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Volume 12 Supplement 1

Breast Cancer Research 2010

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A novel tumour-based test to identify breast cancer due to BRCA1 and BRCA2 mutations


To develop a sensitive and specific pathology-based predictor to improve identification of BRCA1 and BRCA2 gene carriers.


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) from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study. Gene carriers were matched to sporadic cases for ER status. Tissue microarrays were assembled and subjected to immunohistochemical analysis with a panel of 18 antibodies. DNA from tumour tissue and matched patient lymphocytes was subjected to high-resolution tiling path microarray-based comparative genomic hybridisation (aCGH). Bioinformatics analysis highlighted DNA regions significantly differentially lost, gained or amplified in BRCA1 or BRCA2 carrier tumours compared with controls. Chromogenic in situ hybridisation (CISH) identified amplifications in all training samples.


Two neighbouring regions of differential amplification (3q25.31 and 3q25.2) were identified in BRCA1 cases and one in BRCA2 cases (20q13.13). As expected, ER, PR and HER2 negative status was highly predictive of a BRCA1 gene carrier. Using just ER and HER2 plus the CISH probes we were able to assign BRCA1 and BRCA2 cases accurately in 74% and 81% of cases tested. The probability of misclassifying a control as a carrier was 5% and 12% in each case. These results equated to positive and negative predictive values of 0.92 and 0.90 for BRCA1 and 0.72 and 0.92 for BRCA2. The BRCA1 and BRCA2 tumour tests are being validated in a new set of tissue microarrays comprising 223 tumours from the POSH study.


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.

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An, Q., Jones, L., Tapper, W. et al. A novel tumour-based test to identify breast cancer due to BRCA1 and BRCA2 mutations. Breast Cancer Res 12 (Suppl 1), P31 (2010).

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