title: Cyclin D1 gene amplification is highly homogeneous in breast cancer.
abstract: BACKGROUND
  Cyclin D1 (CCND1) gene amplification is a molecular key alteration in breast cancer and was suggested to predict resistance to antihormonal therapy. As tissue heterogeneity may affect diagnostic accuracy of predictive biomarkers, CCND1 genetic heterogeneity was assessed in this study. A novel tissue microarray (TMA) platform was manufactured for this purpose.
  
  
  METHODS
  Primary breast carcinomas from 147 patients were sampled in a "heterogeneity-TMA" by taking eight different tissue cores from 4 to 8 tumor-containing blocks per case. Additional tissue samples were taken from 1 to 4 corresponding nodal metastases in 35 of these patients. CCND1 amplification was assessed by fluorescence in situ hybridization (FISH).
  
  
  RESULTS
  CCND1 amplification was seen in 28 of 133 (21.05 %) informative patients. Amplification was significantly associated with high tumor grade (p = 0.042), but unrelated to tumor type (p = 0.307), stage (p = 0.540) and ER (p = 0.061) or PR (p = 0.871) expression. A discordant Cyclin D1 amplification status was detected in 6 out of 28 (21.43 %) amplified tumors by heterogeneity-TMA analysis. Re-testing on large sections revealed three patients with true heterogeneity of high-level CCND1 amplification and another three patients with variable interpretation of borderline FISH ratios ranging between 1.7 and 2.3. No discrepancies were detected between 22 primary tumors and their matched lymph node metastases.
  
  
  CONCLUSIONS
  The high degree of homogeneity seen for CCND1 amplification suggests that this alteration is an early event in the development of a small subset of breast cancers.
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany. e.burandt@uke.de.
authors.forename: Eike
authors.initials: E
authors.lastname: Burandt
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Grünert
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Lebeau
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Choschzick
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Quaas
authors.affiliation: Department of Gynecology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: Fritz
authors.initials: F
authors.lastname: Jänicke
authors.affiliation: Department of Gynecology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Müller
authors.affiliation: Department of Gynecology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Scholz
authors.affiliation: Department of Internal Medicine II, Oncology Center, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Department of Radiotherapy and Radio-Oncology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: Cordula
authors.initials: C
authors.lastname: Petersen
authors.affiliation: Department of Gynecology, Regio Clinic Pinneberg, 25421, Pinneberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Geist
authors.affiliation: Department of Gynecology, Regio Clinic Pinneberg, 25421, Pinneberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Paluchowski
authors.affiliation: Department of Gynecology, Regio Clinic Elmshorn, 25337, Elmshorn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Wilke
authors.affiliation: Department of Gynecology, Clinical Centre Itzehoe, 25524, Itzehoe, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Heilenkötter
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Wilczak
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018275:Carcinoma, Lobular; D019938:Cyclin D1 / Q000235:genetics*; D005260:Female; D005784:Gene Amplification / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D046888:Tissue Array Analysis
chemical_list: C530104:CCND1 protein, human; D019938:Cyclin D1
keywords: Breast cancer; Cyclin D1; FISH; Heterogeneity; Heterogeneity-TMA