Heterogenic Loss of the Wild-Type BRCA Allele in Human Breast Tumorigenesis

Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Annals of Surgical Oncology (Impact Factor: 3.93). 10/2007; 14(9):2510-8. DOI: 10.1245/s10434-007-9372-1
Source: PubMed


For individuals genetically predisposed to breast and ovarian cancer through inheritance of a mutant BRCA allele, somatic loss of heterozygosity affecting the wild-type allele is considered obligatory for cancer initiation and/or progression. However, several lines of evidence suggest that phenotypic effects may result from BRCA haploinsufficiency.
Archival fixed and embedded tissue specimens from women with germ line deleterious mutations in BRCA1 or BRCA2 were identified. After pathologic review, focal areas of normal breast epithelium, atypical ductal hyperplasia, ductal carcinoma-in-situ, and invasive ductal carcinoma were identified from 14 BRCA1-linked and 9 BRCA2-linked breast cancers. Ten BRCA-linked prophylactic mastectomy specimens and 12 BRCA-linked invasive ovarian carcinomas were also studied. Laser catapult microdissection was used to isolate cells from the various pathologic lesions and corresponding normal tissues. After DNA isolation, real-time polymerase chain reaction assays were used to quantitate the proportion of wild-type to mutant BRCA alleles in each tissue sample.
Quantitative allelotyping of microdissected cells revealed a high level of heterogeneity in loss of heterozygosity within and between preinvasive lesions and invasive cancers from BRCA1 and BRCA2 heterozygotes with breast cancer. In contrast, all BRCA-associated ovarian cancers displayed complete loss of the wild-type BRCA allele.
These data suggest that loss of the wild-type BRCA allele is not required for BRCA-linked breast tumorigenesis, which would have important implications for the genetic mechanism of BRCA tumor suppression and for the clinical management of this patient population.

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    • "Initial studies of LOH in the breast tumours of BRCA1 carriers reported a rate of 75% (75/101) of LOH of the wild type allele [53]-[56]. More recently, quantitative allelotyping has demonstrated a significant degree of variability in the extent and direction of LOH in breast tumours [57]. In some cases, normal tissue shows LOH of the wild type BRCA1 allele, and tumor tissue shows loss of the mutant allele. "
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    PLoS ONE 06/2014; 9(6):e100068. DOI:10.1371/journal.pone.0100068 · 3.23 Impact Factor
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    • "There is mounting evidence that heterozygosity for BRCA2 is sufficient for human carcinogenesis in tissues other than the pancreas, with the attendant implications for therapy using PARP1i. Lack of LOH has been documented using different methods in up to ∼30% of breast cancers (King et al., 2007), by NGS in ∼25% high-grade serous ovarian carcinomas (Cancer Genome Atlas, 2011), and in up to 55% of prostatic cancers associated with BRCA2 mutation carriers (Willems-Jones et al., 2012). Thus, it will be essential in future clinical trial designs to test for LOH in tumour samples to help stratify likely responders to PARP1i or similar targeted therapies. "
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    • "However, loss of the mutant allele is not an unprecedented finding even for a bona fide breast cancer predisposition gene. In a recent study performed by King et al., 23 BRCA-linked breast tumors and 10 BRCA-linked prophylactic mastectomy (PM) specimens were analyzed for loss of the wild-type allele [29]. No loss of heterozygosity (LOH) or LOH involving the mutant allele was observed in a substantial fraction of pre-invasive and invasive breast carcinomas. "
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