Gene variation may play fundamental role in the development and spread of cancer in the body

Oct 9 2005

New research shows that a small gene variation that increases the risk of inherited cancer can also arise during the development of spontaneous, or non-inherited, tumors.

The findings, published in JAMA: The Journal of the American Medical Association, suggest that the variation might play a fundamental role in the development and spread of cancer in the body, and that the variant could be an important target for anticancer drugs.

The research focused on the gene for type 1 transforming growth factor-beta receptor, or TGFBR1, and on a variation of that gene, TGFBR1-6A. The 6A variant can be inherited and can increase cancer susceptibility by 19 percent in individuals with one copy of the gene and by 70 percent in those carrying two copies.

The study showed that the 6A variant, which is carried by nearly one in seven Americans generally and by one in six people with cancer, can also arise as a gene mutation during cancer development.

The research was led by scientists at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.

"Our findings show for the first time that the 6A variation of this gene also arises by mutation during tumor development in patients born with the normal TGFBR1 gene, and that this mutation may contribute to tumor growth and spread," says principal investigator Christopher M. Weghorst, an associate professor with the OSU School of Public Health and a researcher with the Comprehensive Cancer Center.

Furthermore, the researchers found the 6A variant in half of the metastatic liver tumors they examined. These tumors had spread to the liver from the colon.

In some cases, the variants in these tumors had been inherited, but, says lead author Boris Pasche, assistant professor of medicine at Northwestern University , "the majority of the liver metastases had acquired the variant as a mutation during cancer progression. This shows the dramatic impact of this gene on the growth of cancer cells in humans, and suggests that this molecule may become an excellent target for new therapies for patients with colorectal cancer, especially those with liver metastases."

The findings also provide insights into the effects of the signaling molecule transforming growth factor beta. Transforming growth factor beta normally slows the growth of cells known as epithelial cells, and may stimulate the growth of cancerous epithelial cells. (Epithelial cells line the ducts, passages and hollow organs of the body and are the cells in which most cancers arise.)

This signaling molecule works by docking with TGFBR1, which is located on the surface of cells. Normally, the joining of the two molecules tells the cell to stop growing.

This new research indicates, however, that if the normal TGFBR1 gene mutates, causing a cell to have the TGFBR1-6A variant on its surface, the signaling molecule enables the cell to start growing and helps the growing tumor to metastasize.

For this study, Weghorst, Pasche and a group of colleagues looked for the 6A gene variation in tumor tissue from 226 patients with head and neck cancer, 157 patients with primary colorectal cancer, 104 patients with breast cancer and 44 patients with liver metastases from colorectal cancer.

They found the 6A variant in 2.5 percent of primary colorectal tumors and 1.8 percent of head and neck primary tumors, and in 29.5 percent of the tumors that had metastasized to the liver. The tumors had acquired the variant as a mutation. The variant was not found as a mutation in the breast tumors.

"We believe that the presence of the 6A variant places an individual at greater risk for developing some type of cancer compared with someone without the variant, and that this has important public health implications," Weghorst says.

Overall, the evidence from the study suggests that the 6A mutation boosts cancer-cell growth and tumor metastasis. This, in turn, suggests that the molecule would make a good target for anticancer drugs that block the action of the 6A molecule.