Inherited Gene Change Also Found In Spontaneous Tumors

Thefindings, published in the Oct. 5 issue of the Journal of the AmericanMedical Association, suggest that the variation might play afundamental role in the development and spread of cancer in the body,and that the variant could be an important target for anticancer drugs.

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

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

The research was led by scientists at TheOhio State University Comprehensive Cancer Center – Arthur G. JamesCancer Hospital and Richard J. Solove Research Institute and at theRobert H. Lurie Comprehensive Cancer Center at Northwestern University .

“Ourfindings show for the first time that the 6A variation of this genealso arises by mutation during tumor development in patients born withthe normal TGFBR1 gene, and that this mutation may contribute to tumorgrowth and spread,” says principal investigator Christopher M.Weghorst, an associate professor with the OSU School of Public Healthand a researcher with the Comprehensive Cancer Center.

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

In some cases, the variants in these tumors had beeninherited, but, says lead author Boris Pasche, assistant professor ofmedicine at Northwestern University , “the majority of the livermetastases had acquired the variant as a mutation during cancerprogression. This shows the dramatic impact of this gene on the growthof cancer cells in humans, and suggests that this molecule may becomean excellent target for new therapies for patients with colorectalcancer, especially those with liver metastases.”

The findingsalso provide insights into the effects of the signaling moleculetransforming growth factor beta. Transforming growth factor betanormally slows the growth of cells known as epithelial cells, and maystimulate the growth of cancerous epithelial cells. (Epithelial cellsline the ducts, passages and hollow organs of the body and are thecells in which most cancers arise.)

This signaling molecule worksby docking with TGFBR1, which is located on the surface of cells.Normally, the joining of the two molecules tells the cell to stopgrowing.

This new research indicates, however, that if the normalTGFBR1 gene mutates, causing a cell to have the TGFBR1-6A variant onits surface, the signaling molecule enables the cell to start growingand helps the growing tumor to metastasize.

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

Theyfound the 6A variant in 2.5 percent of primary colorectal tumors and1.8 percent of head and neck primary tumors, and in 29.5 percent of thetumors that had metastasized to the liver. The tumors had acquired thevariant as a mutation. The variant was not found as a mutation in thebreast tumors.

“We believe that the presence of the 6A variantplaces an individual at greater risk for developing some type of cancercompared with someone without the variant, and that this has importantpublic health implications,” Weghorst says.

Overall, the evidencefrom the study suggests that the 6A mutation boosts cancer-cell growthand tumor metastasis. This, in turn, suggests that the molecule wouldmake a good target for anticancer drugs that block the action of the 6Amolecule.

Funding from the National Cancer Institute, theNational Institute of Dental and Craniofacial Research, the IllinoisChapter of the American Cancer Society, the Walter S. ManderFoundation, The V Foundation, the Dutch Cancer Society and theNetherlands Organization for Scientific Research supported thisresearch.