Identification of New Potential Prognostic and Predictive Markers in High-Grade Osteosarcoma Using Whole Exome Sequencing

Abstract

Conventional high-grade osteosarcoma (OS) is the most common primary cancer of bone and it typically affects the extremities of adolescents. OS has a complex karyotype, and molecular mechanisms related to carcinogenesis, progression and resistance to therapy are still largely unknown. For this reason, the current standard of care is associated with considerable adverse effects. In this study, our aim was to identify gene alterations in OS patients using whole exome sequencing (WES) to find new potential prognostic biomarkers and therapeutic targets. We performed WES on formalin-fixed paraffin-embedded (FFPE) biopsy materials collected from 19 patients affected by conventional high-grade OS. The clinical and genetic data were analyzed according to response to therapy, presence of metastasis and disease status. By comparing good and poor responders to neoadjuvant therapy, we detected a clear prevalence of mutations in the ARID1A, CREBBP, BRCA2 and RAD50 genes in poor responders that negatively influence the progression-free survival time. Moreover, higher tumor mutational burden values correlated with worse prognosis. The identification of mutations in ARID1A, CREBBP, BRCA2 and RAD50 may support the use of a more specific therapy for tumors harboring these alterations. In particular, BRCA2 and RAD50 are involved in homologous recombination repair, and could thus be used as specific therapy targets of inhibitors of the enzyme Poly ADP Ribose Polymerase (PARP). Finally, tumor mutational burden is found to be a potential prognostic marker for OS.

Amicis Omnia Sunt Communia: NF-κB Inhibition as an Alternative to Overcome Osteosarcoma Heterogeneity

“…Differential expression analysis showed 12 downregulated genes (mostly associated with the negative regulation of transcription: NFKBIB , BTRC , CREBBP , HDAC1 , NCOR2 , and FBXW11 ) and 19 upregulated genes [mostly associated with protein ubiquitination ( SOCS1 , RBX1 , RPS27A , UBB , UBA52 , and UBE2N ), positive regulation of cell proliferation ( CTNNB1 , NRAS , HRAS , CDKN1A , and STAT3 ), and cell surface receptor signaling pathways ( IL6 , IFNA5 , IFNA7 , IFNA16 , and NGF ) in OS samples compared to controls. Several of these genes have already been associated with OS pathophysiology [ 149 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 ]. Moreover, KEGG functional enrichment was assessed through STRING v12 (available at accessed on 17 April 2024) and showed that under-expressed genes belonged mainly to MAPK and WNT signaling pathways, while upregulated genes belonged to the PI3K/AKT and JAK/STAT cascades ( Figure 6 C), reinforcing the concept of NF-κB as a common player underneath OS establishment and progression.…”