Methylation-based reclassification and risk stratification of skull-base chordomas

Xulei Huo; Tengxian Guo; Ke Wang; Bohan Yao; Da Li; Huan Li; Wei Chen; Liang Wang; Zhen Wu

doi:10.3389/fonc.2022.960005

Methylation-based reclassification and risk stratification of skull-base chordomas

Front Oncol. 2022 Nov 11:12:960005. doi: 10.3389/fonc.2022.960005. eCollection 2022.

Authors

Xulei Huo^{1

2}, Tengxian Guo³, Ke Wang^{1

2}, Bohan Yao^{1

2}, Da Li^{1

2}, Huan Li^{1

2}, Wei Chen⁴, Liang Wang⁵, Zhen Wu^{1

2}

Affiliations

¹ Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
² Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, China.
³ Department of Neurosurgery, Beijing Fengtai Hospital, Beijing, China.
⁴ Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing, China.
⁵ Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.

Abstract

Background: Skull-base chordomas are rare malignant bone cancers originating from the remnant of the notochord. Survival is variable, and clinical or molecular factors cannot reliably predict their outcomes. This study therefore identified epigenetic subtypes that defined new chordoma epigenetic profiles and their corresponding characteristics.

Methods: Methylation profiles of 46 chordoma-resected neoplasms between 2008 and 2014, along with clinical information, were collected. K-means consensus clustering and principal component analysis were used to identify and validate the clusters. Single-sample gene set enrichment analysis, methylCIBERSORT algorithm, and copy number analysis were used to identify the characteristics of the clusters.

Results: Unsupervised clustering analysis confirmed two clusters with a progression-free survival difference. Gene set enrichment analysis indicated that the early and late estrogen response pathways and the hypoxia pathway were activated whereas the inflammatory and interferon gamma responses were suppressed. Forty-six potential therapeutic targets corresponding to differentially methylated sites were identified from chordoma patients. Subgroups with a worse outcome were characterized by low immune cell infiltration, higher tumor purity, and higher stemness indices. Moreover, copy number amplifications mostly occurred in cluster 1 tumors and the high-risk group. Additionally, the presence of a CCNE1 deletion was exclusively found in the group of chordoma patients with better outcome, whereas RB1 and CDKN2A/2B deletions were mainly found in the group of chordoma patients with worse outcome.

Conclusions: Chordoma prognostic epigenetic subtypes were identified, and their corresponding characteristics were found to be variable.

Keywords: DNA methylation; copy number variation; infiltration immune level; prognostic biomarker; stemness indices.