title: PTEN genomic deletions that characterize aggressive prostate cancer originate close to segmental duplications.
abstract: 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 breakpoint 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. © 2011 Wiley Periodicals, Inc.
authors: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
authors: Maisa
authors: M
authors: Yoshimoto
authors: Olga
authors: O
authors: Ludkovski
authors: Dave
authors: D
authors: DeGrace
authors: Julia L
authors: JL
authors: Williams
authors: Andrew
authors: A
authors: Evans
authors: Kanishka
authors: K
authors: Sircar
authors: Tarek A
authors: TA
authors: Bismar
authors: Paulo
authors: P
authors: Nuin
authors: Jeremy A
authors: JA
authors: Squire
mesh_terms: D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics; D056905:Chromosome Breakpoints; D002879:Chromosomes, Human, Pair 10; D017353:Gene Deletion; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007399:Interphase; D008297:Male; D060787:Neoplasm Grading; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012091:Repetitive Sequences, Nucleic Acid; D056916:Segmental Duplications, Genomic; D046888:Tissue Array Analysis
chemical_list: C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human