EMBARGOED FOR RELEASE UNTIL 5 p.m., EST, THURSDAY, MARCH 27
Julie A. Penne, M. D. Anderson Cancer Center, 713/792-0662 William Hockett, Myriad Genetics, 801/584-3600
HOUSTON -- Researchers at The University of Texas M. D. Anderson Cancer Center, in collaboration with Myriad Genetics, Inc. of Salt Lake City, have discovered a gene involved in the progression of a fatal form of brain cancer and a number of other cancers.
The identification of the gene, known as MMAC1 (Mutated Multiple Advanced Cancers) is reported in the April 1997 issue of Nature Genetics. Coincidentally, a separate study by researchers at Columbia University's College of Physicians and Surgeons identifying the same brain cancer gene is published in the March 28 issue of Science.
Identification of this gene will provide new insights into not only adult and pediatric glioblastoma multiforme, but also other adult cancers, and is expected to accelerate efforts to develop new treatments.
"This form of brain cancer is very aggressive, and our research suggests that mutations in the MMAC1 gene play a role in the aggressiveness of the tumor," said Dr. Peter Steck, associate professor of neuro-oncology at M. D. Anderson and the study's lead author. "The discovery will extend our understanding of this process not only in glioblastoma multiforme, but in several other solid tumors such as breast, prostate and renal cancers, and melanoma."
According to Dr. Steck, alterations to the gene have predominately been found in advanced forms of these cancers, suggesting that the gene may play a role in the malignant progression of certain cancers.
Dr. Steck cautioned that while identification of the gene is an exciting step in laboratory research, more work lies ahead before new treatment strategies may emerge for patients.
"The sequence of the MMAC1 gene provides a number of important clues to its function, a key step in the search for drug targets and eventually for new treatments," said Sean Tavtigian, Ph.D., director of cancer research at Myriad and the study's senior author. "The predicted function for MMAC1 as a key regulatory enzyme is very amenable to drug intervention. Through our collaboration with M. D. Anderson, we have already begun a directed research effort based on these findings to identify potential drug targets."
An estimated 19,000 new cases of primary malignant brain tumors are expected to be diagnosed in the United States in 1997. They are almost invariably fatal due to their location in the brain and infiltration into surrounding tissue.
Primary brain tumors are the most common solid cancer in children and are a leading cause of cancer deaths among individuals under age 15. These tumors are also the third most common cause of cancer deaths among patients18 to 35 years old.
The research team localized the MMAC1 gene using tumor samples. From the samples, the researchers initially found large areas on chromosome 10 that were deleted. The team then narrowed their search to smaller areas, where both copies of the genetic material on chromosome 10 harbored deletions, and subsequently they identified fragments of the gene. From these fragments, researchers were able to determine the sequence of the entire gene and demonstrate that it was mutated both in tumor cell lines and in primary tumors.
The researchers found the link to disease progression by comparing lower grade brain tumors to the more advanced glioblastomas. The area containing the MMAC1 gene was shown to be deleted in 36 of 37 samples on one of the two copies of chromosome 10 examined. Further analysis of six of these tumors uniformly revealed mutations in the MMAC1 gene on the other copy of chromosome 10. In contrast, while four of 12 lower grade brain tumors exhibited similar deletions, none of them had mutations in the gene.
Analysis of DNA from other types of tumors indicates the MMAC1 is mutated in other cancers, including melanomas and cancers of the prostate, breast and kidney.
One aspect of the MMAC1 gene for future therapeutic discovery is that the gene sequence suggests that it contains a segment encoding an enzyme that is part of a family of proteins called tyrosine phosphatases. These regulatory enzymes function to remove phosphate groups from proteins and act in tandem with specific enzymes, called tyrosine kinases, that add phosphates.
"Blocking the activity of MMAC1's kinase counterpart, which is likely to be an oncogene, may represent a promising therapeutic strategy," said Dr. Tavtigian. "Our research has already identified candidate proteins that interact with MMAC1 with the aim at identifying the specific tyrosine kinases and associated phosphorylation substraits that act along the MMAC1 pathway."
The gene had originally been named BNC1 based on its role in brain cancer, but collaborators have since renamed the gene MMAC1 (Mutated Multiple Advanced Cancers) as it was linked to other high grade cancers.
In addition to Drs. Steck and Tavtigian, the authors on the paper are: M. A. Pershouse, S. A. Jasser, H. Lin, W.K.A. Yung, A. H. Ligon and L.A. Langford from M. D. Anderson; and T. Davis, C. Frye, R. Hu and D.H.F. Teng from Myriad Genetics.
A portion of the research was supported by the National Institutes of Health, the Pediatric Brain Tumor Foundation, the Gilland Foundation and the American Brain Tumor Association.
For more information about the M. D. Anderson Brain Tumor Center or other services, individuals may call 1-800-392-1611, Option 3. The information line is open Monday through Friday, from 9 a.m. to 5 p.m.
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