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    Gerard P. Zambetti, PhD

    Gerard Zambetti, PhD



    Small change in gene mutation has big effect

    The discovery of an unexpected mutation in a patient supports researchers’ belief that different mutations in the same cancer preventing gene—p53—can have vastly different medical consequences. Mutations in p53 are significant because they account for half of all human cancers.

    The St. Jude team discovered that a patient had inherited a mutation in the p53 gene that caused a minor but critical alteration: One of the building blocks of this protein, the 175th amino acid, was changed from arginine to leucine. This finding was unexpected because the mutation that usually occurs in this position changes the arginine to a different amino acid—histidine—according to Gerard Zambetti, PhD, Biochemistry.

    The switch from arginine to histidine, when inherited, is linked to a cancer-causing condition called Li-Fraumeni Syndrome (LFS). People with LFS develop any of a variety of cancers, such as leukemia or cancer of the breast, bone, adrenal or brain; these tumors usually arise when they are children or young adults.

    But the mutation in which leucine instead of histidine was substituted for arginine caused a major change in the cancer profile of the family of the St. Jude patient. “The patient developed adrenal cortical carcinoma without increasing the risk of the other cancers associated with LFS,” Zambetti said.

     “Understanding the consequence of the different p53 mutations on its activity will be very important for genetic counselors to know,” he said. “For example, a woman who inherits the arginine-to-histidine mutation may be advised by her physician to have a double mastectomy due to the likelihood of developing breast cancer. But we showed that a woman who inherits the arginine-to-leucine mutation found in our patient may not be at such a high risk, thereby reducing the benefits of prophylactic surgery.”

    Zambetti is senior author of a report on this work that appeared in the May 15 issue of Cancer Research.

    Other St. Jude authors include Jesse Jenkins, MD, Pathology; Richard Kriwacki, PhD,  Structural Biology; Raul Ribeiro, MD, International Outreach; Carlos Rodriguez-Galindo, MD, Oncology; and Nico West, Biochemistry.

    August 2006