sequencing finds many underlying genetic causes for chordoma, a rare bone
- Mutated PI3
kinase signaling genes, an additional copy of the T gene and a new
cancer gene called LYST all contribute to develop chordoma
- This discovery
opens up novel therapeutic options to treat the cancer.
Scientists from the Wellcome Trust Sanger Institute,
University College London Cancer Institute and the Royal National Orthopedic
Hospital NHS Trust suggest that patients with a rare bone cancer of the
skull and spine called chordoma could be helped by existing drugs.
suggestion was made based on the discovery made by scientists that a group
of chordoma patients have been found to have mutations in genes that are the
target of existing drugs, known as PI3K inhibitors.
This study, the largest genomics study of
chordoma to date, has been published in Nature
Following the discovery, the researchers suggest a
clinical trial of PI3K inhibitors for this particular group of chordoma
patients, who could benefit from existing treatments.
Genomic sequencing was used for the discovery
sequencing was used for the first time to gain a better understanding
of the biology underlying chordoma.
from 104 patients revealed that 16 percent of the tumor samples had genetic
changes, or mutations, in PI3K signaling genes. PI3K genes can be targeted by
existing drugs, known as PI3K inhibitors, which have so far been used to treat
many cancers, including breast cancer, lung cancer and lymphoma, but have not
yet been considered for chordoma.
‘Genomic sequencing has helped find many underlying causes for chordoma, a rare bone cancer, promising new treatment options for a cancer with a poor prognosis.’
Another discovery made through genomic sequencing
was the fact that only one additional copy of the gene brachyury, or T,
seems to drive these tumors.
A new cancer gene specific to chordoma,
known as LYST,
and not found in any other cancer has also been found.
Dr Sam Behjati, joint first author from the
Wellcome Trust Sanger Institute, said: "By sequencing the tumors' DNA, we
get a much clearer view of the genetic changes that drive chordoma. We have
shown that a particular group of chordoma patients could be treated with PI3K
inhibitors, based on their mutations. This would have been missed had we not
done genomic sequencing of their tumors."
Chordoma: Rare Spine
Chordoma is a rare
type of bone
cancer that affects the spine anywhere from the base
of the skull to the tailbone,
causing symptoms of pain,
weakness, or numbness in the back, arms, or legs. The tumors are
slow-growing, gradually extending into the bone and soft tissue around
them; yet they are aggressive and life-threatening. They form in
the vertebral bodies of the spine, the sacrum and base of the skull probably
developing from persistent embryonic tissue, known as the notochord.
One half of the
tumors occur in the base of the spine (sacrum), one third in the base of the
skull (occiput), and the rest in the neck, upper back or lower back vertebrae
of the spine. The signs and symptoms occurring with this cancer arise due to
the growing chordoma that puts pressure on the adjacent areas of the brain or
Chordomas can affect individuals
of all ages but typically occur in adults between ages 40 and 70. They are
rare and affect approximately 1 per million individuals each year; in the UK
they affect 1 in every 800,000 people.
Treatment for the cancer is difficult owing to
the involvement of critical structures such as the brainstem, spinal cord, and
important nerves and arteries. So far, surgery and radiation are the only
effective forms of treatment though they are not foolproof. The tumors
often recur after treatment, and also spread in about 40 percent of cases to
other areas of the body, such as the lungs.
Future plans for the treatment of chordoma
The findings provide a resource for chordoma
research in the future and have opened up three ways of targeting chordoma.
clinical trials using PI3K inhibitors to target the mutated genes
a therapeutic approach to switch off the extra copy of the T gene
the function of LYST as a cancer gene and its role in the development of
Josh Sommer, a survivor of chordoma and Executive
Director of the Chordoma Foundation, USA, said: "These findings represent
a major step forward in understanding the underlying causes of chordoma, and
provide hope that better treatments may soon be available for some patients."
- Patrick S. Tarpey, Sam Behjati, Matthew D. Young, Inigo Martincorena, Ludmil B. Alexandrov, Sarah J. Farndon, Charlotte Guzzo, Claire Hardy, Calli Latimer, Adam P. Butler, Jon W. Teague, Adam Shlien, P. Andrew Futreal, Sohrab Shah, Ali Bashashati, Farzad Jamshidi, Torsten O. Nielsen, David Huntsman, Daniel Baumhoer, Sebastian Brandner, Jay Wunder, Brendan Dickson, Patricia Cogswell, Josh Sommer, Joanna J. Phillips, M. Fernanda Amary, Roberto Tirabosco, Nischalan Pillay, Stephen Yip, Michael R. Stratton, Adrienne M. Flanagan, Peter J. Campbell. The driver landscape of sporadic chordoma. Nature Communications, 2017; 8 (1) DOI: 10.1038/s41467-017-01026-0