The finding is reported in the March 28 issue of the journal, Science. Senior author Ramon Parsons, M.D., Ph.D., assistant professor of pathology and medicine in the Herbert Irving Comprehensive Cancer Center and the departments of pathology and medicine at Columbia-Presbyterian Medical Center, made the finding together with Michael Wigler, Ph.D., of Cold Spring Harbor Laboratory.
"Although initially mutated in breast cancer, we found mutations of P-TEN in brain and prostate cancer and expect to find mutations in other cancers as well," says Dr. Parsons. Unlike mutations of genes such as hMSH2 and BRCA1, which are found in hereditary predispositions to cancer, most P-TEN mutations are found in the more common sporadic cancers. More than 80 percent of all cases of cancer are sporadic.
"Discoveries such as this are rapidly filling in the missing pieces of the cancer puzzle. This discovery represents one of the first genes to be implicated in aggressive and generally fatal brain tumors, a type of cancer in which we desperately need clues that the P-TEN gene may offer," said Richard Klausner, M.D., director of the National Cancer Institute.
There is some evidence to suggest that loss of P-TEN affects the way a benign tumor becomes malignant. "We identified 20 mutations of P-TEN in advanced brain, breast, and prostate cancers," says Dr. Parsons. "Based on our finding, it may someday be possible to test people for mutations of P-TEN, which would give an early warning of cancer danger. P-TEN may also allow us to identify drugs to better treat cancer overall." Although this discovery shows great promise, Dr. Parsons cautions that it is not likely to have an impact on patient care for many years.
P-TEN is located on chromosome 10. The role of this chromosome in the development of various sporadic cancers has been investigated for nearly a decade. For instance, scientists believe that the mutation that causes Cowden's syndrome, a genetic condition that often leads to breast cancer and other tumors, is located on chromosome 10.
P-TEN received its name from its similarity to phosphatases and to tensin, part of a complex of proteins that sits below the cell surface which may be involved in the spread of tumors. The similarity between P-TEN and protein phosphatases, which remove phosphates from proteins, is significant because many oncogenes--genes that activate tumors--are part of a class called tyrosine kinases, which add phosphates to proteins. "This will add a great deal of understanding to the picture of the genetic disarray that takes place when a cell becomes cancerous," says co-author Dr. Wigler.
Representational difference analysis (RDA), an advanced genetic technology developed by Dr. Wigler and Dr. Nikolai Lisitsyn then at Cold Spring Harbor Laboratory, played a key role in the identification of this gene. RDA is a procedure that analyzes the difference between two complex sets of genomes. A genome is the entire DNA sequence of an organism. By comparing DNA from diseased and normal cells from a person, the method can identify DNA sequences that differ between diseased and normal cells from the same person. RDA enriches DNA sequences for unique DNA regions of one of the genomes by removing shared sequences. In this case, RDA was used to find unique sequences present in normal tissue but missing in breast cancer.
Clifford Yen of the Wigler lab used RDA to obtain the first probe for the P-TEN gene. Steven Wang of the Parsons lab and Yen together mapped the probe to chromosome 10. Jing Li and Shikha Bose of the Parsons lab characterized the minimal deletion of chromosome 10 containing the P-TEN gene and along with Danny Liaw and Katrina Podsypanina identified the P-TEN gene and characterized its mutations. Drs. Beppino Giovanella (Stehlin Foundation); Sandra Bigner (Duke University); and Ben Tycko (Columbia University) provided critical tumor material for this project.
The study was funded by the departments of medicine and pathology at Columbia University College of Physicians & Surgeons, Cold Spring Harbor Laboratory, the James S. McDonnell Foundation, the National Cancer Institute, the Department of the Army, Amplicon Corporation, and "1 in 9," a breast cancer advocacy group.
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