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Kahiye M, Yahaya J, Kalungi S, Nalwoga H. HER2 immunohistochemical expression and its association with clinicopathological features of gastric adenocarcinoma in Uganda. Turk J Surg 2024; 40:328-335. [PMID: 39980649 PMCID: PMC11831991 DOI: 10.47717/turkjsurg.2024.6501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 12/04/2024] [Indexed: 02/22/2025]
Abstract
Objectives Despite the remarkable improvement in gastric adenocarcinoma treatment modalities, the prognosis of gastric adenocarcinoma remains poor. The purpose of this study was to determine the prevalence of HER2 immunohistochemical expression and its association with clinicopathological features of patients with gastric adenocarcinoma. Material and Methods This was a cross-sectional study which was conducted at the department of pathology. A total of 86 formalin fixed paraffin embedded tissue blocks of the patients who were confirmed histologically with gastric adenocarcinoma from January 2009 to December 2019 were included in the analysis. Laboratory requisition form and patients' files were used to extract the clinical and pathological data of the cases. Immunohistochemistry to assess HER2 overexpression was done using monoclonal (SP3 clone) rabbit anti-HER2/neu (Thermo Fisher Scientific-USA). Chi-square statistical test was used to determine the association of the clinicopathological characteristics with HER2 expression. P <0.05 was considered statistically significant. Results Mean age of the patients included in the study was 58.5 ± 14.3 years, and over half 54.7% (n= 47) of the patients were males. Poorly cohesive non-signet ring types contributed most (47.7%) (n= 41) of the cases, and diffuse/mixed histological subtypes were more prevalent (57%) (n= 49) subtypes. Poorly differentiated cases accounted for the majority (66.3%) (n= 57) of the cases. The prevalence of HER2 immunohistochemical expression was 8.1% (n= 7). None of the clinicopathological characteristics were associated with HER2 expression. Conclusion This study has shown almost every one in 10 patients with gastric adenocarcinoma may express HER2 when using immunohistochemistry test. However, the HER2 in this study was not associated with age, sex, tumor location, the nature of biopsy, histological subtypes, and tumor grade.
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Affiliation(s)
- Mohamed Kahiye
- Department of Pathology, Sahan Pathology Laboratories, Mogadishu, Somalia
| | - James Yahaya
- Department of Pathology, Soroti University Faculty of Medicine, Soroti, Uganda
| | - Sam Kalungi
- Department of Pathology, Mulago National Referral Hospital, Kampala, Uganda
| | - Hawa Nalwoga
- Department of Pathology, Makerere College of Health Sciences, Kampala, Uganda
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Wang D, Hao S, He H, Zhang J, You G, Wu X, Zhang R, Meng X, Cui X, Bai J, Fu S, Yu J. Contribution of PGAP3 co-amplified and co-overexpressed with ERBB2 at 17q12 involved poor prognosis in gastric cancer. J Cell Mol Med 2023; 27:2424-2436. [PMID: 37386793 PMCID: PMC10424286 DOI: 10.1111/jcmm.17828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 06/10/2023] [Accepted: 06/19/2023] [Indexed: 07/01/2023] Open
Abstract
The locus at 17q12 erb-b2 receptor tyrosine kinase 2 (ERBB2) has been heavily amplificated and overexpressed in gastric cancer (GC), but it remains to be elucidated about the clinical significance of the co-amplification and co-overexpression of PGAP3 gene located around ERBB2 in GC. The profile of PGAP3 and ERBB2 in four GC cell lines and tissue microarrays containing 418 primary GC tissues was assessed to investigate the co-overexpression and clinical significance of the co-amplified genes, and to evaluate the impact of the co-amplified genes on the malignancy of GC. Co-amplification of PGAP3 and ERBB2 accompanied with co-overexpression was observed in a haploid chromosome 17 of NCI-N87 cells with double minutes (DMs). PGAP3 and ERBB2 were overexpressed and positively correlated in 418 GC patients. Co-overexpression of the PGAP3 and ERBB2 was correlated with T stage, TNM stage, tumour size, intestinal histological type and poor survival proportion in 141 GC patients. In vitro, knockdown of the endogenous PGAP3 or ERBB2 decreased cell proliferation and invasion, increased G1 phase accumulation and induced apoptosis in NCI-N87 cells. Furthermore, combined silencing of PGAP3 and ERBB2 showed an additive effect on resisting proliferation of NCI-N87 cells compared with targeting ERBB2 or PGAP3 alone. Taken together, the co-overexpression of PGAP3 and ERBB2 may be crucial due to its significant correlation with clinicopathological factors of GC. Haploid gain of PGAP3 co-amplified with ERBB2 is sufficient to facilitate the malignancy and progression of GC cells in a synergistic way.
