October 11, 2005
Scientists Uncover Target for Colorectal Cancer
CHICAGO—A common, inherited gene that predisposes one in eight people to development of certain forms of cancer is found in 50 percent of metastatic liver tumors from colorectal cancer, a Northwestern University study has found.
The majority of liver metastases that carry the gene, TGFBR1*6A, acquire it during cancer progression, showing the dramatic impact of this gene on the growth of cancer cells in humans, said Boris C. Pasche, MD, PhD, lead researcher on the study, which was published in the October 5 issue of the Journal of the American Medical Association.
“TGFBR1*6A may therefore become an excellent target for new therapies for patients with colorectal cancer, especially those with liver metastases,” Dr. Pasche said.
Dr. Pasche, who discovered the TGFBR1*6A gene in 1998, is assistant professor of medicine, Division of Hematology/Oncology, at Northwestern University’s Feinberg School of Medicine and director of the cancer genetics program at The Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Previous studies have shown that TGFBR1*6A is found in a large proportion of the general population (14 percent) and significantly increases breast, colon, and ovarian cancer risk in the general population and also in a substantial proportion of individuals with hereditary colon cancer. Until now, just how TGFBR1*6A contributes to cancer development has been largely unknown.
“We reasoned that if TGFBR1*6A in the body’s DNA predisposes to these cancers, it might be even more common in the tumors themselves through somatic acquisition [genetic mutation],” Dr. Pasche said.
As reported in the JAMA study, Dr. Pasche and co-researchers found that TGFBR1*6A appears to bestow cancer cells with a dramatic growth advantage in the presence of TGF-beta, a potent, naturally occurring inhibitor of cell growth.
Although TGF-beta is a growth inhibitor in normal cells, cancer cells secrete larger amounts of TGF-beta than normal cells. The association of TGF-beta is strongest in the most advanced stages of tumor progress.
Dr. Pasche and colleagues discovered that the *6A gene acts as a dominant allele (gene variation) that switches TGF-beta growth-inhibitory signals into growth-stimulatory signals in cancer. This means that one single copy of the *6A gene is sufficient to cause its biological effects.
Moreover, they found that the *6A is the first tumor susceptibility gene known to act through its signal sequence, a small piece of protein that is cleaved off during protein synthesis in the cell.
Dr. Pasche and associates conducted genetic testing on DNA from cancerous tumors and other cancer cells and from normal tissues in 531 study participants with a diagnosis of head and neck, colorectal, or breast cancer. They found that *6A was acquired in 30 percent of colorectal cancer metastases, 3 percent of colorectal tumors, 2 percent in head and neck primary tumors, and none of the study participants with breast cancer.
“Individuals who carry the *6A gene, either in the body’s DNA or mutated in the tumor, may have a greater likelihood of developing metastases than individuals who do not care this allele. *6A may therefore serve as a useful biomarker in cancer,” the authors said.
This study was supported by grants CA90386 and CA 89018, DE/CA 11921, CA 67941, and P30 CA16058 from the National Cancer Institute; PO1 DE1204 and RO1 DE0111943 from the National Institute of Dental and Craniofacial Research; the Illinois Division of the American Cancer Society; The Walter S. Mander Foundation; The V Foundation; the Dutch Cancer Society; and the Netherlands Organization for Scientific Research.
Dr. Pasche is the recipient of a career development award from the Avon Foundation.