© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 5, 469-473,
March 3, 1999
© 1999 Oxford University Press
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Frequency of p53 Mutations in Breast Carcinomas From Ashkenazi Jewish Carriers of BRCA1 Mutations
Affiliations of authors: K.-A. Phillips, Center for Cancer Genetics and Samuel Lunenfeld Research Institute of Mt. Sinai Hospital, and Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, ON, Canada; K. Nichol, Center for Cancer Genetics and Samuel Lunenfeld Research Institute of Mt. Sinai Hospital; H. Ozcelik, Center for Cancer Genetics and Samuel Lunenfeld Research Institute of Mt. Sinai Hospital, and Department of Laboratory Medicine and Pathobiology, University of Toronto; J. Knight, Division of Preventive Oncology, Cancer Care Ontario; S. J. Done, Samuel Lunenfeld Institute of Mt. Sinai Hospital, and Department of Laboratory Medicine and Pathobiology, University of Toronto; P. J. Goodwin, Samuel Lunenfeld Research Institute of Mt. Sinai Hospital and Marvelle Koffler Breast Center of Mt. Sinai Hospital; I. L. Andrulis, Center for Cancer Genetics and Samuel Lunenfeld Research Institute of Mt. Sinai Hospital, Department of Laboratory Medicine and Pathobiology and Department of Medical and Molecular Genetics, University of Toronto, and Division of Preventive Oncology, Cancer Care Ontario.
Correspondence to: Irene L. Andrulis, Ph.D., Center for Cancer Genetics, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, 600 University Ave., Toronto, ON M5G 1X5, Canada (e-mail: andrulis{at}mshri.on.ca).
BACKGROUND: Breast carcinomas occurring in carriers of BRCA1 gene mutations may have a distinctly different pathway of molecular pathogenesis from those occurring in noncarriers. Data from murine models implicate loss of p53 (also known as TP53) gene function as a critical early event in the malignant transformation of cells with a BRCA1 mutation. Therefore, breast tumors from BRCA1 mutation carriers might be expected to exhibit a high frequency of p53 mutations. This study examined the frequency of p53 mutations in the breast tumors of Ashkenazi Jewish carriers and noncarriers of BRCA1 mutations. METHODS: Tumor DNA from carriers and noncarriers of BRCA1 mutations was screened for mutations in exons 4 through 10 of the p53 gene by use of the polymerase chain reaction and single-strand conformation polymorphism (SSCP) analysis of the amplified DNA. Direct sequencing was performed on gene fragments that showed altered mobility in SSCP analysis. RESULTS: Mutations in the p53 gene were detected in 10 of 13 tumors from BRCA1 mutation carriers versus 10 of 33 tumors from noncarriers (two-sided P = .007). The p53 mutations were distributed throughout exons 4 through 10 and included both protein-truncating and missense mutations in both groups. CONCLUSIONS: A statistically significantly higher frequency of p53 mutations was found in breast tumors from carriers of BRCA1 mutations than from noncarriers, which adds to the accumulating evidence that loss of p53 function is an important step in the molecular pathogenesis of BRCA1 mutation-associated breast tumors. This finding may have implications for understanding phenotypic differences and potential prognostic differences between BRCA1 mutation-associated hereditary breast cancers and sporadic cancers.
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