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

## TL;DR

TP53 mutations are linked to aggressive chordoma progression and worse patient outcomes, suggesting they could be used as a biomarker for prognosis.

## Contribution

This study identifies TP53 mutations as a novel driver of aggressive chordoma progression and a potential prognostic biomarker.

## Key findings

- TP53 mutations were found in 4 out of 5 aggressive chordoma cases but in only 1 out of 102 conventional chordoma cases.
- TP53 mutations were not present in primary conventional chordoma samples but emerged during progression to aggressive forms.
- TP53-mutated aggressive chordoma patients had significantly worse survival outcomes.

## Abstract

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.

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.

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\documentclass[12pt]{minimal}
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\begin{document}$$\times $$\end{document}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).

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.

The online version contains supplementary material available at 10.1186/s40478-025-02180-z.