title: Prognostic and predictive value of copy number alterations in invasive breast cancer as determined by multiplex ligation-dependent probe amplification.
abstract: BACKGROUND
  Breast cancer is a leading cause of morbidity and mortality in women worldwide. About 70 % of breast cancers are estrogen receptor (ER) positive. Blocking estrogen action by tamoxifen has been the treatment of choice in ER positive breast cancers for more than 30 years. In the past, several studies have revealed associations between gene copy number alterations and responsiveness to tamoxifen therapy, but so far no single gene copy number alteration could completely explain the response variation observed between individual breast cancer patients. Here, we set out to perform a simultaneous analysis of copy number alterations of several genes involved in the prognosis and response to therapy by multiplex ligation-dependent probe amplification (MLPA).
  
  
  METHODS
  A case-control study was designed encompassing 170 non-metastatic ER positive breast cancer patients (case group = 85, control group = 85). All patients in the control group had received standard adjuvant tamoxifen treatment for 5 years without any evidence of recurrence. Patients in the case group had experienced early recurrences while receiving tamoxifen treatment. 76 % of the patients of the case group and 73 % of the patients of the control group had received anthracycline-based adjuvant chemotherapy. Gene copy number alterations detected by MLPA in both groups were compared.
  
  
  RESULTS
  Amplification of CCND1 (OR = 3.13; 95 % CI = 1.35 to 7.26; p = 0.006) and TOP2A (OR = 3.05; 95 % CI = 1.13 to 8.24; p = 0.022) were significantly more prevalent in the case group, compared to the control group. In a multivariate analysis CCND1 (p = 0.01) and TOP2A (p = 0.041) amplifications remained significant predictors of recurrence.
  
  
  CONCLUSIONS
  Our results indicate that CCND1 amplification may serve as a useful biomarker for hormone responsiveness, and that TOP2A amplification may serve as a useful prognostic biomarker.
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Sanaz
authors.initials: S
authors.lastname: Tabarestani
authors.forename: Sayyed Mohammad Hossein
authors.initials: SM
authors.lastname: Ghaderian
authors.forename: Hamid
authors.initials: H
authors.lastname: Rezvani
authors.forename: Reza
authors.initials: R
authors.lastname: Mirfakhraie
authors.forename: Abdolali
authors.initials: A
authors.lastname: Ebrahimi
authors.forename: Hamid
authors.initials: H
authors.lastname: Attarian
authors.forename: Jahangir
authors.initials: J
authors.lastname: Rafat
authors.forename: Mojtaba
authors.initials: M
authors.lastname: Ghadyani
authors.forename: Hossein Afshin
authors.initials: HA
authors.lastname: Alavi
authors.forename: Naser
authors.initials: N
authors.lastname: Kamalian
authors.forename: Afshin
authors.initials: A
authors.lastname: Rakhsha
authors.forename: Eznollah
authors.initials: E
authors.lastname: Azargashb
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D016022:Case-Control Studies; D019938:Cyclin D1 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005784:Gene Amplification / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction / Q000379:methods*; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D000075223:Poly-ADP-Ribose Binding Proteins; D011237:Predictive Value of Tests; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D019938:Cyclin D1; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C530104:CCND1 protein, human; C508053:ERBB2 protein, human; C000618811:TOP2A protein, human