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Affiliation(s)
- Dong Wang
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Siyu Hao
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Hongjie He
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Jian Zhang
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Ge You
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Xin Wu
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Rui Zhang
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Xiangning Meng
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University)Ministry of EducationHarbinChina
| | - Xiaobo Cui
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University)Ministry of EducationHarbinChina
| | - Jing Bai
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University)Ministry of EducationHarbinChina
| | - Songbin Fu
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University)Ministry of EducationHarbinChina
| | - Jingcui Yu
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University)Ministry of EducationHarbinChina
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Abstract
Trimodality therapy, or the use of concurrent chemoradiation followed by surgery, is the cornerstone of contemporary management of esophageal cancer. This article discusses the landmark trials and most current data to understand the concepts, applications, and outcomes from trimodality therapy in locally advanced esophageal cancer.
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Affiliation(s)
- Ammara A Watkins
- Division of Thoracic Surgery and Interventional Pulmonology, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 185 Pilgrim Road, Boston, MA 02215, USA
| | - Jessica A Zerillo
- Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Shapiro 9, Boston, MA 02215, USA
| | - Michael S Kent
- Division of Thoracic Surgery and Interventional Pulmonology, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 185 Pilgrim Road, Boston, MA 02215, USA.
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4
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Gürbüz M, Akkuş E, Sakin A, Urvay S, Demiray AG, Şahin S, Şakalar T, Erol C, Şendur MAN, Şahin AB, Çubukçu E, Güven DC, Kılıçkap S, Ergün Y, Uncu D, Turhal NS, Üskent N, Çınkır HY, Demir A, Acar R, Karadurmuş N, Türker S, Altınbaş M, Karaoğlan M, Şenler FÇ. Trastuzumab ± Capecitabine Maintenance After the First-Line Treatment of HER2-Positive Advanced Gastric Cancer: Retrospective Observational Real-Life Data of Turkish Oncology Group. J Gastrointest Cancer 2021; 53:282-288. [PMID: 33538958 DOI: 10.1007/s12029-021-00594-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/24/2021] [Indexed: 02/05/2023]
Abstract
PURPOSE In the ToGA trial for HER2-positive advanced gastric cancer, cisplatin plus fluoropyrimidine was given for 6 cycles; trastuzumab was given until disease progression. However, there is a lack of real-life data about trastuzumab maintenance after 6 cycle chemotherapy. This study aims to present real-life data of trastuzumab ± capecitabine maintenance after 6 cycles of platinum, fluoropyrimidine, and trastuzumab in non-progressive patients. METHODS This is a retrospective multicenter study of the Turkish Oncology Group. A total of 35 HER2-positive, inoperable locally advanced, recurrent, or metastatic gastric adenocarcinoma patients being non-progressive at the end of 6 cycle chemotherapy and being given trastuzumab ± capecitabine as maintenance treatment were included from sixteen oncology centers. Baseline characteristics, objective tumor responses, progression free and overall survival data, and toxicities were determined. RESULTS About 68% of the patients were given CF, and 32% were given FOLFOX with trastuzumab as the first-line treatment. The best response in 6 cycle chemotherapy was complete 8 (22%), partial 24 (68%), and stable disease 3 (8%). All patients had trastuzumab maintenance (median cycle 13; range 7-51), and 49% of the patients had capecitabine with trastuzumab (median capecitabine cycle 6; range 2-30). The median PFS of the patients was 12.0 months (95% CI 10.3-13.7), and median OS was 17.4 months (95% CI 15.2-19.5). There were 2 patients with grade 1 cardiotoxicity. CONCLUSION Trastuzumab maintenance ± capecitabine after 6 cycles of trastuzumab plus combined chemotherapy treatment revealed efficacy and safety in non-progressive HER2-positive advanced gastric cancer.
