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Researchers find genetic variant associated with rare skull and spine cancer

Research led by one of our BRC researchers has discovered a genetic variant associated with a five-fold increase in the risk of developing chordoma, a rare cancer which affects the bones of the skull and spine.

The research, led by Professor Adrienne Flanagan and published in Nature Genetics, found that over 95% of European chordoma patients have a single letter variation in the DNA sequence of a gene called brachyury.

Chordoma is a devastating form of cancer that frequently returns after surgery, and is resistant to radiation and conventional chemotherapy. Most patients ultimately succumb to their disease after an average of seven years. No drugs are approved to treat chordoma, and, until recently, little was known about the biology of chordoma.

Dr Nischalan Pillay, who has spent the last 3 years working on this project as part of his PhD says, “This study makes a strong case that this particular variation in the brachyury gene contributes significantly to the development of chordoma in nearly all patients. It is a major step forward in our understanding of how chordoma develops, and can open the door to the development of an effective, targeted treatment.”

Brachyury is a gene of emerging significance for cancer. In addition to chordoma, it has recently been implicated in other types of cancer, including colon cancer and lung cancer. It is highly expressed in nearly all chordomas as well as a number of other cancers, but not in normal tissues.

In 2009 scientists found that inheriting an extra copy of brachyury is responsible for causing familial chordoma. Individuals with familial chordoma receive three copies of this gene rather than the two copies normally inherited, one each from mother and father. This latest finding confirms that the brachyury gene also plays a central role in the more typical sporadic (non-familial) version of the cancer.

Recently, Professor Flanagan and colleagues demonstrated that genetically ‘silencing’ brachyury stops the growth of chordoma cells in laboratory experiments. In a paper published in the Journal of Pathology, Dr Pillay showed that brachyury acts as a master regulator of a network of molecules that contribute to uncontrolled growth of chordoma cells.

Upcoming research will focus on understanding why the alteration in brachyury is so critical for chordoma development, and what other factors are at play. Answering these questions may enable scientists to develop an effective treatment that reverses or blocks the effect of the alteration. The researchers are currently working on developing a means of inhibiting brachyury and the pathway of molecules it controls in cancer.

These research results are the latest outcome of the Chordoma Genome Project, a collaborative effort funded by the Chordoma Foundation, which aims to catalogue all of the genetic changes that drive chordoma in hopes of identifying new targets for treatment. The Rosetrees Trust and Skeletal Cancer Action Trust (Scat), UK provided additional support for this research.