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One Key Gene is Likely "First Hit" in Triggering Development of Cancers TORONTO, April 1, 1997 -- Clinical scientists at the Ontario Cancer Institute/Princess Margaret Hospital (OCI/PMH) have moved a step closer in revealing one of the critical mechanisms responsible for altering genes in blood cancers such as leukemia and lymphoma, and most likely in breast, ovarian and other cancers. In a report released today in the prestigious international journal Blood, authors Drs. Robert Lowsky and John DeCoteau detailed the role of the MSH2 gene in triggering a cascade of genetic mutations or changes which results in the development of cancer. To date, a mutation in the MSH2 gene has only been linked with hereditary nonpolyposis colon cancer in humans. Dr. Lowsky is a clinical scientist in the Dept. of Medical Oncology and Hematology at OCI/PMH, and Dr. DeCoteau is a clinical scientist in the Dept. of Oncologic Pathology at OCI/PMH and an assistant professor at the University of Toronto. The study was done in the laboratory of OCI/PMH senior scientist and leukemia unit head Dr. Mark Minden, and in collaboration with scientists at Harvard Medical School and Tohoku University Hospital in Japan. Dr. Minden is a professor of medicine at the University of Toronto. MSH2 mutation triggers cancer-causing genes The authors were able to show for the first time that the MSH2 gene is abnormal and mutated in cancer cells from patients who have lymphoma and leukemia. They also found that the MSH2 mutation triggers other cancer-causing genes to become active. When the cancer-causing genes or oncogenes are activated by the mutated MSH2 gene, cancer results from these continuously acquired genetic mutations. It is estimated that a normal cell must accumulate at least 5 to 10 mutations in key genes for it to become malignant. "Our findings have broad implications for the development of cancers in general,'' noted Dr. Lowsky, "Scientists will start looking at other known cancer-causing genes and linking them to MSH2. It will be a race now.'' MSH2 acts like "a detective'' The MSH2 gene is a key member of a family of about six known genes that are involved in DNA repair. Typically, when MSH2 is functioning normally, it acts like a detective, constantly surveying the cell for any mistakes to its DNA as the DNA is copied during cell replication. When it spots any, it quickly repairs them. If the MSH2 gene is not functioning properly, the efficient DNA repair system slips up and lets the error become a permanent mutation in one or more of the cell's genes and in that same gene or genes in all the offspring cells. It is these successive additions of genetic defects that cause cells to proliferate wildly and become tumours. "MSH2 is probably a common mechanism for the development of many cancers,'' said Dr. DeCoteau, noting that all cancers go through the same process of acquiring genetic mutations. He added that although "there will not ever be one gene that can explain all cancers, the MSH2 gene seems to be a very critical gene. A mutation in this gene appears to be a very important step in the development of at least three human cancers, with good evidence mounting for its role in ovarian and breast cancer. Moreover, as scientists really start examining this gene, we believe that it will most likely be linked to other cancers as well.'' E-mail this page to a friend or colleague! To print, use this version