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Affiliation(s)
- Mustafa Gürbüz
- Faculty of Medicine, Department of Medical Oncology, Ankara University, Ankara, Turkey.
| | - Erman Akkuş
- Faculty of Medicine, Department of Internal Medicine, Ankara University, Ankara, Turkey
| | - Abdullah Sakin
- Faculty of Medicine, Department of Medical Oncology, Van Yüzüncü Yıl University, Van, Turkey
| | - Semiha Urvay
- Department of Medical Oncology, Kayseri Acıbadem Hospital, Kayseri, Turkey
| | - Atike Gökçen Demiray
- Faculty of Medicine, Department of Medical Oncology, Pamukkale University, Denizli, Turkey
| | - Süleyman Şahin
- Department of Medical Oncology, University of Health Sciences, Van Training and Research Hospital, Van, Turkey
| | - Teoman Şakalar
- Department of Medical Oncology, Necip Fazıl City Hospital, Kahramanmaraş, Turkey
| | - Cihan Erol
- Faculty of Medicine, Department of Medical Oncology, Yıldırım Beyazıt University, Ankara, Turkey
| | - Mehmet Ali Nahit Şendur
- Faculty of Medicine, Department of Medical Oncology, Yıldırım Beyazıt University, Ankara, Turkey
| | - Ahmet Bilgehan Şahin
- Faculty of Medicine, Department of Medical Oncology, Uludağ University, Bursa, Turkey
| | - Erdem Çubukçu
- Faculty of Medicine, Department of Medical Oncology, Uludağ University, Bursa, Turkey
| | - Deniz Can Güven
- Faculty of Medicine, Department of Medical Oncology, Hacettepe University, Ankara, Turkey
| | - Saadettin Kılıçkap
- Faculty of Medicine, Department of Medical Oncology, Hacettepe University, Ankara, Turkey
| | - Yakup Ergün
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Doğan Uncu
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | | | - Necdet Üskent
- Anadolu Medical Center, Department of Medical Oncology, Kocaeli, Turkey
| | - Havva Yeşil Çınkır
- Faculty of Medicine, Department of Medical Oncology, Gaziantep University, Gaziantep, Turkey
| | - Atakan Demir
- Department of Medical Oncology, Maslak Acıbadem Hospital, Istanbul, Turkey
| | - Ramazan Acar
- Department of Medical Oncology, University of Health Sciences, Gülhane Training and Research Hospital, Ankara, Turkey
| | - Nuri Karadurmuş
- Department of Medical Oncology, University of Health Sciences, Gülhane Training and Research Hospital, Ankara, Turkey
| | - Sema Türker
- Department of Medical Oncology, Diskapi Yildirim Beyazid Education and Research Hospital, Ankara, Turkey
| | - Mustafa Altınbaş
- Department of Medical Oncology, Diskapi Yildirim Beyazid Education and Research Hospital, Ankara, Turkey
| | - Mert Karaoğlan
- Faculty of Medicine, Department of Internal Medicine, Ankara University, Ankara, Turkey
| | - Filiz Çay Şenler
- Faculty of Medicine, Department of Medical Oncology, Ankara University, Ankara, Turkey
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5
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Gürbüz M, Akkuş E, Sakin A, Urvay S, Demiray AG, Şahin S, Şakalar T, Erol C, Şendur MAN, Şahin AB, Çubukçu E, Güven DC, Kılıçkap S, Ergün Y, Uncu D, Turhal NS, Üskent N, Yeşil Çınkır H, Demir A, Acar R, Karadurmuş N, Türker S, Altınbaş M, Karaoğlan M, Çay Şenler F. Combination of trastuzumab and taxane-containing intensified chemotherapy in first-line treatment of HER2-positive advanced gastric cancer. TUMORI JOURNAL 2020; 107:416-423. [PMID: 33167790 DOI: 10.1177/0300891620969823] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
PURPOSE Taxane-containing combinations are recommended for the first-line therapy of advanced gastric cancer. It is not known which chemotherapy regimen is the best with trastuzumab for HER2-positive patients. The aim of this study was to compare taxane-containing intensified chemotherapy versus standard chemotherapy in combination with trastuzumab in the first-line treatment of HER2-positive advanced gastric adenocarcinoma. METHODS This study is a retrospective multicenter study of the Turkish Oncology Group. A total of 130 HER2-positive patients with inoperable locally advanced, recurrent, or metastatic gastric adenocarcinoma being given chemotherapy plus trastuzumab as the first-line treatment were included from 16 different oncology centers. Trastuzumab combination with intensified chemotherapy including taxane or standard chemotherapy was compared in terms of progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS There were 108 patients in the