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Lobular and Ductal Carcinomas of the Breast Have Distinct Genomic and Expression Profiles

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Lobular and Ductal Carcinomas of the Breast Have Distinct Genomic and Expression Profiles Oncogene (2008) 27, 5359–5372 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc ONCOGENOMICS Lobular and ductal carcinomas of the breast have distinct genomic and expression profiles F Bertucci1,11, B Orsetti2,11,VNe` gre2, P Finetti1, C Rouge´ 2, J-C Ahomadegbe3, F Bibeau2,4, M-C Mathieu5, I Treilleux6, J Jacquemier1, L Ursule2, A Martinec7, Q Wang8,JBe´ nard5,9, A Puisieux8,10, D Birnbaum1 and C Theillet2 1INSERM UMR891, Centre de Recherche en Cance´rologie de Marseille, Institut Paoli-Calmettes, Marseille, France; 2INSERM U896, Institut de Recherche en Cance´rologie de Montpellier, CRLC Val d’Aurelle-Paul Lamarque, Montpellier, France; 3Universite´ Paris XI, UPRES 3535, Institut Gustave Roussy, Villejuif, France; 4CRLC Val d’Aurelle-Paul Larmarque, Laboratoire d’Anatomopathologie, Montpellier, France; 5Institut Gustave Roussy, De´partement de Biopathologie, Villejuif, France; 6Centre Le´on Be´rard, laboratoire d’Anatomopathologie, Lyon, France; 7Ipsogen S.A., Marseille-Luminy, France; 8Centre Le´on Be´rard, laboratoire d’Oncologie Mole´culaire, Lyon, France; 9CNRS UMR 8126, Institut Gustave Roussy, Villejuif, France and 10INSERM U590, Centre Le´on Be´rard, Lyon, France Invasive ductal carcinomas (IDCs) and invasive lobular Introduction carcinomas (ILCs) are the two major pathological types of breast cancer. Epidemiological and histoclinical data Breast cancer is a complex and heterogeneous disease, suggest biological differences, but little is known about the which, despite important efforts, remains difficult to molecular alterations involved in ILCs. We undertook a describe comprehensively and, therefore, to treat appro- comparative large-scale study by both array-compared priately. Up to 20 pathological types have been defined, genomic hybridization and cDNA microarray of a set of but two of them, invasive ductal carcinomas (IDCs) and 50 breast tumors (21 classic ILCs and 29 IDCs) selected invasive lobular carcinomas (ILCs), account for about on homogeneous histoclinical criteria. Results were 90% of all breast tumors. Median incidence of ILCs is validated on independent tumor sets, as well as by about 12% and increases disproportionately compared quantitative RT–PCR. ILCs and IDCs presented differ- to IDCs in western countries (Li et al., 2003). ILCs and ences at both the genomic and expression levels with ILCs IDCs differ from each other with respect to various being less rearranged and heterogeneous than IDCs. histological, biological and clinical features. Remark- Supervised analysis defined a 75-BACs signature discri- ably ILCs are less cohesive than IDCs and tend to form minating accurately ILCs from IDCs. Expression profiles single files of invading cells. This feature has been identified two subgroups of ILCs: typical ILCs (B50%), associated with the frequent inactivation of the which were homogeneous and displayed a normal-like E-cadherin gene (CDH1; Berx et al., 1995). ILCs are molecular pattern, and atypical ILCs, more heterogeneous predominantly estrogen receptor (ER) and progesterone with features intermediate between ILCs and IDCs. receptor positive, and thus presumably more homoge- Supervised analysis identified a 75-gene expression neous than IDCs. Their pathological grade is signature that discriminated ILCs from IDCs, with many generally lower than that of IDCs and they show a lower genes involved in cell adhesion, motility, apoptosis, protein proliferation index (Sastre-Garau et al., 1996). ILCs are folding, extracellular matrix and protein phosphorylation. less sensitive to chemotherapy (Katz et al., 2007) and are Although ILCs and IDCs share common alterations, our more prone to form bone, gastrointestinal, peritoneal and data show that ILCs and IDCs could be distinguished on the ovarian metastases than IDCs (Lamovec and Bracko, basis of their genomic and expression profiles suggesting that 1991). Despite these differences, ILCs show similar they evolve along distinct genetic pathways. prognosesasIDCs(Toikkanenet al., 1997), and the Oncogene (2008) 27, 5359–5372; doi:10.1038/onc.2008.158; treatment of ILCs and IDCs is similar. Patients would ONCOGENOMICS published online 19 May 2008 benefit from a better tailored treatment. Therefore, it appears crucial to gain insight in the molecular differences Keywords: breast cancer; DNA microarray; genetic that distinguish the two pathological types. profiles; array-CGH There are a number of reasons to suspect that ILCs and IDCs represent distinct molecular entities. Cyto- genetic-based studies have suggested that they differ at Correspondence: Dr C Theillet, IRCM, INSERM U896, CRLC Val the karyotype level, with ILCs being specified by a d’Aurelle-Paul Lamarque, Rue de la croix verte, Montpellier, Cedex 5, combination of gains at 1q and losses at 16q (Flagiello F-34298, France. et al., 1998). However, chromosomal compared genomic E-mail: [email protected] hybridization (CGH)-based studies have shown contra- 11These