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). Samples from three additional DCs and one PDC underwent targeted sequencing of cancer-related genes. 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.