title: Co-amplification of the HER2 gene and chromosome 17 centromere: a potential diagnostic pitfall in HER2 testing in breast cancer.
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.
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland. zsuzsanna.varga@usz.ch
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Varga
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tubbs
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Aurelia
authors.initials: A
authors.lastname: Noske
authors.forename: Doris
authors.initials: D
authors.lastname: Kradolfer
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bosshard
authors.forename: Wolfram
authors.initials: W
authors.lastname: Jochum
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Christian
authors.initials: C
authors.lastname: Öhlschlegel
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000175:diagnosis / Q000235:genetics*; D002503:Centromere / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D056915:DNA Copy Number Variations; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003951:Diagnostic Errors; D005260:Female; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D012189:Retrospective Studies; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
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; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D016159:Tumor Suppressor Protein p53; C000607071:RARA protein, human; C495901:TP53 protein, human; C508053:ERBB2 protein, human; C000618811:TOP2A protein, human