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Introduction <p>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.</p> Methods <p>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.</p> Results <p>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 <i>TP53</i> and <i>BRCA1</i> deleterious mutations, along with copy-number alterations, including loss of 6q containing the <i>TBXT</i> locus. Targeted sequencing identified <i>TP53</i> mutations in 4/5 DC&amp;PDC cases compared to 1/102 cases in combined CC cohorts (<i>p</i> = 2.7<InlineEquation ID="IEq1"> <EquationSource Format="TEX">\(\times \)</EquationSource> </InlineEquation>10<sup>−5</sup>, OR=162.9). In 3 recurrent DC samples with <i>TP53</i> variant, presence of the mutation was assessed in primary CC sample and in neither, this variant was found. Literature review revealed <i>TP53</i> mutations in 9/23 (39%) DC&amp;PDC cases versus 5/445 (1.24%) CC cases. Survival analysis demonstrated that <i>TP53</i> mutations confer a significantly worse prognosis in DC patients (<i>p</i> = 0.03).</p> Conclusion <p><i>TP53</i> mutations are acquired during chordoma progression and are associated with an aggressive phenotype; <i>TP53</i> sequencing could serve as a prognostic and potentially predictive biomarker in aggressive chordomas.</p>

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

  • 期刊论文

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  • 发表日期：

    2025年12月19日

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  • Szymon Baluszek,
  • Paulina Kober,
  • Michał Wa̧grodzki,
  • Jacek Kunicki,
  • Bartosz Wojtaś,
  • Paulina Szadkowska,
  • Bożena Kamińska,
  • Thibault Passeri,
  • Tomasz Mandat,
  • Mateusz Bujko

摘要

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 \(\times \) 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.