Inheriting an Extra Copy of the T (Brachyury) Gene May Cause a Rare Form of Bone Cancer
The Bottom Line
Results from genetic studies of people with a familial, or hereditary, form of a rare type of bone cancer called chordoma show that inheriting an extra copy of an entire gene, known as the T (brachyury) gene, may cause some cases of the disease.
The Whole Story
Chordoma is a rare type of bone cancer that develops at the base of the skull, along the spine, or in the upper part of the tailbone (sacrum). The cells that give rise to chordoma are left over from a structure called the notochord, which guides the development of the spinal column in a developing embryo.
Although rare, with about 300 new cases diagnosed each year in the United States, chordoma is the most common primary malignant tumor of the spine and sacrum. There are few effective treatments for this cancer and no cure. Most people with chordoma have no other affected family members. However, chordoma can run in families, which suggests that it can be caused by inheritance of an altered or mutated gene.
To look for genetic changes that could cause inherited chordoma, NCI researchers and their colleagues studied seven families in which two or more blood relatives were diagnosed with the disease. Using an approach called linkage analysis, they first tried to determine whether specific genetic markers that have known locations in the human genome are inherited along with the disease in affected family members. This approach helps narrow down the location of possible disease-related genes to specific regions of certain chromosomes.
With this initial analysis, the researchers identified six regions of the genome that merited additional study. More detailed genetic analysis subsequently showed that a region on chromosome 6 was most likely to be associated with familial chordoma. This region contains a gene, called T, or brachyury, that plays an important role in notochord development. Previous studies had shown that the T gene is expressed in virtually all chordomas but not in a wide variety of normal tissues or other cancer types. These observations made the T gene a good candidate for involvement in familial chordoma.
Next, the research team looked for potential disease-causing mutations in the T gene in people with familial chordoma, but they did not find any in the T gene or in 20 other nearby genes that they examined. They then searched for a different kind of genetic change, known as a copy number variation, or CNV. In a CNV, a region of DNA on a chromosome is duplicated or deleted, meaning that the chromosome carries an altered copy of the gene(s) contained within that region.
The researchers found that, in four of the seven chordoma families, all of the people with chordoma, but no unaffected family members, had an extra copy of the T gene. No T gene duplications were present in any of the chordoma patients from the other affected families or in 100 healthy, normal control individuals.
The results of this study suggest that the T gene plays an important role in at least some cases of familial chordoma and that inheriting an extra copy of this gene can contribute to disease development. In the three families without T gene duplications, the researchers say, chordoma may result from mutations in other genes or from a still-unidentified process involving the T gene.
These findings also have broader importance for other studies into the causes of familial cancers. Novel approaches that look for large-scale rearrangements of the genome, such as CNVs, in addition to traditional approaches that look for smaller alterations or simple DNA mutations may help identify relevant genetic changes more quickly.
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