standard and 22 patients in the intensified chemotherapy group. PFS of the standard and intensified group were 5.6 months (95% confidence interval [CI] 4.8-6.4) and 5.3 months (95% CI 2.6-8), respectively (p = 0.70). OS of the standard and intensified group were 11.1 months (95% CI 8.3-13.9) and 15.2 months (95% CI 12.7-17.7), respectively (p = 0.03). Repeated analysis excluding patients given any previous therapy revealed similar results. The intensified group had more fever and febrile neutropenia. CONCLUSION Trastuzumab combination with intensified chemotherapy provides better OS in first-line treatment of HER2-positive advanced gastric cancer. Further large-scale studies should be performed in HER2-positive patients.
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Affiliation(s)
- Mustafa Gürbüz
- Department of Medical Oncology, Ankara University Faculty of Medicine, Ankara, Turkey
| | - Erman Akkuş
- Department of Internal Medicine, Ankara University Faculty of Medicine, Ankara, Turkey
| | - Abdullah Sakin
- Department of Medical Oncology, Van Yüzüncü Yıl University Faculty of Medicine, Van, Turkey
| | - Semiha Urvay
- Department of Medical Oncology, Kayseri Acıbadem Hospital, Kayseri, Turkey
| | - Atike Gökçen Demiray
- Department of Medical Oncology, Pamukkale University Faculty of Medicine, Denizli, Turkey
| | - Süleyman Şahin
- Department of Medical Oncology, University of Health Sciences, Van Training and Research Hospital, Van, Turkey
| | - Teoman Şakalar
- Department of Medical Oncology, Necip Fazıl City Hospital, Kahramanmaraş, Turkey
| | - Cihan Erol
- Department of Medical Oncology, Yıldırım Beyazıt University Faculty of Medicine, Ankara, Turkey
| | - Mehmet Ali Nahit Şendur
- Department of Medical Oncology, Yıldırım Beyazıt University Faculty of Medicine, Ankara, Turkey
| | - Ahmet Bilgehan Şahin
- Department of Medical Oncology, Uludağ University Faculty of Medicine, Bursa, Turkey
| | - Erdem Çubukçu
- Department of Medical Oncology, Uludağ University Faculty of Medicine, Bursa, Turkey
| | - Deniz Can Güven
- Department of Medical Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Saadettin Kılıçkap
- Department of Medical Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Yakup Ergün
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Doğan Uncu
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | | | - Necdet Üskent
- Department of Medical Oncology, Anadolu Medical Center, Kocaeli, Turkey
| | - Havva Yeşil Çınkır
- Department of Medical Oncology, Gaziantep University Faculty of Medicine, Gaziantep, Turkey
| | - Atakan Demir
- Department of Medical Oncology, Maslak Acıbadem Hospital, Istanbul, Turkey
| | - Ramazan Acar
- Department of Medical Oncology, University of Health Sciences, Gülhane Training and Research Hospital, Ankara, Turkey
| | - Nuri Karadurmuş
- Department of Medical Oncology, University of Health Sciences, Gülhane Training and Research Hospital, Ankara, Turkey
| | - Sema Türker
- Department of Medical Oncology, Diskapi Yildirim Beyazid Education and Research Hospital, Ankara, Turkey
| | - Mustafa Altınbaş
- Department of Medical Oncology, Diskapi Yildirim Beyazid Education and Research Hospital, Ankara, Turkey
| | - Mert Karaoğlan
- Department of Internal Medicine, Ankara University Faculty of Medicine, Ankara, Turkey
| | - Filiz Çay Şenler
- Department of Medical Oncology, Ankara University Faculty of Medicine, Ankara, Turkey
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Hou G, Deng J, You X, Chen J, Jiang Y, Qian T, Bi Y, Song B, Xu Y, Yang X. Mining topoisomerase isoforms in gastric cancer. Gene 2020; 754:144859. [PMID: 32535049 DOI: 10.1016/j.gene.2020.144859] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 05/20/2020] [Accepted: 06/05/2020] [Indexed: 01/04/2023]
Abstract
