GENES, CHROMOSOMES & CANCER 51:149–160 (2012) PTEN Genomic Deletions that Characterize Aggressive Prostate Cancer Originate Close to Segmental Duplications Maisa Yoshimoto, 1 Olga Ludkovski, 2 Dave DeGrace, 1 Julia L. Williams, 1 Andrew Evans, 3 Kanishka Sircar, 4 Tarek A. Bismar, 5 Paulo Nuin, 1,6 and Jeremy A. Squire 1 * 1 Department of Pathology and Molecular Medicine,Queen’s University,Kingston,ON,Canada 2 Applied Molecular Oncology, Princess Margaret Hospital,Toronto,ON,Canada 3 Department of Pathology, Princess Margaret Hospital,Toronto,ON,Canada 4 Department of Pathology,University of Texas MD Anderson Cancer Center, Houston,TX 5 Department of Pathology and Laboratory Medicine,University of Calgary, AB,Canada 6 Ontario Cancer Biomarker Network,Toronto,ON,Canada Deletion of PTEN at 10q23.3 occurs in 40% of human prostate cancers and is associated with aggressive metastatic potential, poor prognosis, and androgen-independence. This high frequency of recurrent PTEN deletions in prostate cancer suggests there may be unusual genomic features close to this locus that facilitate DNA alteration at 10q23.3. To explore possible mechanisms for deletions in the PTEN region, a meta-analysis of 311 published human genome array datasets was conducted and determined that the minimal prostate cancer-associated deletion at 10q23.3 corresponds to 2.06 MB region flanked by BMPR1A and FAS. On a separate cohort comprising an additional 330 tumors, four-color fluorescence in situ hybridization analysis using probes for BMPR1A, FAS, cen(10), and PTEN showed that 132 of 330 (40%) tumors had PTEN loss, 50 (15%) of which were homozygous losses (comprising in total 100 deletion events). Breakpoints between PTEN and BMPR1A or FAS were subsequently mapped in 100 homozygous and 82 hemizygous PTEN losses, revealing that 125/182 PTEN microdeletions occurred within the 940 kB interval between BMPR1A and PTEN. Furthermore, this break- point interval coincides with a repeat-rich region of 414 kB containing the SD17 and SD18 segmental duplications, which contain at least 13 homologous inverted repeat sequences. Together, these data suggest that a strong selective growth advantage for loss of PTEN and upregulation of PI3K/AKT, combined with the close proximity of PTEN to a large unstable segment of repeated DNA comprising SD17 and SD18, can lead to recurrent microdeletions of the PTEN gene in prostate cancer. V V C 2011 Wiley Periodicals, Inc. INTRODUCTION Prostate cancer is characterized by distinct classes of chromosomal rearrangement and these common alterations are being increasingly evaluated for their prognostic associations (Dong, 2001; Gurel et al., 2008; Sardana et al., 2008; Ishkanian et al., 2010; Reid et al., 2010; Shen and Abate-Shen, 2010; Troutman et al., 2010). Of the relatively small number of genetic alterations commonly found in prostate cancer, submicroscopic PTEN gene dele- tion (cytoband 10q.23.3) is one of the most fre- quent. However, the molecular mechanism of genomic rearrangements in 10q23.3, as well as the associated clinical consequences of copy number losses in this region are poorly understood. Early studies using loss of heterozygosity analy- ses estimated that 35–58% of 10q deletions in advanced prostate cancers include PTEN (Feilot- ter et al., 1998; Muller et al., 2000; Verhagen et al., 2006). Submicroscopic deletions of PTEN have been characterized more extensively by fluo- rescence in situ hybridization (FISH) and are found to be present in 30–60% of localized pros- tate cancer (Hermans et al., 2004; Verhagen et al., 2006; Yoshimoto et al., 2006, 2007, 2008; Lapointe et al., 2007; Ishkanian et al., 2009; Liu et al., 2009; Sircar et al., 2009; Bednarz et al., 2010; Reid et al., 2010; Taylor et al., 2010; Bismar et al., 2011). The benign precursor of prostate cancer, high-grade prostatic intraepithelial neoplasia, also exhibits PTEN deletions but at a lower frequency of 20% (Yoshimoto et al., 2006; Holcomb et al., 2009; Additional Supporting Information may be found in the online version of this article. Supported by: Canadian Cancer Society, Grant number: 18124. *Correspondence to: Jeremy A. Squire, Department of Pathol- ogy and Molecular Medicine, Kingston General Hospital and Queen’s University, 88 Stuart St, Kingston, ON, K7L 3N6 Canada. E-mail: jsquireinsp@gmail.com Received 4 May 2011; Accepted 19 September 2011 DOI 10.1002/gcc.20939 Published online 1 November 2011 in Wiley Online Library (wileyonlinelibrary.com). V V C 2011 Wiley Periodicals, Inc.