DNA methylation-based prognostic subtypes of chordoma tumors in tissue and plasma
Open accessAbstract
BACKGROUND: Chordomas are rare malignant bone cancers of the skull-base and spine. Patient survival is variable and not reliably predicted using clinical factors or molecular features. This study identifies prognostic epigenetic chordoma subtypes that are detected noninvasively using plasma methylomes. METHODS: Methylation profiles of 68 chordoma surgical samples were obtained between 1996 and 2018 across three international centers along with matched plasma methylomes where available. RESULTS: Consensus clustering identified two stable tissue clusters with a disease-specific survival difference that was independent of clinical factors in a multivariate Cox analysis (HR = 14.2, 95%CI: 2.1-94.8, P = 0.0063). Immune-related pathways with genes hypomethylated at promoters and increased immune cell abundance were observed in the poor-performing "Immune-infiltrated" subtype. Cell-to-cell interaction plus extracellular matrix pathway hypomethylation and higher tumor purity were observed in the better-performing "Cellular" subtype. The findings were validated in additional DNA methylation and RNA sequencing datasets as well as with immunohistochemical staining. Plasma methylomes distinguished chordomas from other clinical differential diagnoses by applying fifty chordoma-versus-other binomial generalized linear models in random 20% testing sets (mean AUROC = 0.84, 95%CI: 0.52-1.00). Tissue-based and plasma-based methylation signals were highly correlated in both prognostic clusters. Additionally, leave-one-out models accurately classified all tumors into their correct cluster based on plasma methylation data. CONCLUSIONS: Here, we show the first identification of prognostic epigenetic chordoma subtypes and first use of plasma methylome-based biomarkers to noninvasively diagnose and subtype chordomas. These results may transform patient management by allowing treatment aggressiveness to be balanced with patient risk according to prognosis.
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Methylation-based approaches may provide value in osteosarcoma, chordoma, and other low-mutation contexts.
“while methylation-based approaches may provide value in osteosarcoma, chordoma, and other low-mutation contexts [ 18 , 19 , 20 , 21 ].”
From Signals Alongside Scans: A Genomics-Guided Framework for Liquid Biopsy in Bone and Soft-Tissue Sarcomas (2026) · cites this paper as [19]
Mutation-based assays may be informative in selected chondrosarcoma cases.
“Similarly, mutation-based assays may be informative in selected chondrosarcoma cases”
From Signals Alongside Scans: A Genomics-Guided Framework for Liquid Biopsy in Bone and Soft-Tissue Sarcomas (2026) · cites this paper as [19]
In chondrosarcoma and chordoma, mutation- and methylation-based strategies may be informative in selected molecularly defined cases.
“In chondrosarcoma and chordoma, mutation- and methylation-based strategies may be informative in selected molecularly defined cases, but these approaches are not universally applicable across all patients [ 18 , 19 , 20 , 38 ].”
From Signals Alongside Scans: A Genomics-Guided Framework for Liquid Biopsy in Bone and Soft-Tissue Sarcomas (2026) · cites this paper as [19]
Mutation- and methylation-based strategies are not universally applicable across all chondrosarcoma and chordoma patients.
“In chondrosarcoma and chordoma, mutation- and methylation-based strategies may be informative in selected molecularly defined cases, but these approaches are not universally applicable across all patients [ 18 , 19 , 20 , 38 ].”
From Signals Alongside Scans: A Genomics-Guided Framework for Liquid Biopsy in Bone and Soft-Tissue Sarcomas (2026) · cites this paper as [19]
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Alabid, I., Yousef, A. J., Patni, M. M., Aloti, R. A., Qassim, Z. A.-A. M., Alothman-Agha, A. A., Hamdy, H. A., Noury, F. M., & Abdelfattah, M. T. (2026) · Cells · doi:10.3390/cells15141271
- Authors
- Zuccato, J. A., Patil, V., Mansouri, S., Liu, J. C., Nassiri, F., Mamatjan, Y., Chakravarthy, A., Karimi, S., Almeida, J. P., Bernat, A.-L., Hasen, M., Singh, O., Khan, S., Kislinger, T., Sinha, N., Froelich, S., Adle-Biassette, H., Aldape, K. D., De Carvalho, D. D., & Zadeh, G.
- Affiliations
- University Health Network (CA)
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Hôpital Lariboisière (FR)
- University of Manitoba (CA)
- Health Sciences Centre (CA)
- Neurosurgery Department, Hôpital Lariboisiere, APHP, Université Paris Diderot, Paris, France
- Department of Pathology, Lariboisière Hospital, Assistance Publique - Hôpitaux de Paris, Université de Paris, Paris, France
- National Cancer Institute (US)
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Corresponding author
- Zadeh, Gelareh
- ORCID
- Venue
- Neuro-Oncology
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-10-06
- Volume
- 24
- Issue
- 3
- Pages
- 442-454
- ISSN
- 1522-8517 (ISSN-L)
- 1523-5866
- PMC
- PMC8917394
- OpenAlex
- W3202924187
- Cited by
- 53
- References
- 42
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 19 · 2023: 7 · 2022: 12
- FWCI
- 7.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Neuro-Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Beijing Municipal Science and Technology Commission (Z171100000117002)
- Public Welfare Industry of Health (201402008)
- National Institutes of Health
- Canadian Institutes of Health Research (201512MSH360794-228629, FDN 148430, PJT 165986)
- Princess Margaret Cancer Foundation
- Canada Research Chairs
- Natural Sciences and Engineering Research Council of Canada (489073)
- Terry Fox Research Institute (1106)
- Ontario Institute for Cancer Research
- Canadian Cancer Society (706135)
- Topics
- Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
- Health Sciences › Medicine › Surgery › Head and Neck Surgical Oncology
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Keywords
- chordoma, DNA methylation, prognostic subtypes, liquid biopsy, epigenetic biomarkers, tumor immune infiltration, extracellular matrix pathway, tumor purity, disease-specific survival, non-invasive diagnosis
- MeSH terms
- Chordoma, Humans, Prognosis, Multivariate Analysis, Cluster Analysis, DNA Methylation
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