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

Area of Science:

• Oncology
• Genomics
• Pharmacology

Background:

• Osteosarcoma, a common primary bone cancer, presents challenges due to chemotherapy's systemic toxicity and lack of tumor specificity.
• Identifying novel therapeutic targets and drugs is crucial for improving osteosarcoma treatment outcomes.
• Oncogene-induced replication stress (ORS) is implicated in aggressive cancers, suggesting its potential as a therapeutic target.

Purpose of the Study:

• To identify novel biomarkers associated with oncogene-induced replication stress (ORS) in osteosarcoma.
• To screen for potential anti-osteosarcoma drugs targeting identified biomarkers.
• To develop a prognostic model for osteosarcoma based on replication stress-related genes (RSGs).

Main Methods:

• Analysis of 89 osteosarcoma samples from the TARGET database to identify differentially expressed genes (DEGs) related to ORS.
• Screening of key RSGs using LASSO regression and Cox proportional regression prognostic model.
• Validation of the prognostic model using the GSE21257 dataset from the GEO database and drug screening in L1000PWD and DGIdb databases.

Main Results:

• Seven key RSGs (TCF7L2, SLC27A4, PCSK5, NOL6, CHCHD4, EIF3B, SCO1) were identified and associated with ORS in osteosarcoma.
• A prognostic model based on these seven RSGs was validated.
• Six potential anti-osteosarcoma drugs were identified: repaglinide, tacrolimus, sirolimus, cyclosporine, hydrochlorothiazide, and VU-0365117-1.

Conclusions:

• The identified seven RSGs are potentially linked to ORS signatures in osteosarcoma, serving as valuable biomarkers.
• The screened drugs represent promising candidates for novel osteosarcoma therapies.
• This study provides a foundation for developing targeted therapies against osteosarcoma based on replication stress pathways.