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Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer

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 het...

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Autores principales: Stahl, Phillip, Seeschaaf, Carsten, Lebok, Patrick, Kutup, Asad, Bockhorn, Maximillian, Izbicki, Jakob R, Bokemeyer, Carsten, Simon, Ronald, Sauter, Guido, Marx, Andreas H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324419/
https://www.ncbi.nlm.nih.gov/pubmed/25649416
http://dx.doi.org/10.1186/s12876-015-0231-4
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author Stahl, Phillip
Seeschaaf, Carsten
Lebok, Patrick
Kutup, Asad
Bockhorn, Maximillian
Izbicki, Jakob R
Bokemeyer, Carsten
Simon, Ronald
Sauter, Guido
Marx, Andreas H
author_facet Stahl, Phillip
Seeschaaf, Carsten
Lebok, Patrick
Kutup, Asad
Bockhorn, Maximillian
Izbicki, Jakob R
Bokemeyer, Carsten
Simon, Ronald
Sauter, Guido
Marx, Andreas H
author_sort Stahl, Phillip
collection PubMed
description 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. CONCLUSION: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12876-015-0231-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-43244192015-02-12 Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer Stahl, Phillip Seeschaaf, Carsten Lebok, Patrick Kutup, Asad Bockhorn, Maximillian Izbicki, Jakob R Bokemeyer, Carsten Simon, Ronald Sauter, Guido Marx, Andreas H BMC Gastroenterol Research Article 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. CONCLUSION: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12876-015-0231-4) contains supplementary material, which is available to authorized users. BioMed Central 2015-02-05 /pmc/articles/PMC4324419/ /pubmed/25649416 http://dx.doi.org/10.1186/s12876-015-0231-4 Text en © Stahl et al.; licensee BioMed Central. 2015 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Stahl, Phillip
Seeschaaf, Carsten
Lebok, Patrick
Kutup, Asad
Bockhorn, Maximillian
Izbicki, Jakob R
Bokemeyer, Carsten
Simon, Ronald
Sauter, Guido
Marx, Andreas H
Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer
title Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer
title_full Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer
title_fullStr Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer
title_full_unstemmed Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer
title_short Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer
title_sort heterogeneity of amplification of her2, egfr, ccnd1 and myc in gastric cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324419/
https://www.ncbi.nlm.nih.gov/pubmed/25649416
http://dx.doi.org/10.1186/s12876-015-0231-4
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