DNA topoisomerases essentially remove topological strains generated during DNA replication, transcription, DNA repair, and other cytogenetic processes. However, distinct expression level and prognostic significance of individual topoisomerase isoforms in gastric cancer (GC) remain largely unexplored. In this study, we utilized Oncomine and Kaplan-Meier plotter database to detect the mRNA expression level of individual topoisomerase isoforms as well as assess their prognostic significance in GC patients. With the exception of TOP3B and TOP2B, levels of all topoisomerase isoforms were found to be elevated in GC patients when compared to the normal tissues. Elevated expression of TOP1 and TOP1MT was relevant to longer overall survival (OS) in GC and gastric intestinal type adenocarcinoma (GITA) patients, but not in diffuse gastric adenocarcinoma (DFA) patients. Increased expression of TOP2A and TOP2B was related to better OS in GC, as well as in GITA and DFA patients. In contrast, increased expression TOP3A and TOP3B was associated with shorter OS in GC, as well as in GITA and DFA patients. We also applied the Tumor IMmune Estimation Resource (TIMER) tool to assess the correlations between distinct topoisomerase isoforms and the infiltrating immune cell landscape. Furthermore, we found that down-regulating the expression of TOP3A by shRNA significantly inhibited the proliferation and colony formation in GC cells compared to control shRNA treated cells. Thus our study lays the framework for utilizing topoisomerases in better understanding the complexity and heterogeneity of GC and for developing strategies for novel customized therapy in GC patients.
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Affiliation(s)
- Guoxin Hou
- Department of Oncology, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Jingjing Deng
- Department of Respiratory, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Xin You
- The First Department of Chemotherapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Jing Chen
- Department of Oncology, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Yiming Jiang
- Department of Oncology, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Tingting Qian
- Department of Oncology, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Yanyu Bi
- Department of Oncology, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Binbin Song
- Department of Oncology, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Yufen Xu
- Department of Oncology, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Xinmei Yang
- Department of Oncology, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.
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Li H, Long J, Xie F, Kang K, Shi Y, Xu W, Wu X, Lin J, Xu H, Du S, Xu Y, Zhao H, Zheng Y, Gu J. Transcriptomic analysis and identification of prognostic biomarkers in cholangiocarcinoma. Oncol Rep 2019; 42:1833-1842. [PMID: 31545466 PMCID: PMC6787946 DOI: 10.3892/or.2019.7318] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 08/20/2019] [Indexed: 12/27/2022] Open
Abstract
Cholangiocarcinoma (CCA) is acknowledged as the second most commonly diagnosed primary liver tumor and is associated with a poor patient prognosis. The present study aimed to explore the biological functions, signaling pathways and potential prognostic biomarkers involved in CCA through transcriptomic analysis. Based on the transcriptomic dataset of CCA from The Cancer Genome Atlas (TCGA), differentially expressed protein-coding genes (DEGs) were identified. Biological function enrichment analysis, including Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, was applied. Through protein-protein interaction (PPI) network analysis, hub genes were identified and further verified using open-access datasets and qRT-PCR. Finally, a survival analysis was conducted. A total of 1,463 DEGs were distinguished, including 267 upregulated genes and 1,196 downregulated genes. For the GO analysis, the upregulated DEGs were enriched in ‘cadherin binding in cell-cell adhesion’, ‘extracellular matrix (ECM) organization’ and ‘cell-cell adherens junctions’. Correspondingly, the downregulated DEGs were enriched in the ‘oxidation-reduction process’, ‘extracellular exosomes’ and ‘blood microparticles’. In regards to the KEGG pathway analysis, the upregulated DEGs were enriched in ‘ECM-receptor interactions’, ‘focal adhesions’ and ‘small cell lung cancer’. The downregulated DEGs were enriched in ‘metabolic pathways’, ‘complement and coagulation cascades’ and ‘biosynthesis of antibiotics’. The PPI network suggested that CDK1 and another 20 genes were hub genes. Furthermore, survival analysis suggested that CDK1, MKI67, TOP2A and PRC1 were significantly associated with patient prognosis. These results enhance the current understanding of CCA development and provide new insight into distinguishing candidate biomarkers for predicting the prognosis of CCA.
