Topoisomerase II alpha gene copy loss has adverse prognostic significance in ERBB2-amplified breast cancer: a retrospective study of paraffin-embedded tumor specimens and medical charts.
BACKGROUND
Amplification of the ERBB2 (Her-2/neu) oncogene, which occurs in approximately 25% of breast carcinomas, is a known negative prognostic factor. Available data indicate that a variable number of nearby genes on chromosome 17q may be co-amplified or deleted, forming a continuous amplicon of variable size. In approximately 25% of these patients, the amplicon extends to the gene for topoisomerase II alpha (TOP2A), a target for anthracyclines. We sought to understand the significance of these associated genomic changes for breast cancer prognosis and predicting response to therapy.


METHODS
Archival tissue samples from 63 breast cancer patients with ERBB2 amplification, stages 0-IV, were previously analyzed with FISH probes for genes located near ERBB2. In the present study, the clinical outcome data were determined for all patients presenting at stages I-III for whom adequate clinical follow up was available.


RESULTS
Four amplicon patterns (Classes) were identified. These were significantly associated with the clinical outcome, specifically, recurrence of breast cancer. The Amplicon class IV with deleted TOP2A had 67% (6/9) cases with recurrence, whereas the other three classes combined had only 12% (3/25) cases (p-value = 0.004) at the time of last follow-up. TOP2A deletion was also significantly associated with time to recurrence (p-value = 0.0002). After adjusting for age in Cox regression analysis, the association between TOP2A deletion and time to recurrence remains strongly significant (p-value = 0.002) whereas the association with survival is marginally significant (p-value = 0.06).


CONCLUSIONS
TOP2A deletion is associated with poor prognosis in ERBB2-amplified breast carcinomas. Clarification of the mechanism of this association will require additional study.
Usha
Lydia
L
Division of Hematology and Oncology, Department of Medicine, Rush University, Chicago, Illinois, 60612, USA. lydia_usha@rush.edu
Tabesh
Bita
B
Morrison
Larry E
LE
Rao
Ruta D
RD
Jacobson
Kris
K
Zhu
April
A
Basu
Sanjib
S
Coon
John S
JS
D000951:Antigens, Neoplasm / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D049109:Cell Proliferation; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D017353:Gene Deletion; D018628:Gene Dosage; D018734:Genes, erbB-2; D006801:Humans; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D012189:Retrospective Studies
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human