Duke University LogoDuke University Medical Center and National Cancer Institute scientists have discovered that a new genetic alteration seems to be a cause of familial chordoma. Genetic alteration is known to be a second copy of an entire gene. Also, chordoma is believed to be a rare form of cancer arising in bones and normally affects the nervous system.

Apparently, chordoma is rare which strikes only one in every million people. However, it seems to have a shocking diagnosis. It was noted that people who suffer from the disorder usually develop tumors at the base of the skull, in the pelvis, or along the spinal column. The growths are believed to have arisen from remnants of the notochord, an embryonic precursor to spinal column. Supposedly, there are few treatments and no cure for chordoma. For instance, most of the people who have the disease generally appear to die within 10 years.

Inherited differences in gene copy number which is known as copy number variation (CNV) appears to have been implicated in some hereditary diseases. However, it was observed that none of the previously discovered familial cancer genes has had CNV as the genetic change.

“This alteration is unlike anything we have ever seen before in families that tend to develop the same kind of cancers. We are not talking about a mutation in a single gene, but the duplication of an entire gene. This discovery is a classic example of where science answers one question but raises many, many more,” says senior author of the study, Michael Kelley, M.D., an associate professor at Duke University Medical Center.

It was observed that Kelley, chief of hematology and oncology at the Durham Veterans Affairs Medical Center, has been studying chordoma for years along with Dilys Parry, a co-author of the study at the National Cancer Institute. They discovered a family with a history of the disease spanning several generations.

They were of the opinion that there appears to have been some sort of inherited genetic defect at work. For this purpose, Parry carried out clinical studies that ultimately identified six additional families with multiple associations with chordoma.

The initial work seemed to have focused on potential defects on chromosome 7. However, no defect could be found which was shared by all of those affected. The study experts further conducted linkage studies that revealed six novel areas in the genome where possible mutations appear to be likely.

But it wasn’t until they utilized a method called array comparative genomic hybridization which may be able to identify the source of the culprit. Supposedly, array comparative genomic hybridization is a method which allowed them to see structural changes in the genome in exquisite detail. They were noted to have identified it as the T (Brachyury) gene on chromosome 6.

“Brachyury is a transcription factor that helps regulate the development of the notochord and we know the gene is overly active in the tumor tissue in many people with chordoma. So we were pretty sure we were on to something,” adds Kelley.

For the purpose of the study, experts screened approximately 65 individuals in which nearly 21 had chordoma in about seven families with a history of the disease, particularly looking for any alterations in the T gene. The findings revealed that all the patients with chordoma in four of the seven families seem to have a second copy of the T gene. In addition, the duplication did not appear among members of the three other families, nor did it show in nearly 100 healthy, normal controls.

Kelley further stated that, “It is likely that other genes are at work here, or that some other mechanism we do not yet understand is in play. Based on our research, however, we do feel that it may be worthwhile to screen for complex genomic rearrangements when trying to find the cause of familial cancers. It may be a more productive route than traditional gene-mapping methods.”

Kelley claimed that the experts do not understand what Brachyury does in order to cause chordoma. Supposedly, Brachyury expression was found in tissue from chordomas not only in patients who had inherited the duplication but also in those who did not have the duplication.

The findings of the study have been published in the journal, Nature Genetics.