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Affiliation(s)
- Hanyu Li
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Junyu Long
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Fucun Xie
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Kai Kang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Yue Shi
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Weiyu Xu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Xiaoqian Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Jianzhen Lin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Haifeng Xu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Yiyao Xu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Yongchang Zheng
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Jin Gu
- MOE Key Laboratory of Bioinformatics, BNIRST Bioinformatics Division, Department of Automation, Tsinghua University, Beijing 100084, P.R. China
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Hu S, Liao Y, Chen L. Identification of Key Pathways and Genes in Anaplastic Thyroid Carcinoma via Integrated Bioinformatics Analysis. Med Sci Monit 2018; 24:6438-6448. [PMID: 30213925 PMCID: PMC6151107 DOI: 10.12659/msm.910088] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND To provide a better understanding of anaplastic thyroid carcinoma (ATC) at the molecular level, this study aimed to identify the genes and key pathways associated with ATC by using integrated bioinformatics analysis. MATERIAL AND METHODS Based on the microarray data GSE9115, GSE65144, and GSE53072 derived from the Gene Expression Omnibus, the differentially expressed genes (DEGs) between ATC samples and normal controls were identified. With DEGs, we performed a series of functional enrichment analyses. Then, a protein-protein interaction (PPI) network was constructed and visualized, with which the hub gene nodes were screened out. Finally, modules analysis for the PPI network was performed to further investigate the potential relationships between DEGs and ATC. RESULTS A total of 537 common DEGs were screened out from all 3 datasets, among which 247 genes were upregulated and 275 genes were downregulated. GO analysis indicated that upregulated DEGs were mainly involved in cell division and mitotic nuclear division and the downregulated DEGs were significantly enriched in ventricular cardiac muscle cell action potential. KEGG pathway analysis showed that the upregulated DEGs were mainly enriched in cell cycle and ECM-receptor interaction and the downregulated DEGs were mainly enriched in thyroid hormone synthesis, insulin resistance, and pathways in cancer. The top 10 hub genes in the constructed PPI network were CDK1, CCNB1, TOP2A, AURKB, CCNA2, BUB1, AURKA, CDC20, MAD2L1, and BUB1B. The modules analysis showed that genes in the top 2 significant modules of PPI network were mainly associated with mitotic cell cycle and positive regulation of mitosis, respectively. CONCLUSIONS We identified a series of key genes along with the pathways that were most closely related with ATC initiation and progression. Our results provide a more detailed molecular mechanism for the development of ATC, shedding light on the potential biomarkers and therapeutic targets.
