, including transcription factor 7 like 2 (TCF7L2), solute carrier family 27 member 4 (SLC27A4), proprotein convertase subtilisin/kexin type 5 (PCSK5), nucleolar protein 6 (NOL6), coiled-coil-coil-coil-coil-helix domain containing 4 (CHCHD4), eukaryotic translation initiation factor 3 subunit B (EIF3B), and synthesis of cytochrome C oxidase 1 (SCO1). Then, we screened the seven key RSGs in two drug databases and found six potential anti-osteosarcoma drugs (D GIdb database: repaglinide, tacrolimus, sirolimus, cyclosporine, and hydrochlorothiazide; L1000PWD database: the small molecule VU-0365117-1). Seven RSGs (TCF7L2, SLC27A4, PCSK5, NOL6, CHCHD4, EIF3B, and SCO1) may be associated with the ORS gene signatures in osteosarcoma. Repaglinide, tacrolimus, sirolimus, cyclosporine, hydrochlorothiazide and the small molecule VU-0365117-1 are potential therapeutic drugs for osteosarcoma.