ORIGINAL PAPER Journal of Pathology J Pathol 2010; 222: 282–298 Published online 2 September 2010 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/path.2763 Mucinous carcinoma of the breast is genomically distinct from invasive ductal carcinomas of no special type Magali Lacroix-Triki, 1,2 Paula H Suarez, 1 Alan MacKay, 1 Maryou B Lambros, 1 Rachael Natrajan, 1 Kay Savage, 1 Felipe C Geyer, 1 Britta Weigelt, 3 Alan Ashworth 1 and Jorge S Reis-Filho 1 * 1 The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK 2 Institut Claudius Regaud, 31052, Toulouse, France 3 Cancer Research UK, London Research Institute, London, WC2A 3PX, UK *Correspondence to: Professor Jorge S Reis-Filho, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK e-mail: Jorge.Reis-Filho@icr.ac.uk Abstract Mucinous carcinomas are a rare entity accounting for up to 2% of all breast cancers, which have been shown to display a gene expression profile distinct from that of invasive ductal carcinomas of no special type (IDC-NSTs). Here, we have defined the genomic aberrations that are characteristic of this special type of breast cancer and have investigated whether mucinous carcinomas might constitute a genomic entity distinct from IDC- NSTs. Thirty-five pure and 11 mixed mucinous breast carcinomas were assessed by immunohistochemistry using antibodies against oestrogen receptor (ER), progesterone receptor, HER2, Ki67, cyclin D1, cortactin, Bcl-2, p53, E-cadherin, basal markers, neuroendocrine markers, and WT1. Fifteen pure mucinous carcinomas and 30 grade- and ER-matched IDC-NSTs were microdissected and subjected to high-resolution microarray-based comparative genomic hybridization (aCGH). In addition, the distinct components of seven mixed mucinous carcinomas were microdissected separately and subjected to aCGH. Pure mucinous carcinomas consistently expressed ER (100%), lacked HER2 expression (97.1%), and showed a relatively low level of genetic instability. Unsupervised hierarchical cluster analysis revealed that pure mucinous carcinomas were homogeneous and preferentially clustered together, separately from IDC-NSTs. They less frequently harboured gains of 1q and 16p and losses of 16q and 22q than grade- and ER-matched IDC-NSTs, and no pure mucinous carcinoma displayed concurrent 1q gain and 16q loss, a hallmark genetic feature of low-grade IDC-NSTs. Finally, both components of all but one mixed mucinous carcinoma displayed similar patterns of genetic aberrations and preferentially clustered together with pure mucinous carcinomas on unsupervised clustering analysis. Our results demonstrate that mucinous carcinomas are more homogeneous between themselves at the genetic level than IDC-NSTs. Both components of mixed mucinous tumours are remarkably similar at the molecular level to pure mucinous cancers, suggesting that mixed mucinous carcinomas may be best classified as variants of mucinous cancers rather than of IDC-NSTs. Copyright  2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Keywords: colloid carcinoma; microarrays; comparative genomic hybridization; immunohistochemistry; in situ hybridization; genetics Received 11 May 2010; Revised 22 July 2010; Accepted 24 July 2010 No conflicts of interest were declared. Introduction Breast cancer special types account for up to 25% of all breast cancers. The latest edition of the World Health Organization (WHO) classification recognizes the exis- tence of at least 17 entities, which are mainly defined by their histological features [1–3]. It has been hypoth- esized that tumours pertaining to each special type of breast cancer might be more homogeneous between themselves at the molecular level than invasive ductal carcinomas of no special type (IDC-NSTs) and could therefore constitute a useful model for the identifica- tion of molecular drivers of breast cancers [2–5]. In addition, the genes whose expression determines the clinical behaviour of special types of breast cancer may differ from those implicated in the prognosis of IDC-NSTs, as exemplified by the relatively poor per- formance of prognostic gene signatures in special types of breast cancer [4–6]. Mucinous carcinoma is a rare histological type of breast cancer characterized by abundant production of extracellular and/or intracellular mucin. Pure mucinous carcinomas (defined as tumours with more than 90% of mucinous component) account for up to 2% of all breast carcinomas, preferentially affect older women, and are usually associated with a good clinical outcome [7–9]. Such tumours are characterized by uniform neo- plastic cells arranged in clusters floating in a large amount of mucin. Nuclear atypia and mitotic figures are uncommon [1]. Mucinous carcinomas are further subdivided in two subtypes, mucinous A (hypocellu- lar variant) and mucinous B (hypercellular variant), Copyright  2010 Pathological Society of Great Britain and Ireland. J Pathol 2010; 222: 282–298 Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk www.thejournalofpathology.com