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Affiliation(s)
- Shengqing Hu
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (mainland)
| | - Yunfei Liao
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (mainland)
| | - Lulu Chen
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (mainland)
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Petrini I, Lencioni M, Vasile E, Fornaro L, Belluomini L, Pasquini G, Ginocchi L, Caparello C, Musettini G, Vivaldi C, Caponi S, Ricci S, Proietti A, Fontanini G, Naccarato AG, Nardini V, Santi S, Falcone A. EGFR and AKT1 overexpression are mutually exclusive and associated with a poor survival in resected gastric adenocarcinomas. Cancer Biomark 2018; 21:731-741. [DOI: 10.3233/cbm-170865] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Iacopo Petrini
- Medical Oncology, University Hospital of Pisa, 56126 Pisa, Italy
| | - Monica Lencioni
- Medical Oncology, University Hospital of Pisa, 56126 Pisa, Italy
| | - Enrico Vasile
- Medical Oncology, University Hospital of Pisa, 56126 Pisa, Italy
| | - Lorenzo Fornaro
- Medical Oncology, University Hospital of Pisa, 56126 Pisa, Italy
| | | | - Giulia Pasquini
- Medical Oncology, University Hospital of Pisa, 56126 Pisa, Italy
| | - Laura Ginocchi
- Medical Oncology, University Hospital of Pisa, 56126 Pisa, Italy
| | - Chiara Caparello
- Medical Oncology, University Hospital of Pisa, 56126 Pisa, Italy
| | - Gianna Musettini
- Medical Oncology, University Hospital of Pisa, 56126 Pisa, Italy
| | - Caterina Vivaldi
- Medical Oncology, University Hospital of Pisa, 56126 Pisa, Italy
| | - Sara Caponi
- Medical Oncology, University Hospital of Pisa, 56126 Pisa, Italy
| | - Sergio Ricci
- Medical Oncology, University Hospital of Pisa, 56126 Pisa, Italy
| | - Agenese Proietti
- Surgical Pathology, Unit 3, University Hospital of Pisa, 56126 Pisa, Italy
| | | | | | - Vincenzo Nardini
- Surgical Pathology, Unit 2, University Hospital of Pisa, 56126 Pisa, Italy
| | - Stefano Santi
- Esophageal Surgery, University Hospital of Pisa, 56126 Pisa, Italy
| | - Alfredo Falcone
- Medical Oncology, University Hospital of Pisa, 56126 Pisa, Italy
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10
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Epidermal growth factor receptor intron-1 CA repeat polymorphism on protein expression and clinical outcome in Taiwanese oral squamous cell carcinoma. Sci Rep 2017; 7:4963. [PMID: 28694429 PMCID: PMC5504053 DOI: 10.1038/s41598-017-04954-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 05/23/2017] [Indexed: 12/16/2022] Open
Abstract
This study was designed to explore the relationship between epidermal growth factor receptor (EGFR) CA repeats polymorphism and protein expression in oral cavity squamous cell carcinoma (OSCC). A total of 194 OSCCs were examined for EGFR protein overexpression, gene copy number and the length of their CA repeats. The length of the EGFR CA repeats was found not to be associated with EGFR gene copy number or with protein overexpression. To exclude the effect of EGFR gene copy number on protein overexpression, only those OSCC tumors with disomy of the EGFR gene were included in further analysis. In this subgroup, EGFR protein overexpression was significantly associated with poor differentiation of the tumor cells and lymph node metastasis, especially extra-capsular spread. However, EGFR CA repeats were not related to any clinicopathological factor. Interestingly, patients genetically found to have the EGFR CA repeats SS genotype and having tumors with EGFR protein overexpression were found to have a worst prognosis in terms of disease-free survival (DFS) (HR = 2.68; 95% CI, 1.03-6.98) after multivariate adjustment. The present study demonstrates that concurrent overexpression of EGFR protein in the presence genetically of the SS form CA repeats acts as a predictor for poor DFS.
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11
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Zeichner SB, Goldstein DA, Kohn C, Flowers CR. Cost-effectiveness of precision medicine in gastrointestinal stromal tumor and gastric adenocarcinoma. J Gastrointest Oncol 2017; 8:513-523. [PMID: 28736638 DOI: 10.21037/jgo.2016.04.03] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Over the past 20 years, with the incorporation of genetic sequencing and improved understanding regarding the mechanisms of cancer growth/metastasis, novel targets and their associated treatments have emerged in oncology and are now regularly incorporated into the clinical care of patients in the US. Novel, more tumor-specific, non-chemotherapy agents, including agents that are commonly used in the treatment of patients with gastric adenocarcinoma (GA) and gastrointestinal stromal tumor (GIST), fall under a broader treatment strategy, termed "precision medicine". While diagnostic testing and associated treatments in metastatic GA (mGA) are costly and may produce marginal benefit, those associated with GIST, despite being costly, produce significant improvements in patient outcomes. Despite the significant difference in impact, the agents associated with these cancers have similar acquisition costs. In this paper, we will review the current literature regarding cost and cost-effectiveness associated with precision medicine diagnosis and treatment strategies for GA and GIST.
