Gene Expression Profiling Identifies Two Chordoma Subtypes Associated with Distinct Molecular Mechanisms and Clinical Outcomes

Abstract

Purpose: Chordoma is a rare bone tumor with a high recurrence rate and limited treatment options. The aim of this study was to identify molecular subtypes of chordoma that may improve clinical management. Experimental Design: We conducted RNA sequencing in 48 tumors from Chinese skull-base chordoma patients and identified two major molecular subtypes. We then replicated the classification using a NanoString panel in 48 chordoma patients from North America. Results: Tumors in one subtype were more likely to have somatic mutations and reduced expression in chromatin remodeling genes, such as PBRM1 and SETD2, while the other subtype was characterized by the upregulation of genes in epithelial-mesenchymal transition and Sonic Hedgehog pathways. Immunohistochemical staining of top differentially expressed genes between the two subtypes in 312 Chinese chordoma patients with long-term follow-up data showed that the expression of some markers such as PTCH1 was significantly associated with survival outcomes. Conclusions: Our findings may improve the understanding of subtype-specific tumorigenesis of chordoma and inform clinical prognostication and targeted options.

DNA methylation, combined with RNA sequencing, provide novel insight into molecular classification of chordomas and their microenvironment

“…No gene expression-based subclassification of skull base chordomas was also found in previous RNA-seq analyses [ 16 , 47 ]. The existence of the distinct expression groups of skull base chordomas was described recently [ 18 ], however, it was not observed in our data. Correlation-based analysis of the role of DNA methylation in gene expression suggests that in chordomas a small proportion of all the genes is-controlled by DNA methylation of promoter regions.…”

“…Moreover, some light has also been shed on the transcriptomic definition of chordoma [ 15 – 17 ]. Some researchers were struggling to identify any subgroups within their populations [ 15 ], while others identified two gene expression-based clusters [ 18 ]. Comparisons of gene expression profiles of tumors with those of the nucleus pulposus (NP, central component of the intervertebral disc, a notochord remnant) samples have revealed differences in expression of brachyury ( T ) [ 15 , 16 ], SAMD-5 [ 16 ], and other genes associated with development [ 15 ].…”

Unravelling the role of immune cells and FN1 in the recurrence and therapeutic process of skull base chordoma

“…Additional examination through GSEA indicated that TumourC1 cells were linked to signalling pathways such as TGF‐β, Notch, ECM–receptor interaction and Hedgehog, which have been connected to the advancement of tumours and the ability to resist cancer treatments (Figure 5D ). 7 , 8 , 50 , 51 Given these findings, we focused on investigating the role of TumourC1 in chordoma recurrence. In the analysis of TumourC1 cells, we found DEGs between primary and recurrent chordomas.…”

Multimodal profiling of chordoma immunity reveals distinct immune contextures

“…In other tumour types (e.g., melanoma, carcinomas) spontaneous immune responses can often be explained by the mutation burden of a cancer where tumours with high mutation burden more often experience spontaneous anti-tumour immune responses as a consequence of high neoantigen abundance. In contrast, similar to most other sarcomas, the number of somatic, coding mutations in chordomas is generally low and stable between patients making it unlikely that distinct immune responses can be explained by the overall mutation burden of the tumours 13–15,32 . Although we only found evidence for strong clonal expansion in two T cell high chordomas, the TCR repertoire was less diverse in T cell high chordoma than T cell low chordomas, which would support that antigen recognition is a potential driver of immunity in chordomas.…”