authors contributed equally to this work. Received 17 July 2007; revised 4 December 2007; accepted 11 April 2007; dictory results (Loveday et al., 2000; Gunther et al., published online 19 May 2008 2001), and only two studies based on array-CGH have IDC and ILC are distinct at the genetic level F Bertucci et al 5360 compared ILCs and IDCs (Loo et al., 2004; Stange all but one tumor of the training set. Genomic et al., 2006). Expression profiling studies have revealed imbalances were more frequent in IDCs than ILCs the transcriptional heterogeneity and new molecular (17.4 vs 11% of the bacterial artificial chromosomes subtypes of breast cancer, but these studies were mainly (BACs) showing CNC, P ¼ 0.004; Figures 1a and b). performed on IDCs (Bertucci et al., 2006). Three studies The two pathological types shared common aberrations, (Korkola et al., 2003; Zhao et al., 2004; Turashvili et al., with frequent (occurrence >20%) gains and some peaks 2007) reported expression signatures that distinguish (>40%) at 1q41–q43, 8q13 and 8q24, 16p13, 17q23 and IDCs from ILCs with reasonable accuracy. However, 20q13. Frequent losses exceeded 20% occurrence and save for CDH1, the gene sets generated in either study were found at 6q, 8p, distal 11q, 13, 16q. However, show little overlap. differences between IDCs and ILCs were apparent and No comprehensive genomic and transcriptomic could be visualized on frequency difference plots study comparing ILCs and IDCs has been reported yet. (Figures 1c and d). In IDCs, most prevalent CNCs As breast cancer is heterogeneous and different pheno- were gains at 8q, 16p, 17q and 20q, and losses at 3p, 4q, types may possibly intermingle making the comparisons 7p, 8p, 15q, 18q and X. In ILCs, the most prevalent delicate, we reasoned that working with stringently defined changes were gains at 1q, 7p12, 11q13, 16p13 and Xp11, tumor sets could prove crucial to establish clear-cut genetic and losses at 11q21-qter, 13, 17q and 22. DNA differences between IDCs and ILCs. We thus constituted a amplification at 11q13was evenly distributed through- tumor training set selected on homogeneous and focused out ILCs and IDCs (40% and 20–33% at CCND1 and phenotypic criteria, comprising 21 classic ILCs and 29 PAK1, respectively), whereas that at 17q24.1, (THRAP1 IDCs. Molecular profiles were determined at the DNA and SMURF2) was restricted to IDCs (37%). A two- and RNA levels using microarrays. Tumors were also sample Wilcoxon test identified 114 BACs differently analysed for the presence of TP53 and CDH1 mutations. involved in ILCs and IDCs (Figure 1e). Our data support the idea that the two major histological Copy number profiles may be used to stratify breast types of breast cancer arise along distinct genetic routes. cancers in three groups referred to as simplex, complex and amplifier (Fridlyand et al., 2006; Hicks et al., 2006). Simplex profiles are characterized by infrequent gains or Results losses involving whole chromosomal arms, complex by highly rearranged patterns involving multiple regions of Phenotypic characteristics of the tumor training set gains and losses and infrequent amplification, and In order to limit the heterogeneity of the analysed amplifier by high-level amplification associated to tumor set and avoid its dispersion in smaller entities, moderately rearranged patterns. We found simplex, we worked on a selected tumor collection. Our aim was complex or amplifiers in both IDCs and ILCs (see to compare matched sets of tumors and because Supplementary Table 1). However, simplex tumors were ILCs are predominantly grade 2 and hormone recep- more frequent in ILCs (47.6%) than IDCs (31%; tor-positive, we preferentially selected grade 2, pT2, difference not significant). ER þ , invasive tumors with less than three involved axillary lymph nodes. A total of 21 ILCs and 29 Genomic imbalances discriminating ILC from IDC and IDCs were selected after crosschecking by four patho- definition of a genomic classifier.Toidentifyregionsof logists. All ILCs were of the classic subtype and other CNC that discriminate ILCs from IDCs, we applied a ILC subtypes were voluntarily excluded, thus restricting supervised analysis based on a combination of signal-to- our study to a subset of lobular cancers. noise (S2N) and support vector machine (SVM). S2N The 50 tumor samples were analysed at both the was used to select differential features, SVM to classify genomic (array-CGH) and expression (cDNA tumors and LOOCV (leave-one-out cross-validation) to microarrays) levels and for the presence of mutations estimate the performance of the classifier. By LOOCV, 43 in CDH1 and exons 4–10 of TP53. Although some tumors of the training set were correctly classified (86% mutations may have been lost in our analysis, we overall accuracy; Figure 2), with 25/29 (86.3%) for IDCs detected 6 tumors with TP53 mutations and 13with and 18/21 (85.7%) for ILCs. Most IDCs bearing a TP53 CDH1 mutations. TP53 mutations were restricted to the mutation (5/6) were classified as IDC. Only 2/13ILCs IDCs and CDH1 mutations to the ILCs. It must be with a CDH1 mutation were misclassified as IDC mentioned that in addition to mutations and loss, (Figure 2a).
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