title: Adjusting breast cancer patient prognosis with non-HER2-gene patterns on chromosome 17.
abstract: BACKGROUND
  HER2 and TOP2A gene status are assessed for diagnostic and research purposes in breast cancer with fluorescence in situ hybridization (FISH). However, FISH probes do not target only the annotated gene, while chromosome 17 (chr17) is among the most unstable chromosomes in breast cancer. Here we asked whether the status of specifically targeted genes on chr17 might help in refining prognosis of early high-risk breast cancer patients.
  
  
  METHODS
  Copy numbers (CN) for 14 genes on chr17, 4 of which were within and 10 outside the core HER2 amplicon (HER2- and non-HER2-genes, respectively) were assessed with qPCR in 485 paraffin-embedded tumor tissue samples from breast cancer patients treated with adjuvant chemotherapy in the frame of two randomized phase III trials.
  
  
  RESULTS
  HER2-genes CN strongly correlated to each other (Spearman's rho >0.6) and were concordant with FISH HER2 status (Kappa 0.6697 for ERBB2 CN). TOP2A CN were not concordant with TOP2A FISH status (Kappa 0.1154). CN hierarchical clustering revealed distinct patterns of gains, losses and complex alterations in HER2- and non-HER2-genes associated with IHC4 breast cancer subtypes. Upon multivariate analysis, non-HER2-gene gains independently predicted for shorter disease-free survival (DFS) and overall survival (OS) in patients with triple-negative cancer, as compared to luminal and HER2-positive tumors (interaction p = 0.007 for DFS and p = 0.011 for OS). Similarly, non-HER2-gene gains were associated with worse prognosis in patients who had undergone breast-conserving surgery as compared to modified radical mastectomy (p = 0.004 for both DFS and OS). Non-HER2-gene losses were unfavorable prognosticators in patients with 1-3 metastatic nodes, as compared to those with 4 or more nodes (p = 0.017 for DFS and p = 0.001 for OS).
  
  
  CONCLUSIONS
  TOP2A FISH and qPCR may not identify the same pathology on chr17q. Non-HER2 chr17 CN patterns may further predict outcome in breast cancer patients with known favorable and unfavorable prognosis.
authors.affiliation: Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kotoula
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Mattheos
authors.initials: M
authors.lastname: Bobos
authors.affiliation: Department of Biostatistics, Health Data Specialists Ltd, Athens, Greece.
authors.forename: Zoi
authors.initials: Z
authors.lastname: Alexopoulou
authors.affiliation: Department of Clinical Therapeutics, "Alexandra" Hospital, University of Athens School of Medicine, Athens, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Papadimitriou
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Papadopoulou
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Elpida
authors.initials: E
authors.lastname: Charalambous
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Tsolaki
authors.affiliation: Breast Clinic, "REA" Hospital, Piraeus, Greece.
authors.forename: Grigorios
authors.initials: G
authors.lastname: Xepapadakis
authors.affiliation: Department of Histopathology, "Agii Anagriri" Cancer Hospital, Athens, Greece.
authors.forename: Irene
authors.initials: I
authors.lastname: Nicolaou
authors.affiliation: Department of Pathology, "Alexandra" Hospital, Athens, Greece.
authors.forename: Irene
authors.initials: I
authors.lastname: Papaspirou
authors.affiliation: Second Department of Medical Oncology, "Agii Anargiri" Cancer Hospital, Athens, Greece.
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Aravantinos
authors.affiliation: Second Department of Medical Oncology, "Metropolitan" Hospital, Piraeus, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Christodoulou
authors.affiliation: Department of Pathology, "Papageorgiou" Hospital, Thessaloniki, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Efstratiou
authors.affiliation: First Department of Medicine, "Laiko" General Hospital, University of Athens, Medical School, Athens, Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Gogas
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D043171:Chromosomal Instability; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015996:Survival Rate
chemical_list: D000951:Antigens, Neoplasm; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C000618811:TOP2A protein, human
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