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

in Clinical cancer research : an official journal of the American Association for Cancer Research by Jiwei Bai, Jianxin Shi, Yazhuo Zhang, Chuzhong Li, Yujia Xiong, Hela Koka, Difei Wang, Tongwu Zhang, Lei Song, Wen Luo, Bin Zhu, Belynda Hicks, Amy Hutchinson, Erin Kirk, Melissa A Troester, Mingxuan Li, Yutao Shen, Tianshun Ma, Junmei Wang, Xing Liu, Shuai Wang, Songbai Gui, Mary L McMaster, Stephen J Chanock, Dilys M Parry, Alisa M Goldstein, Xiaohong R Yang

TLDR

  • Chordoma is a rare bone tumor that is difficult to treat. This study looked at the genetic makeup of chordoma tumors and found two different types. One type had more mutations and lower levels of certain genes, while the other type had more genes that were involved in a process called epithelial-mesenchymal transition. The study also found that some markers were associated with how long patients lived. This information could help doctors better understand the different types of chordoma and develop better treatments.

Abstract

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. We conducted RNA sequencing in 48 tumors from patients with Chinese skull-base chordoma and identified two major molecular subtypes. We then replicated the classification using a NanoString panel in 48 patients with chordoma from North America. Tumors in one subtype were more likely to have somatic mutations and reduced expression in chromatin remodeling genes, such as PBRM1 and SETD2, whereas the other subtype was characterized by the upregulation of genes in epithelial-mesenchymal transition and Sonic Hedgehog pathways. IHC staining of top differentially expressed genes between the two subtypes in 312 patients with Chinese chordoma with long-term follow-up data showed that the expression of some markers such as PTCH1 was significantly associated with survival outcomes. Our findings may improve the understanding of subtype-specific tumorigenesis of chordoma and inform clinical prognostication and targeted options.

Overview

  • The study aimed to identify molecular subtypes of chordoma that may improve clinical management. RNA sequencing was conducted in 48 tumors from patients with Chinese skull-base chordoma and identified two major molecular subtypes. The study replicated the classification using a NanoString panel in 48 patients with chordoma from North America. Tumors in one subtype were more likely to have somatic mutations and reduced expression in chromatin remodeling genes, such as PBRM1 and SETD2, whereas the other subtype was characterized by the upregulation of genes in epithelial-mesenchymal transition and Sonic Hedgehog pathways. IHC staining of top differentially expressed genes between the two subtypes in 312 patients with Chinese chordoma with long-term follow-up data showed that the expression of some markers such as PTCH1 was significantly associated with survival outcomes. The study may improve the understanding of subtype-specific tumorigenesis of chordoma and inform clinical prognostication and targeted options.

Comparative Analysis & Findings

  • The study identified two major molecular subtypes of chordoma. Tumors in one subtype were more likely to have somatic mutations and reduced expression in chromatin remodeling genes, such as PBRM1 and SETD2, whereas the other subtype was characterized by the upregulation of genes in epithelial-mesenchymal transition and Sonic Hedgehog pathways. IHC staining of top differentially expressed genes between the two subtypes in 312 patients with Chinese chordoma with long-term follow-up data showed that the expression of some markers such as PTCH1 was significantly associated with survival outcomes.

Implications and Future Directions

  • The study's findings may improve the understanding of subtype-specific tumorigenesis of chordoma and inform clinical prognostication and targeted options. Future research should validate the molecular subtypes identified in this study in larger cohorts and explore the clinical implications of these subtypes. Additionally, the study suggests that targeted therapies that target specific genes or pathways may be more effective in chordoma treatment. Future research should investigate the efficacy of these targeted therapies in clinical trials.
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