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Breast Cancer Research and Treatment

, Volume 132, Issue 3, pp 925–935 | Cite as

Co-amplification of the HER2 gene and chromosome 17 centromere: a potential diagnostic pitfall in HER2 testing in breast cancer

  • Zsuzsanna Varga
  • Raymond R. Tubbs
  • Zhen Wang
  • Yang Sun
  • Aurelia Noske
  • Doris Kradolfer
  • Giovanna Bosshard
  • Wolfram Jochum
  • Holger Moch
  • Christian Öhlschlegel
Preclinical Study

Abstract

Co-amplification of the centromere on chromosome 17 (CEP17) and HER2 can occur in breast cancer. Such aberrant patterns (clusters) on CEP17 can be misleading to calculate the HER2/CEP17 ratio, and thus underreporting of HER2 amplification. We identified 14 breast cancers retrospectively with HER2/CEP17 co-amplification and performed FISH (fluorescence in situ hybridization) with additional chromosome 17 probes (17p11.1–q11.1, 17p11.2–p12, TP53 on 17p13.1, RARA on 17q21.1–3 and TOP2 on 17q21.3–22) to characterize the spanning of the amplicon in these cases. Furthermore, the HER2 status was analyzed by means of HER2 silver in situ hybridization (SISH) and immunohistochemistry (IHC). The co-amplification of HER2/CEP17 was compared between the three institutions. TP53 was eusomic in all cases, 17p11.2–p12 in 79% (11/14), whereas 17p11.1–q11.1 showed chromosomal gain in all cases. RARA was amplified in 10/14 cases (71%) and TOP2 in 3/14 cases (21%). HER2 was amplified with FISH/SISH in all 14 cases. 9/14 tumors were 3+ IHC positive (64%) and 3 cases were 2+ IHC positive. In our cohort the CEP17 amplicon almost always involves the HER2 but not the TOP2 locus. Overall agreement on HER2/CEP17 ratio (when applying ASCO/CAP guidelines) was only 64% (9/14 cases) between the institutions. Discrepant ratios varied from 1.1 to 14.3. The HER2/CEP17 co-amplification is not defined in the ASCO/CAP guidelines, and may result in inaccurate HER2-FISH/SISH status, particularly if only the calculated HER2/CEP17 ratio is reported. It is recommended to report separate CEP17 and HER2 signals in complex HER2/CEP17 patterns.

Keywords

HER2 CEP17 Co-amplification FISH Breast cancer 

Notes

Acknowledgments

The authors wish to thank Dr. Günter Seile for providing case Nr. 14 to the study and Dr. Adriana von Teichman for critical proof-reading and thorough rewriting of the manuscript. There is no conflict of interest for any of the authors.

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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Zsuzsanna Varga
    • 1
  • Raymond R. Tubbs
    • 2
  • Zhen Wang
    • 2
  • Yang Sun
    • 2
  • Aurelia Noske
    • 1
  • Doris Kradolfer
    • 3
  • Giovanna Bosshard
    • 1
  • Wolfram Jochum
    • 3
  • Holger Moch
    • 1
  • Christian Öhlschlegel
    • 3
  1. 1.Institute of Surgical PathologyUniversity Hospital ZurichZurichSwitzerland
  2. 2.Section of Molecular Oncologic Pathology, Department of Molecular Pathology, Pathology and Laboratory Medicine InstituteCleveland Clinic FoundationClevelandUSA
  3. 3.Institute of PathologyCantonal HospitalSt. GallenSwitzerland

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