title: Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer.
abstract: BACKGROUND
  Intra-tumor heterogeneity is a potential cause for failure of targeted therapy in gastric cancer, but the extent of heterogeneity of established (HER2) or potential (EGFR, CCND1) target genes and prognostic gene alterations (MYC) had not been systematically studied.
  
  
  METHODS
  To study heterogeneity of these genes in a large patient cohort, a heterogeneity tissue microarray was constructed containing 0.6 mm tissue cores from 9 different areas of the primary gastric cancers of 113 patients and matched lymph node metastases from 61 of these patients. Dual color fluorescence in-situ hybridization was performed to assess amplification of HER2, EGFR, CCND1 and MYC using established thresholds (ratio ≥ 2.0). Her2 immunohistochemistry (IHC) was performed in addition.
  
  
  RESULTS
  Amplification was found in 17.4% of 109 interpretable cases for HER2, 6.4% for EGFR, 17.4% for CCND1, and 24.8% for MYC. HER2 amplification was strongly linked to protein overexpression by IHC in a spot-by-spot analysis (p < 0.0001). Intra-tumor heterogeneity was found in the primary tumors of 9 of 19 (47.3%) cancers with HER2, 8 of 17 (47.0%) cancers with CCND1, 5 of 7 (71.4%) cancers with EGFR, and 23 of 27 (85.2%) cancers with MYC amplification. Amplification heterogeneity was particularly frequent in case of low-level amplification (<10 gene copies). While the amplification status was often different between metastases, unequivocal intra-tumor heterogeneity was not found in individual metastases.
  
  
  CONCLUSIONS
  The data of our study demonstrate that heterogeneity is common for biomarkers in gastric cancer. Given that both TMA tissue cores and clinical tumor biopsies analyze only a small fraction of the tumor bulk, it can be concluded that such heterogeneity may potentially limit treatment decisions based on the analysis of a single clinical cancer biopsy.
authors: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. p.stahl@uke.de.
authors: Phillip
authors: P
authors: Stahl
authors: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. seeschaaf@gmx.de.
authors: Carsten
authors: C
authors: Seeschaaf
authors: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. p.lebok@uke.de.
authors: Patrick
authors: P
authors: Lebok
authors: General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. a.kutup@uke.de.
authors: Asad
authors: A
authors: Kutup
authors: General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. m.bockhorn@uke.de.
authors: Maximillian
authors: M
authors: Bockhorn
authors: General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. izbicki@uke.de.
authors: Jakob R
authors: JR
authors: Izbicki
authors: II Med. Klinik, Oncology, Hematology with section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. c.bokemeyer@uke.de.
authors: Carsten
authors: C
authors: Bokemeyer
authors: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. r.simon@uke.de.
authors: Ronald
authors: R
authors: Simon
authors: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. g.sauter@uke.de.
authors: Guido
authors: G
authors: Sauter
authors: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. a.marx@uke.de.
authors: Andreas H
authors: AH
authors: Marx
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics*; D005784:Gene Amplification; D018773:Genes, erbB-1; D018734:Genes, erbB-2; D016259:Genes, myc; D018740:Genetic Heterogeneity; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008207:Lymphatic Metastasis; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; D019938:Cyclin D1
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