Title : BRCA 1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP 53 mutations

Background: Basal-like breast cancers (BLBC) are aggressive breast cancers for which, so far, no targeted therapy is available because they typically lack expression of hormone receptors and HER2. Phenotypic features of BLBCs, such as clinical presentation and early age of onset, resemble those of breast tumors from BRCA1-mutation carriers. The genomic instability of BRCA1-mutated tumors can be effectively targeted with DNA-damaging agents and poly-(ADP-ribose) polymerase 1 (PARP1) inhibitors. Molecular similarities between BLBCs and BRCA1-mutated tumors may therefore provide predictive markers for therapeutic response of BLBCs. Methods: There are several known molecular features characteristic for BRCA1-mutated breast tumors: 1) increased numbers of genomic aberrations, 2) a distinct pattern of genomic aberrations, 3) a high frequency of TP53 mutations and 4) a high incidence of complex, protein-truncating TP53 mutations. We compared the frequency of TP53 mutations and the pattern and amount of genomic aberrations between BRCA1-mutated breast tumors, BLBCs and luminal breast tumors by TP53 gene sequencing and array-based comparative genomics hybridization (aCGH) analysis. Results: We found that the high incidence of protein truncating TP53 mutations and the pattern and amount of genomic aberrations specific for BRCA1-mutated breast tumors are also characteristic for BLBCs and different from luminal breast tumors. Conclusions: Complex, protein truncating TP53 mutations in BRCA1-mutated tumors may be a direct consequence of genomic instability caused by BRCA1 loss, therefore, the presence of these types of TP53 mutations in sporadic BLBCs might be a hallmark of BRCAness and a potential biomarker for sensitivity to PARP inhibition. Also, our data suggest that a small subset of genomic regions may be used to identify BRCA1-like BLBCs. BLBCs share molecular features that were previously found to be specific for BRCA1-mutated breast tumors. These features might be useful for the identification of tumors with increased sensitivity to (high-dose or dose-dense) alkylating agents and PARP inhibitors. Background Lobules and ducts within the normal human breast are lined with a double layer of epithelial cells: an inner layer of luminal cells and an outer layer of basal/myoepithelial cells that are in direct contact with the basement membrane. Transformation of different mammary epithelial cells results in considerable heterogeneity in breast cancer subtypes, giving rise to differences in clinical presentation, histology and response to therapy [1]. Gene expression profiling has identified five molecular breast tumor subtypes: luminal A, luminal B, normal breast-like, human epidermal growth factor 2 (HER2/ ERBB2) positive, and basal-like [2,3]. In the clinic however, only immunohistochemistry data for estrogen receptor (ER), progesterone receptor (PR) and HER2 status are used to guide treatment choice [4]. * Correspondence: j.jonkers@nki.nl Division of Molecular Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands Full list of author information is available at the end of the article Holstege et al. BMC Cancer 2010, 10:654 http://www.biomedcentral. com/1471-2407/10/654 © 2010 Holstege et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Approximately ~70-80% of all breast tumors are hormone receptor positive [5] and therefore sensitive to adjuvant endocrine therapy [6]. These tumors classify mostly as luminal A/B breast tumors [3]. The addition of trastuzumab to adjuvant chemotherapy considerably improved the outcome of HER2-positive breast tumors [7]. However, approximately 10-20% of all breast tumors do not express hormone receptors or HER2, and are therefore insensitive to endocrine or trastuzumab treatment. Currently, the only treatment available for these triple-negative breast cancers (TNBCs) is cytotoxic chemotherapy [8]. The TNBC group as defined by immunohistochemical staining consists for approximately 80% of basal-like breast cancers (BLBCs) as defined by gene expression profiling [9]. BLBCs express luminal (CK19 and CK18) as well as basal cytokeratins (CK5/6, CK17 and CK14), suggesting that these tumors originate from an undifferentiated, dual-lineage stem/progenitor cell type. Furthermore, the TP53 gene is often mutated in BLBCs [10], and the gene expression profiles of TP53-mutated breast tumors show strong association with the BLBC subgroup [11]. Consequently, BLBCs are aggressive tumors with an expansive growth pattern (pushing margins), a high proliferation rate, high relapse rates and poor survival. Moreover, BLBCs occur more frequently in premenopausal women than in postmenopausal women and are often difficult to detect by mammography or ultrasound [9]. Although TNBC/BLBC has a relatively poor prognosis in the first five years after diagnosis, approximately 60% of patients even without adjuvant chemotherapy do not relapse, and after ~8 years of follow up have a high chance of being cured (reviewed in [9]). This indicates that within the TNBC/BLBC tumor group there is considerable heterogeneity in tumor behavior. At present however, all TNBC/BLBC patients are treated with cytotoxic adjuvant chemotherapy because there are no clinically useful prognostic and predictive markers to identify patients with aggressive, chemotherapy-sensitive TNBC/BLBC, leading to unnecessary exposure to chemotherapy of a substantial number of patients [8]. In recent years it is becoming clear that phenotypic features of TNBC/BLBC may also apply to the majority of hereditary BRCA1-mutated breast tumors [12,13]. Since BRCA1 function is required for homology-directed repair of DNA double-strand breaks (DSBs), BRCA1mutated tumors and BRCA1-like BLBCs are predicted to be sensitive to DSB inducing therapy [14]. Indeed, breast tumors from BRCA1-mutation carriers are sensitive to inhibition of DNA single-strand break (SSB) repair by poly(ADP-ribose) polymerase (PARP) inhibitors [15] and to chemotherapy that causes DSBs, such as platinum drugs, alkylating agents and topoisomerase I poisons [16,17]. It will therefore be important to identify features of sporadic BLBCs [14] that may be useful as predictive biomarkers for response to DSB-inducing chemotherapy or PARP inhibitors. Known molecular features characteristic for BRCA1-mutated breast tumors are 1) a high degree of genomic instability due to homologous recombination (HR) deficiency [18], 2) a distinct pattern of genomic aberrations [19-22] 3) a high frequency of TP53 mutations and 4) a high incidence of complex, protein-truncating TP53 mutations [10,23]. In this study, we determined to what extent these molecular characteristics of BRCA1-mutated tumors are present in BLBCs.