TP53 mutations as drivers of chordoma progression and hallmarks of aggressive chordoma
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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.
