title: Relevance of PTEN loss in brain metastasis formation in breast cancer patients.
abstract: BACKGROUND
  With the improvement of therapeutic options for the treatment of breast cancer, the development of brain metastases has become a major limitation to life expectancy in many patients. Therefore, our aim was to identify molecular markers associated with the development of brain metastases in breast cancer.
  
  
  METHODS
  Patterns of chromosomal aberrations in primary breast tumors and brain metastases were compared with array-comparative genetic hybridization (CGH). The most significant region was further characterized in more detail by microsatellite and gene-expression analysis, and finally, the possible target gene was screened for mutations.
  
  
  RESULTS
  The array CGH results showed that brain metastases, in general, display similar chromosomal aberrations as do primary tumors, but with a notably higher frequency. Statistically significant differences were found at nine different chromosomal loci, with a gain and amplification of EGFR (7p11.2) and a loss of 10q22.3-qter being among the most significant aberrations in brain metastases (P < 0.01; false discovery rate (fdr) < 0.04). Allelic imbalance (AI) patterns at 10q were further verified in 77 unmatched primary tumors and 21 brain metastases. AI at PTEN loci was found significantly more often in brain metastases (52%) and primary tumors with a brain relapse (59%) compared with primary tumors from patients without relapse (18%; P = 0.003) or relapse other than brain tumors (12%; P = 0.006). Loss of PTEN was especially frequent in HER2-negative brain metastases (64%). Furthermore, PTEN mRNA expression was significantly downregulated in brain metastases compared with primary tumors, and PTEN mutations were frequently found in brain metastases.
  
  
  CONCLUSIONS
  These results demonstrate that brain metastases often show very complex genomic-aberration patterns, suggesting a potential role of PTEN and EGFR in brain metastasis formation.
authors.affiliation: Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistreet 52, 20246 Hamburg, Germany. h.wikman@uke.uni-hamburg.de
authors.forename: Harriet
authors.initials: H
authors.lastname: Wikman
authors.forename: Katrin
authors.initials: K
authors.lastname: Lamszus
authors.forename: Niclas
authors.initials: N
authors.lastname: Detels
authors.forename: Liubov
authors.initials: L
authors.lastname: Uslar
authors.forename: Michaela
authors.initials: M
authors.lastname: Wrage
authors.forename: Christian
authors.initials: C
authors.lastname: Benner
authors.forename: Ina
authors.initials: I
authors.lastname: Hohensee
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.forename: Kathrin
authors.initials: K
authors.lastname: Eylmann
authors.forename: Marc
authors.initials: M
authors.lastname: Zapatka
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Dirk
authors.initials: D
authors.lastname: Kemming
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.forename: Volkmar
authors.initials: V
authors.lastname: Müller
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
mesh_terms: D022981:Allelic Imbalance; D001932:Brain Neoplasms / Q000235:genetics* / Q000556:secondary* / Q000601:surgery; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002879:Chromosomes, Human, Pair 10; D055028:Comparative Genomic Hybridization; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human