BRCA haploinsufficiency in human breast tumorigenesis.

9512 Background: For individuals genetically predisposed to breast and ovarian cancer through inheritance of a mutant BRCA allele, somatic loss of heterozygosity (LOH) affecting the wild-type allele is considered obligatory for cancer initiation. However, several lines of evidence suggest that phenotypic effects may result from BRCA haploinsufficiency. Here, we test the hypothesis that BRCA haploinsufficiency is associated with human breast tumorigenesis.,Archival breast tissue specimens were obtained from 14 BRCA1-linked breast cancer cases, four BRCA1-linked prophylactic mastectomy (PM) cases, 10 BRCA2-linked breast cancer cases, and six BRCA2-linked PM cases. Laser-catapult microdissection was used to isolate cells from invasive ductal carcinoma (IDC), ductal carcinoma in situ (DCIS), atypical ductal hyperplasia (ADH), and normal epithelium (NE). Following DNA isolation, the ratio of mutant to wild-type allele in each sample was assessed using quantitative real-time PCR. Six BRCA1-linked and six BRCA2-linked cases of ovarian cancer were also analyzed.,Seven of 12 (58%) BRCA1-linked IDCs showed partial or no LOH; one IDC showed complete LOH of the mutant allele. Five of nine (56%) BRCA2-linked IDCs showed partial or no LOH; one case showed complete LOH of the mutant allele. Six of 11 (55%) BRCA1-linked DCIS lesions showed partial or no LOH; one case showed complete LOH of the mutant allele. Three of six (50%) BRCA2-linked DCIS lesions displayed partial or no LOH; one case displayed complete LOH of the mutant allele. In 11 samples of NE associated with BRCA1-linked IDC, one case showed complete LOH of the wild-type allele and six cases showed complete LOH of the mutant allele. In eight samples of NE associated with BRCA2-linked IDC, two cases showed LOH of the wild-type allele and one case showed LOH of the mutant allele. Similar data were obtained from PM specimens containing NE, ADH, and DCIS. In all 12 ovarian cancers, complete LOH of the wild-type allele was observed.,These data indicate that LOH affecting the wild-type BRCA allele is not obligatory for breast tumorigenesis. These data have important implications for the genetic mechanism of BRCA tumor suppression and for the clinical management of this patient population. No significant financial relationships to disclose.