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Selective Loss of Heterozygosity in Multiple Breast Cancers from a Carrier of Mutations in Both BRCA1 and BRCA2¹

Center for Cancer Risk Analysis [D. W. B., D. A. H.] and Molecular Pathology Unit [D. C. S.], Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, and Division of Hematology/Oncology, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111 [J. E.]

Carriers of one mutant allele of either BRCA1 or BRCA2 are at risk for somatic loss of the second wild-type allele, leading to the initiation of breast tumorigenesis. We identified a patient of Ashkenazi Jewish heritage with germ-line heterozygous mutations in both BRCA1 (5382insC) and BRCA2 (6174delT), who had developed three independent breast cancers by age 47. Two breast cancers demonstrated inactivation of both BRCA2 alleles but retention of the wild-type BRCA1 allele, and the third showed loss of heterozygosity for BRCA1 but not BRCA2. The observation that breast tumors arising in a double heterozygote show biallelic inactivation of either BRCA1 or BRCA2, but not both, suggests that these genetic events are functionally equivalent in initiating tumorigenesis. The distinct histopathological features of these tumors may reflect the acquisition of subsequent genetic events.

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				B Leegte, A H van der Hout, A M Deffenbaugh, M K Bakker, I M Mulder, A ten Berge, E P Leenders, J Wesseling, J de Hullu, N Hoogerbrugge, et al. Phenotypic expression of double heterozygosity for BRCA1 and BRCA2 germline mutations J. Med. Genet., March 1, 2005; 42(3): e20 - e20. [Full Text] [PDF]