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Results of the Chordoma Genome Project reveal genetic changes that drive chordoma

By comparing chordoma tumor DNA to normal DNA, researchers were able to catalog the genetic changes that occur in chordoma tumors, which yielded several important findings.


This month, a group of chordoma scientists led by Dr. Adrienne Flanagan of University College London (UCL) and Dr. Peter Campbell of the Wellcome Trust Sanger Institute published results of the Chordoma Genome Project — the first major genetic sequencing study of sporadic (non-inherited) chordoma. Their findings, which appear in the leading research journal, Nature Communications, provide the most comprehensive insights to date about how chordoma forms, and important clues about how it could be treated.

This publication represents the culmination of a multi-year $215,000 investment by the Foundation which enabled the UCL and Sanger Institute teams to use advanced DNA sequencing technologies to analyze 104 chordoma tumor samples.

Key findings

In recent years, new sequencing technologies have enabled a revolution in the understanding of cancer at a genetic level. This study represents the first time those techniques have been applied at a large scale to chordoma.

By comparing chordoma tumor DNA to normal DNA from the same individuals, the researchers were able to catalog the genetic changes that occur in chordoma tumors. This yielded several important findings, including:

  • Amplification of the brachyury gene is common in sporadic chordoma
    Previous work supported by the Chordoma Foundation found that inheriting an extra copy of brachyury is responsible for familial (inherited) chordoma. The current study revealed that >20% of sporadic (non-inherited) chordomas also acquire an extra copy of the brachyury gene during the development of the tumor. This discovery confirms a close relationship between familial and sporadic chordoma and provides further evidence that brachyury plays an essential role in driving the disease. It also highlights the importance of research to understand better how brachyury functions in chordoma and to develop therapies that target brachyury.
  • Mutations in the PI3K pathway
    The PI3K/Akt/mTOR pathway is activated in the majority of chordomas and this study found that 16% of tumor samples had a mutation in the PI3K signaling pathway. These findings provide further rationale to investigate therapeutics targeting the PI3K pathway in chordoma patients.
  • Mutations in SWI/SNF chromatin remodeling genes
    This publication is the first to implicate a specific subset of mutations affecting the SWI/SNF chromatin remodeling complex in chordoma patients. Mutations in genes in this complex were identified in 17% of chordoma patients, suggesting that epigenetic changes may play an important role in the development of chordoma. This finding may also point to a new therapeutic approach for some chordoma patients.
  • Mutations in the LYST gene
    Novel mutations in lysosomal trafficking regulator gene, LYST, were identified in 10% of chordoma patients – the first time the LYST gene has been implicated in cancer. These mutations are believed to prevent the LYST protein from functioning properly and cause cells to transform into chordoma. Further research will be needed to understand the full role of LYST in chordoma and determine if mutations in the gene can be used to help guide diagnosis or treatment.
  • Low mutational load
    Compared to other tumor types, chordoma has a relatively small number of genetic changes. In total, potentially causative genetic mutations were found in only 45% of tumors. This indicates that the key drivers of many chordoma tumors may be epigenetic changes or structural rearrangements within the genome that are not obvious with current analysis techniques.

Exploring new leads

These findings provide several important leads to pursue which could yield new therapeutic options for chordoma patients.

In the near term, there is now strong rationale for evaluating drugs that target the PI3K and SWI/SNF complex defects observed in this study. Several research groups have already begun work in this area, and are collaborating with the Foundation to test drugs through our Drug Screening Program.

Additionally, the results of this study underscore the urgency to develop therapies that target brachyury. As one of the Foundation’s top research priorities, we plan to invest significantly in this area over the next several years.

Finally, building on this study, research is needed to characterize the epigenetic changes that contribute to chordoma development. By adding this additional layer of data on top of the genetic changes characterized by this study, we will likely gain a more complete picture of how chordoma forms and the key pathways responsible for driving it.

A team effort

These important findings are the product of an impressive collaboration among a team comprising pathologists, surgeons, cancer biologists, and bioinformaticians from over a dozen institutions in North America and Europe. Our Co-Founder and Executive Director Josh Sommer and Manager of Research Patty Cogswell were also intimately involved in orchestrating the project and are co-authors on the paper.

The work was enabled by the generous contributions of many in the chordoma community in the US, Canada, and the UK. Special thanks go to Gerry and Susan Fitz-Gibbon whose organization, Chordoma UK provided vital support to Dr. Flanagan’s lab.

“This critical addition to the scientific knowledge base about chordoma would not have been possible without the dedication and involvement of patients and family members around the world. Thanks to them, we now have a clearer roadmap for how to attack chordoma and improve treatment in the future.”
– Professor Adrienne Flanagan, University College London and the Royal National Orthopaedic Hospital NHS Trust

The Foundation is grateful to all the investigators and donors who by working together made this study possible. It represents a major step forward for patients, researchers, and clinicians in understanding the genetic basis of chordoma and paves the way for better and more personalized treatments to come.

Access the full Nature Communications article »
Read the Sanger Institute’s press release »
Learn more about the CGP »

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