GENES, CHROMOSOMES & CANCER 48:351–365 (2009) Loss of 16q in High Grade Breast Cancer is Associated with Estrogen Receptor Status: Evidence for Progression in Tumors with a Luminal Phenotype? Rachael Natrajan, 1 Maryou B. K. Lambros, 1 Felipe C. Geyer, 1 Caterina Marchio, 1,2 David S. P. Tan, 1 Radost Vatcheva, 1 Kai-Keen Shiu, 1 Daniela Hungermann, 3 Socorro Maria Rodriguez-Pinilla, 4 Jose Palacios, 5 Alan Ashworth, 1 Horst Buerger, 6 * and Jorge S. Reis-Filho 1 * 1 The Breakthrough Breast Cancer Research Centre,Institute of Cancer Research,London SW3 6JB,UK 2 Department of Biomedical Sciences and Human Oncology,University of Turin,Turin, Italy 3 Institute of Pathology,University of Muenster, Muenster,Germany 4 Centro Nacional de Investigaciones Oncolo¤ gicas, Madrid, Spain 5 Hospital Universitario Virgen del RocÕo, Seville, Spain 6 Institute of Pathology,Co-Operative Breast Centre, Paderborn,Germany Loss of the long arm of chromosome 16 (16q) is observed in the vast majority of low grade/grade I (GI) invasive ductal carcinomas of no special type (IDC-NSTs), whereas this event is uncommonly seen in high grade/grade III (GIII) IDC- NSTs. Together with data on the pathology and genetics of breast cancer recurrences, this has led to the proposal that GI and GIII breast cancers evolve through distinct genetic pathways and that progression from GI to GIII is an unlikely biologi- cal phenomenon. We compared the genomic profiles of GIII-IDC-NSTs with 16q whole arm loss (16qWL) according to estrogen receptor (ER) status. 16qWL was found in 36.5% of cases and was significantly associated with ER expression and luminal phenotype. ERþ GIII-IDC-NSTs with 16qWL displayed significantly higher levels of genomic instability than ERþ IDC-NSTs without 16qWL. Furthermore, ERþ and ER IDC-NSTs stratified according to the presence of 16qWL harbored distinct patterns of genetic aberrations. Interestingly, ERþ/16qWL tumors displayed genetic features usually found in tumors with homologous DNA repair defects and significantly more frequently harbored heterozygous loss of BRCA2 than the remaining ERþ cancers. Our results demonstrate that approximately one third of GIII tumors harbor 16qWL, confirming that progression from low to high grade breast cancer is not found in the majority of breast cancers. 16qWL was significantly more prevalent in ERþ/luminal GIII-IDC-NSTs. Given that GI breast cancers harbor a luminal phe- notype, our results suggest that if progression from GI to GIII breast cancer does happen, it may preferentially occur in breast cancers of luminal phenotype. V V C 2009 Wiley-Liss, Inc. INTRODUCTION Invasive ductal carcinomas of no special type (IDC-NSTs) comprise a heterogeneous group of tumors that account for up to 65% of all breast cancers (Ellis et al., 1992; Lacroix et al., 2004; Simpson et al., 2005). Histological grade has been shown to be an independent predictor of out- come for patients with IDC-NSTs, with grade I (GI) IDC-NSTs having longer overall survival than patients with grade III (GIII) IDC-NSTs (Rakha et al., 2008). Another prognostic and pre- dictive factor for IDC-NSTs is the expression of estrogen receptor (ER), and a clear association between GI cancers and strong expression of ER has been consistently reported (Lacroix et al., 2004; Simpson et al., 2005). With the advent of comparative genomic hybridization (CGH), it has become apparent that histological grade is strongly associated with the type, pattern and complexity of numerical chro- mosomal aberrations found in breast cancer (Buerger et al., 1999, 2001; Roylance et al., 1999; Simpson et al., 2005). Grade I IDC-NSTs are usually diploid or near-diploid and are character- ized by recurrent physical loss of the long arm of chromosome 16 (16q), which is found in >85% of these cancers (Buerger et al., 1999, 2001; Roy- lance et al., 1999; Simpson et al., 2005). Interest- ingly, despite the greater genetic complexity and Additional Supporting Information may be found in the online version of this article. Supported by: Breakthrough Breast Cancer. The authors acknowledge NHS funding to the NIHR Biomedical Research Centre. *Correspondence to: Horst Buerger, Institute of Pathology, Paderborn, Germany. E-mail: buerger@histopatho.eu. or Jorge S. Reis-Filho, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK. E-mail: Jorge.Reis-Filho@icr.ac.uk Received 18 October 2008; Accepted 17 December 2008 DOI 10.1002/gcc.20646 Published online 20 January 2009 in Wiley InterScience (www.interscience.wiley.com). V V C 2009 Wiley-Liss, Inc.