J Breast Cancer.  2012 Mar;15(1):24-33. 10.4048/jbc.2012.15.1.24.

Multiplication of Chromosome 17 Centromere Is Associated with Prognosis in Patients with Invasive Breast Cancers Exhibiting Normal HER2 and TOP2A Status

• Kim A
• Shin HC
• Bae YK
• Kim MK
• Kang SH
• Lee SJ
• Lee EH

• KMID: 2286470
• DOI: http://doi.org/10.4048/jbc.2012.15.1.24

Abstract

PURPOSE
This study aimed to investigate the clinical significance of chromosome 17 centromere (CEP17) multiplication (increased copy number of CEP17) related to human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) status in patients with invasive breast cancer.
METHODS
We constructed tissue microarrays using 594 invasive breast cancer samples and performed single-color silver-enhanced in situ hybridization (SISH) assay for HER2, TOP2A, and CEP17 to assess for copy number aberrations. The association of CEP17 multiplication with patient survival was analyzed according to HER2 and TOP2A status.
RESULTS
Among 567 informative cases, HER2 amplification was noted in 22.8%, TOP2A amplification in 8.3% and TOP2A deletion in 11.1%. CEP17 multiplication was identified in 33.2% and was significantly associated with worse overall survival (OS) (p=0.02) and disease-free survival (DFS) (p=0.02). CEP17 multiplication correlated with patient survival in patients with normal TOP2A or non-amplified HER2 status, but the prognostic significance was lost in those with altered TOP2A or amplified HER2. On multivariate analyses, CEP17 multiplication was an independent prognostic factor for poorer OS (p=0.02) and DFS (p=0.01) in patients with normal TOP2A and non-amplified HER2.
CONCLUSION
CEP17 multiplication was identified as a promising prognostic marker in patients with invasive breast cancer exhibiting either non-amplified HER2 or normal TOP2A status.

Keyword

Breast neoplasms; Chromosome 17; HER2 gene; In situ hybridization; Topoisomerase II alpha

MeSH Terms

Antigens, Neoplasm
Breast
Breast Neoplasms
Centromere
Chromosomes, Human, Pair 17
Coat Protein Complex I
Disease-Free Survival
DNA Topoisomerases, Type II
DNA-Binding Proteins
Genes, erbB-2
Humans
In Situ Hybridization
Multivariate Analysis
Prognosis
Receptor, Epidermal Growth Factor
Receptor, erbB-2
Antigens, Neoplasm
Coat Protein Complex I
DNA Topoisomerases, Type II
DNA-Binding Proteins
Receptor, Epidermal Growth Factor
Receptor, erbB-2

Figure

• 

  Figure 1 Silver-enhanced in situ hybridization results for HER2. (A) Negative for HER2 amplification. The average number of HER2 signals per nucleus was 1.9 and the HER2/CEP17 ratio was 0.95 (×400). (B) Positive for HER2 amplification. The average number of HER2 signals per nucleus was 20 and the HER2/CEP17 ratio was 9.62 (×400).

• 

  Figure 2 Silver-enhanced in situ hybridization results for TOP2A. (A) Deletion of TOP2A. The majority of tumor cells have single signal for TOP2A (×400). The average number of TOP2A signals per nucleus was 1.2 and the TOP2A/CEP17 ratio was 0.7. (B) Amplification of the TOP2A gene. Hybridization signals are conglomerated (×400). The average number of TOP2A signals per nucleus was 20 and the TOP2A/CEP17 ratio was 17.4.

• 

  Figure 3 Silver-enhanced in situ hybridization results for CEP17. (A) Normal CEP17 signals. The majority of cells have one or two hybridization signals (×400). The average number of CEP17 signals per nucleus was 1.65. (B) CEP17 multiplication. The average number of CEP17 signals per nucleus was 3.4 in this case (×400).

• 

  Figure 4 Kaplan-Meier curves of overall survival and disease-free survival according to CEP17 copy number. (A, B) Survival curves of patients with tumors exhibiting non-amplified HER2. (C, D) Survival curves in patients with tumors exhibiting amplified HER2 status. (E, F) Survival curves of patients with tumors exhibiting normal TOP2A. (G, H) Survival curves of patients with tumors exhibiting altered TOP2A status.

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