Chordoma Management and Prognostic Factors

Chordoma is a rare, malignant bone tumour arising from notochordal remnants, most often affecting the skull base and sacral spine. Optimal management hinges on en bloc surgical resection with negative margins, frequently combined with high-dose radiotherapy modalities such as proton or carbon-ion therapy. Advances in molecular profiling have revealed recurrent homozygous deletions of CDKN2A/2B, duplications of the brachyury locus and mutations in chromatin-remodelling genes, informing emerging targeted and immunotherapeutic strategies. Established clinical prognostic factors encompass patient age, tumour size, location and histological subtype, as well as completeness of resection. On a molecular level, alterations such as PBRM1 mutation and CDKN2A/2B loss correlate with shortened recurrence-free and disease-specific survival. The composition of the tumour micro-environment, including immune infiltrates and extracellular matrix components, further impacts therapeutic response and long-term outcomes.

Research from Nature Portfolio

Large-scale functional genomic screens have systematically mapped essential genes for chordoma cell survival, confirming brachyury as a central dependency and uncovering additional vulnerabilities, including PTPN11, EGFR and CDK6. Preclinical validation demonstrates that small-molecule inhibitors of SHP2 exert potent antitumour activity, offering new avenues for therapy. Complementary whole-genome sequencing of skull-base chordomas has identified recurrent mutations in PBRM1 and frequent homozygous deletions of CDKN2A/2B. Co-occurrence of PBRM1 alteration with chromosome 22q loss shows strong associations with reduced recurrence-free and disease-specific survival, highlighting the critical role of copy number alterations and chromatin regulation in disease progression.

Chordoma Management and Prognostic Factors publication trend

The graph below shows the total number of articles in chordoma management and prognostic factors across all publications each year (not limited to Nature Index journals).

Technical terms

Brachyury (TBXT): A notochordal transcription factor overexpressed in chordoma and essential for tumour cell survival.

CRISPR-Cas9 loss-of-function screen: A genome-editing approach used to identify genes critical for cancer cell viability.

Copy number alteration: Somatic gains or losses of chromosomal segments that alter gene dosage in tumours.

PBRM1: A subunit of the SWI/SNF chromatin-remodelling complex frequently mutated in skull-base chordoma.

Progression-free survival (PFS): The time period during which a patient’s disease does not worsen following treatment.

Recurrence-free survival (RFS): The duration after primary therapy during which the tumour does not recur.

References

1. Mapping the landscape of genetic dependencies in chordoma. Nature Communications (2023).
2. Unravelling the role of immune cells and FN1 in the recurrence and therapeutic process of skull base chordoma. Clinical and Translational Medicine (2023).
3. Best practices for the management of local-regional recurrent chordoma: a position paper by the Chordoma Global Consensus Group. Annals of Oncology (2017).
4. Chordoma: a systematic review of the epidemiology and clinical prognostic factors predicting progression-free and overall survival. European Spine Journal (2018).
5. The driver landscape of sporadic chordoma. Nature Communications (2017).
6. Whole genome sequencing of skull-base chordoma reveals genomic alterations associated with recurrence and chordoma-specific survival. Nature Communications (2021).
7. Chordoma—Current Understanding and Modern Treatment Paradigms. Journal of Clinical Medicine (2021).