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- W2043502827 abstract "Background: Family history and young onset are the usual indicators of an underlying genetic predisposition to breast cancer development. BRCA1 associated breast tumours are more likely to be ER negative and express “basal” markers, however most patients with ER negative/ basal marker positive breast cancers (especially young onset) do not have inherited BRCA1 mutations. BRCA1 and BRCA2 gene carriers may have novel treatment options available and may need to consider future cancer prevention strategies. Genetic counselling and germline mutation analysis remains a relatively expensive option that is not appropriate for most breast cancer patients.Aim: To design a sensitive and specific pathology based predictor that would improve identification of BRCA1 and 2 gene carriers.Method: We assembled a training panel of breast cancer tumour blocks from 67 BRCA1, 71 BRCA2 associated and 105 sporadic young onset cases (≤ 40 years at diagnosis). All gene carriers were diagnosed before 50 years and were matched to sporadic cases for ER status. Tissue micro arrays (TMAs) were assembled and subjected to immunohistochemical analysis with a panel of 18 antibodies. DNA was extracted from micro dissected tumour tissue and matched patient lymphocytes and subjected to high resolution tiling path microarray-based Comparative Genomic Hybridisation (aCGH). Using robust statistical approaches, regions significantly differentially lost, gained or amplified in BRCA1, BRCA2 and controls were identified. Probes for chromogenic in situ hybridisation (CISH) for amplified regions were generated.Results: Two differentially amplified clones in BRCA1 cases designated P1 at 3q25.31 and P2 at 3q25.2 and one in BRCA2 cases, P3 at 20q13.13, were identified and amplifications validated in the training set using CISH. Logistic regression analysis of the panel comprising CISH and IHC markers was used to develop the best predictor. The best predictor for BRCA1 gene carriers was a combination of P1, ER and HER2. This combination outperformed all combinations of immunohistochemical markers, including ER and basal markers; the Positive Predictive Value (PPV) was 87.5% and NPV 92% giving a Receiver Operator Characteristic (ROC) curve with an AUC of 0.92 (CI 0.88-0.97). The BRCA2 signature panel is currently being evaluated. These BRCA1 and BRCA2 predictor panels are being validated in a new set of TMAs comprising 223 tumours from the POSH study 1 .Conclusion: This tumour based predictor for BRCA1 and BRCA2 carriers may prove useful to identify gene carriers at low a priori chance of having a mutation, to direct BRCA1/2 targeted treatment approaches and to identify familial non BRCA1/2 cases that may be suitable for new gene discovery studies.1. Eccles D et al. BMC Cancer 2007; 7(1):160. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5032." @default.
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- W2043502827 date "2009-12-15" @default.
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- W2043502827 title "A Novel Tumour-Based Test To Identify Breast Cancer Due to BRCA1 and BRCA2 Mutations." @default.
- W2043502827 doi "https://doi.org/10.1158/0008-5472.sabcs-09-5032" @default.
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