title: Partial PTEN deletion is linked to poor prognosis in breast cancer.
abstract: BACKGROUND
  Deletions of chromosome 10q23, including the PTEN (phosphatase and tensin homolog) locus, are known to occur in breast cancer, but systematic analyses of its clinical relevance are lacking.
  
  
  METHODS
  We thus analyzed a tissue microarray (TMA) with 2,197 breast cancers by fluorescence in-situ hybridization (FISH) using a PTEN-specific probe.
  
  
  RESULTS
  PTEN deletions were detected in 19% of no special type, 9% of lobular, 4% of tubular cancers and 46% in carcinomas with medullary features. 98.7% of deletions were heterozygous and only 1.3% were homozygous. PTEN deletion was significantly linked to advanced tumor stage (p=0.0054), high-grade (p<0.0001), high tumor cell proliferation (Ki67 Labeling Index; p<0.0001), and shortened overall survival (p=0.0090). PTEN deletions were inversely associated with features of luminal type breast cancers (ER/PR positivity; p<0.0001 each, and CCND1 amplification; p=0.0020). PTEN deletions were also strongly linked to amplification of genes involved in the PTEN/AKT pathway such as MYC (p=0.0430) and HER2 (p=0.0065). Remarkably the combined analysis of MYC, HER2, CCND1 and PTEN aberrations suggested that aberrations of multiple PTEN/AKT pathway genes have a strong additive effect on breast cancer prognosis. While cancers with one of these aberrations behaved only marginally different from cancers with none, disease outcome was markedly worse in cancers with two or more aberrations as compared to those with only one aberration (p=0.0002). In addition, the particularly poor prognosis of patients with HER2 amplification and PTEN deletions challenges the concept of PTEN deletions interfering with trastuzumab therapy.
  
  
  CONCLUSIONS
  PTEN deletion occurs in a relevant fraction of breast cancers, and is linked to aggressive tumor behavior. Reduced PTEN function cooperates with MYC and HER2 activation in conferring aggressive phenotype to cancer cells.
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. p.lebok@uke.de.
authors.forename: P
authors.initials: P
authors.lastname: Lebok
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. valeria.kopperschmidt@gmail.com.
authors.forename: V
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authors.lastname: Kopperschmidt
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. m.kluth@uke.de.
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authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. c.hube@uke.de.
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authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. cansu.ozden@yahoo.com.
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authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. berivant@hotmail.de.
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authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. afrinlady5@hotmail.de.
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authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. anja_mittenzwei@onlinehome.de.
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authors.lastname: Mittenzwei
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. a.lebeau@uke.de.
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authors.lastname: Lebeau
authors.affiliation: Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. iwitzel@uke.de.
authors.forename: I
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authors.lastname: Witzel
authors.affiliation: Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. lwoelber@uke.de.
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authors.affiliation: Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. s.mahner@uke.de.
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authors.affiliation: Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. jaenicke@uke.de.
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authors.affiliation: Department of Gynecology, Regio Clinic Pinneberg, Pinneberg, Germany. gyngebh.pinneberg@regiokliniken.de.
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authors.affiliation: Department of Gynecology, Regio Clinic Pinneberg, Pinneberg, Germany. gyngebh.pinneberg@regiokliniken.de.
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authors.affiliation: Department of Gynecology, Regio Clinic Elmshorn, Elmshorn, Germany. christian.wilke@sana.de.
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authors.affiliation: Department of Gynecology, Clinical Centre Itzehoe, Itzehoe, Germany. u.heilenkoetter@kh-itzehoe.de.
authors.forename: U
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authors.lastname: Heilenkötter
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. r.simon@uke.de.
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. g.sauter@uke.de.
authors.forename: Guido
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authors.lastname: Sauter
authors.affiliation: Department of Pathology, Basel University Clinics, Basel, Switzerland. lterracciano@uhbs.ch.
authors.forename: L
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authors.lastname: Terracciano
authors.affiliation: Institute of Pathology, Clinical Centre Osnabrück, Osnabrück, Germany. pathologie@ncid.net.
authors.forename: R
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authors.affiliation: Breast Centre Osnabrück, Osnabrück, Germany. senologie@franziskus.com.
authors.forename: A
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authors.lastname: von d Assen
authors.affiliation: Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. v.mueller@uke.de.
authors.forename: V
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authors.lastname: Müller
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. e.burandt@uke.de.
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mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002872:Chromosome Deletion; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011379:Prognosis; D046888:Tissue Array Analysis
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human