title: Allelic imbalance at the HER2/TOP2A locus in breast cancer.
abstract: BACKGROUND
  Breast cancer is a heterogeneous disease with various histological features and molecular markers. These are utilized for the prediction of clinical outcome and therapeutic decision making. In addition to well established markers such as HER2 overexpression and estrogen and progesterone receptor (ER and PR) status, chromosomal instability is evolving as an important hallmark of cancers. The HER2/TOP2A locus is of great importance in breast cancer. The copy number variability at this locus has been proposed to be a marker for the degree of chromosomal instability. We therefore developed a Single Nucleotide Polymorphism (SNP) assay to evaluate allelic imbalance at the HER2/TOP2A locus in three different entities of primary breast tumors.
  
  
  METHODS
  Eleven SNPs were carefully selected and detected by real time PCR using DNA extracted from paired (histologically normal and tumor) paraffin-embedded tissues. Primary breast tumors of 44 patients were included, 15 tumors with HER2 overexpression, 16 triple negative tumors, defined by the absence of HER2 overexpression and a negative ER and PR status and 13 ER and PR positive tumors without HER2 overexpression. As controls, histologically normal breast tissues from 10 patients with no breast tumor were included.
  
  
  RESULTS
  Allelic imbalance was observed in 13/15 (87 %) HER2 positive tumors, the remaining 2 being inconclusive. Of the 16 triple negative tumors, 12 (75 %) displayed instability, 3 (19 %) displayed no instability, and 1 was inconclusive. Of the 13 hormone receptor positive tumors, 5 (38 %) displayed allelic imbalance, while 8 did not.
  
  
  CONCLUSIONS
  We conclude that the SNP assay is suitable for rapid testing of allelic (im)balance at the HER2/TOP2A locus using paraffin-embedded tissues. Based on allelic imbalance at this locus, both triple negative and ER and PR positive breast tumors can be subcategorized. The clinical relevance of the allelic (im)balance status at the HER2/TOP2A locus in breast cancer is subject of future study.
  The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2086062232155220.
authors.affiliation: Laboratory of Molecular Diagnostics, Jeroen Bosch Hospital, PO Box 90153, 5200 ME, 's-Hertogenbosch, The Netherlands. r.huysmans@jbz.nl.
authors.forename: Cornelis J J
authors.initials: CJ
authors.lastname: Huijsmans
authors.affiliation: Laboratory of Molecular Diagnostics, Jeroen Bosch Hospital, PO Box 90153, 5200 ME, 's-Hertogenbosch, The Netherlands. a.v.d.brule@jbz.nl.
authors.forename: Adriaan J C
authors.initials: AJ
authors.lastname: van den Brule
authors.affiliation: Laboratory of Pathology, Jeroen Bosch Hospital, PO Box 90153, 5223 GZ, 's-Hertogenbosch, The Netherlands. h.rigter@jbz.nl.
authors.forename: Henny
authors.initials: H
authors.lastname: Rigter
authors.affiliation: Laboratory of Molecular Diagnostics, Jeroen Bosch Hospital, PO Box 90153, 5200 ME, 's-Hertogenbosch, The Netherlands. j.poodt@labhelp.nl.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Poodt
authors.affiliation: Laboratory of Pathology, Jeroen Bosch Hospital, PO Box 90153, 5223 GZ, 's-Hertogenbosch, The Netherlands. h.v.d.linden@jbz.nl.
authors.forename: Johannes C
authors.initials: JC
authors.lastname: van der Linden
authors.affiliation: Medical Microbiology and Infection Control, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands. paul.savelkoul@mumc.nl.|Department Medical Microbiology, Maastricht University Medical Center, PO box 5800, 6202 AZ, Maastricht, The Netherlands. paul.savelkoul@mumc.nl.
authors.forename: Paul H M
authors.initials: PH
authors.lastname: Savelkoul
authors.affiliation: Jeroen Bosch Academy, Jeroen Bosch Hospital, PO Box 90153, 5223 GZ, 's-Hertogenbosch, The Netherlands. m.hilbink@jbz.nl.
authors.forename: Mirrian
authors.initials: M
authors.lastname: Hilbink
authors.affiliation: Laboratory of Molecular Diagnostics, Jeroen Bosch Hospital, PO Box 90153, 5200 ME, 's-Hertogenbosch, The Netherlands. m.hermans@jbz.nl.
authors.forename: Mirjam H A
authors.initials: MH
authors.lastname: Hermans
mesh_terms: D000328:Adult; D000368:Aged; D022981:Allelic Imbalance; D000951:Antigens, Neoplasm / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D001706:Biopsy; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008875:Middle Aged; D016612:Paraffin Embedding; D010641:Phenotype; D000075223:Poly-ADP-Ribose Binding Proteins; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000235:genetics*; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D012189:Retrospective Studies; D064726:Triple Negative Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human; C000618811:TOP2A protein, human