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Loss of Heterozygosity and p53 Gene Mutations in Breast Cancer¹

Geraldine Brush Cancer Research Institute, California Pacific Medical Center, San Francisco, California 94115-1932 [G. D., L-C. C., D. R. S., H. S. S.]; Department of Pathology [A. T.], Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Department of Pathology [V. B., B-M. L.] and Laboratory Medicine [K. C.], University of California, San Francisco, California 94143

² To whom requests for reprints should be addressed, at Geraldine Brush Cancer Research Institute, 2330 Clay Street, Room 201, San Francisco, CA 94115.

Immunopositivity for the p53 tumor suppressor gene product was evaluated in 133 breast cancers and compared to loss of heterozygosity (LOH) at various chromosomal loci. The validity of p53 immunopositivity as an indicator for p53 mutations was verified using two molecular assays of p53 mutations: single stranded conformational polymorphism (32 cases) and/or direct sequencing (14 cases). Immunopositivity was highly specific for mutations, since all of 15 strongly immunopositive tumors (>10% of the cells are positive) and seven of nine cases with borderline immunopositivity had mutations by molecular analysis but were somewhat lower in sensitivity, p53 mutations being also detected in three of 23 (13%) immunonegative cases. LOH was measured at loci on the following chromosomes (1p,q; 2p; 3p; 7q; 11p,q; 13q; 16q; 17p; 18p,q; and 22q) by Southern blotting, polymerase chain reaction amplification of restriction fragment length polymorphisms, or repetitive cytidine and adenine stretches (CA repeats). There was no association between p53 mutations and one measure of genomic instability, namely, high incidence of overall LOH. In contrast, p53 mutations strongly associated with LOH at two specific loci, 3p24–26 (P < 0.001) and 7q31 (P < 0.05). There was no association between p53 mutations and LOH at 17p (site of the p53 gene), suggesting that breast cancers often have only one defective allele of the p53 gene.

¹ This work was supported by Grant PO1 CA44768 from the National Cancer Institute.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/ 1/93. Accepted 11/ 8/93.

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