TP53 Mutations as Drivers of Chordoma Progression and Hallmarks of Aggressive Chordoma

Introduction: Dedifferentiated (DC) and poorly differentiated chordomas (PDC) are rare, aggressive chordomas with a significantly worse prognosis than conventional chordomas (CC). The molecular mechanisms, driving them, remain poorly understood. Methods: Matched primary CC and recurrent DC cryopreserved samples from one patient were analyzed with whole-exome sequencing (WES). Targeted sequencing of cancer-related genes in three additional DC cases, one PDC. Furthermore, 102 CC cases - 32 novel and 70 from literature were analyzed. Functional and survival analysis was performed. Results: WES revealed striking genomic changes during progression from CC to DC, with the number of somatic mutations increasing from 211 in primary to 430 in the recurrent DC; recurrence acquired TP53 and BRCA1 deleterious mutations, along with copy-number alterations, including loss of 6q containing the TBXT locus. Targeted sequencing identified TP53 mutations in 4/5 DC&PDC cases compared to 1/102 cases in combined CC cohorts (p=2.7×10-5, OR=162.9). In 3 recurrent DC samples with TP53 variant, presence of the mutation was assessed in primary CC sample and in neither this variant was found. Literature review revealed TP53 mutations in 9/23 (39\%) DC&PDC cases versus 5/445 (1.24\%) CC cases. Survival analysis demonstrated that TP53 mutations confer a significantly worse prognosis in DC patients (p = 0.03). Conclusion: TP53 mutations are acquired during chordoma progression and are associated with an aggressive phenotype; TP53 sequencing could serve as a prognostic and potentially predictive biomarker in aggressive chordomas.