Osteosarcoma (OS)

Overview

Osteosarcoma is a primary malignant bone tumor classified under BONE in the OncoTree hierarchy. It can arise sporadically or as a radiation-associated sarcoma.

Cohorts in the corpus

Recurrent alterations

  • TP53 LOF mutations/deletions in 42% of RT-OS vs 14% sporadic OS PMID:37350195.
  • CDKN2A/CDKN2B deletions in 33% of RT-OS PMID:37350195.
  • PTEN truncating mutations/deletions in 17% of RT-OS vs 14% sporadic OS PMID:37350195.
  • FGFR1 amplification in 17% of RT-OS vs 7% sporadic OS PMID:37350195.
  • PTPRT missense mutations in 17% of RT-OS vs 7% sporadic OS PMID:37350195.
  • FGA of 32% in RT-OS PMID:37350195.
  • Translocations were more frequent in RT-OS (and RT-MPNST) compared to other RT-sarcoma histotypes PMID:37350195.
  • PIPseq cohort identified TSC1 splice-site c.2503-1G>C (mTOR-inhibitor target), RAD51C F8L (PARP-inhibitor target), PDGFRA/KDR overexpression (MTKI treated), MYC/MCL1/CCNE1 overexpression (BET- and CDK4/6 targets), CUL4A overexpression (NAE-inhibitor target), RB1 splice-site c.1216-3A>G (germline, increased second-cancer risk), and TNNT2 R141Q (ACMG secondary, dilated cardiomyopathy) in osteosarcoma patients PMID:28007021
  • Germline WES of 372 pediatric cancer patients (Düsseldorf) included osteosarcoma cases; TP53 LP/PV carriers (Li-Fraumeni syndrome) presented with osteosarcoma; three of six TP53 carriers (50%) developed SMNs including one osteosarcoma patient PMID:29489754

Subtypes

  • Radiation-associated osteosarcoma (RT-OS): Higher TP53 alteration rate (42% vs 14%) and enrichment for FGFR1 and PTPRT alterations compared to sporadic OS. Median latency from radiation: 9.0 years PMID:37350195.
  • Sporadic osteosarcoma: Lower TP53 alteration frequency (14%) and similar PTEN rates PMID:37350195.

Therapeutic landscape

  • Genomic profiling supports histotype-specific treatment; RT-OS shows distinct alterations (FGFR1 amplification, PTPRT mutations) that may represent therapeutic targets PMID:37350195.

Sources

  • PMID:37350195 — Dermawan JK et al., J Pathol 2023. Comparative genomic analysis of 82 RT-sarcomas including 12 RT-osteosarcomas.

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