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Departments of Medicine, Microbiology, and Molecular Genetics and Vermont Cancer Center, University of Vermont, Burlington, Vermont 05405 [M. S. G., J. P. B.]; Departments of Medicine and Oncology and Cancer Prevention Research Unit, Sir M. B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, Canada [P. O. C., W. D. F.]; and McGill University Health Centre Research Institute and Departments of Medicine, Human Genetics, and Oncology, Montreal General Hospital, McGill University, Montreal, Quebec H3G 1A4, Canada [P. O. C., N. H., W. D. F.]
Several groups have studied the molecular pathology of inherited breast cancer. By combining several such studies, we show in this study that somatic TP53 abnormalities are more common in breast cancer associated with BRCA1 or BRCA2 germ-line mutations than in sporadic breast cancers (odds ratio, 2.8; P = 0.0003). Then, we compared the spectrum of TP53 mutations for breast cancers in the IARC TP53 mutation database with the 82 mutations reported in BRCA1/2-associated breast cancers. The spectrum differed significantly both in distribution (P < 1 x 10-6) and in base changes (P = 0.025). Mutations at A:T bp were more common in BRCA1/2-associated tumors and strand bias suggesting DNA repair abnormalities was found. Changes were common at TP53 codons that are not mutation hotspots. Structural modeling showed that most of these p53 non-hotspot amino acids characterized in breast tumors isolated from patients with deficient BRCA1/2 function are distributed in a region of the protein on the opposite side of the p53 DNA-binding surface. Our results suggest that BRCA1/2 mutations influence the type and distribution of TP53 mutations seen in breast cancer.
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