1972P - Molecular mechanism study of recurrence/metastasis for Enneking IIb osteosarcoma

Background

Osteosarcoma (OS) is a common primary bone malignancy in children and adolescents, with most patients diagnosed with Enneking stage IIB. However, the prognosis for these patients is inconsistent, with over half experiencing recurrence or metastasis under standard treatment. The Enneking staging system alone cannot accurately distinguish the risk group for recurrence and metastasis, highlighting the need for further research into the molecular mechanisms.

Methods

74 Chinese patients with Enneking stage IIB OS under standard treatment were included, followed up for over two years. Targeted deep sequencing was performed by YUANSU panel (OrigiMed, Shanghai, China) with 706 cancer-related genes and the Kaplan-Meier method was used to calculate survival curves.

Results

The cohort included 74 patients, 50 males and 24 females, with 40 experiencing recurrence or metastasis and 34 not. The high frequency mutated genes in IIB primary OS were found to be TP53 (33%) FLCN (29%) GID4 (29%) NCOR1 (28%) VEGFA (24%) CCND3 (21%). The group with recurrence or metastasis had significantly higher TMB than the group without (p<0.05). Survival analysis revealed that genetic mutations in MCL1, MYC, TFEB, CCND3, AURKB, ALOX12B, and VEGFA increase the likelihood of recurrence and metastasis in IIB OS patients. (MCL1/MYC/TFEB/CCND3/AURKB/ALOX12B, p<0.05; VEGFA, p=0.065); Abnormalities in the MYC, WNT, and Cell cycle pathways are associated with a worse prognosis (MYC/WNT, p<0.05; Cell cycle, p=0.057). These results indicate that genetic variants and pathway abnormalities are significant risk factors for IIB OS.

Conclusions

Our study represents the largest cohort investigating the molecular mechanisms of Chinese IIB OS. Mutations of MCL1/MYC/TFEB/CCND3/AURKB/ALOX12B/VEGFA genes and MYC/WNT/cell-cycle pathways are high-risk factors for recurrence/metastasis. Given the high mutation frequency and poor prognosis of patients with VEGFA and cell cycle signaling pathway abnormalities, anti-angiogenic agents and cell cycle inhibitors may be more effective treatment options compared with standard therapy. Further studies are needed to confirm their efficacy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The First Affiliated Hospital of Sun Yat-sen University.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.