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Affiliation(s)
- Simon B Zeichner
- Winship Cancer Institute at Emory University, Division of Hematology & Oncology, Atlanta, GA 30322, USA
| | - Daniel A Goldstein
- Davidoff Cancer Center, Rabin Medical Center, Petah Tikva 4941492, Israel
| | - Christine Kohn
- University of Saint Joseph School of Pharmacy, Hartford Hospital Evidence-based Practice Center, Hartford, CT 06103, USA
| | - Christopher R Flowers
- Winship Cancer Institute at Emory University, Division of Hematology & Oncology, Atlanta, GA 30322, USA
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12
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Personeni N, Baretti M, Bozzarelli S, Spaggiari P, Rubino L, Tronconi MC, Fumagalli Romario U, Rosati R, Giordano L, Roncalli M, Santoro A, Rimassa L. Assessment of HER2 status in patients with gastroesophageal adenocarcinoma treated with epirubicin-based chemotherapy: heterogeneity-related issues and prognostic implications. Gastric Cancer 2017; 20:428-437. [PMID: 27530622 DOI: 10.1007/s10120-016-0625-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Accepted: 08/02/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND HER2 and topoisomerase 2 alpha (TOP2A) genomic status was previously reported to predict benefit from anthracyclines in breast cancer. We sought to define the prognostic impact and possible pitfalls related to these biomarkers in resectable gastroesophageal adenocarcinoma. METHODS HER2 and TOP2A gene amplification by fluorescent in situ hybridization and HER2 protein expression by immunohistochemistry (IHC) were assessed on whole tissue sections from 101 patients receiving peri- or postoperative epirubicin-based chemotherapy. In a subgroup of patients, at least two matched tumor blocks, originating either from surgical procedures (n = 88) or diagnostic biopsies (n = 32), were available for HER2 analyses by IHC. RESULTS Eighteen of 101 patients (17.8 %) were HER2 positive, whereas TOP2A was amplified in 4 of 84 patients (4.7 %). HER2 positivity was significantly associated with improved disease-free survival [HR = 0.47 (95 % CI 0.22-0.99), P = 0.046] and overall survival [HR = 0.33 (95 % CI 0.13-0.83), P < 0.018], independent of clinical-pathologic features. HER2 expression in matched tumor blocks from the same resection specimen was discordant in up to 11.8 % of pairs, while this rate increased up to 27.2 % when diagnostic biopsies and paired surgical samples were compared. CONCLUSIONS HER2 status is an independent prognostic biomarker in gastroesophageal adenocarcinomas receiving epirubicin-based chemotherapy. Compared to diagnostic biopsies, HER2 assessment in multiple resection specimens might lower the risk of sampling errors. These findings have several implications with respect to the optimal choice of the sample to be submitted to IHC testing of HER2.
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Affiliation(s)
- Nicola Personeni
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy. .,Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
| | - Marina Baretti
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy
| | - Silvia Bozzarelli
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy
| | - Paola Spaggiari
- Department of Pathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Luca Rubino
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy
| | - Maria Chiara Tronconi
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy
| | | | - Riccardo Rosati
- Department of General Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.,Ospedale San Raffaele, Milan, Italy
| | - Laura Giordano
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy
| | - Massimo Roncalli
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.,Department of Pathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Armando Santoro
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy.,Humanitas University, Rozzano, Milan, Italy
| | - Lorenza Rimassa
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy
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13
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Li S, Li B, Wang J, Zhang D, Liu Z, Zhang Z, Zhang W, Wang Y, Bai D, Guan J, Zhang Y. Identification of Sensitivity Predictors of Neoadjuvant Chemotherapy for the Treatment of Adenocarcinoma of Gastroesophageal Junction. Oncol Res 2017; 25:93-97. [PMID: 28081737 PMCID: PMC7840763 DOI: 10.3727/096504016x14719078133564] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The identification of reliable predictors of chemotherapy sensitivity and early screening of adenocarcinoma of gastroesophageal junction (AGEJ) patients who are resistant to chemotherapy has become an important area of clinical and translational research. We aimed to investigate the predictive value of seven cancer-associated cellular proteins for neoadjuvant chemotherapy in AGEJ patients. Clinical data of 93 patients who received neoadjuvant chemotherapy for locally advanced AGEJ between June 2010 and December 2014 were reviewed. All patients were administered the combination regimen of S-1 and oxaliplatin (SOX). Expression of P-glycoprotein (P-gp), glutathione S-transferase-π (GST-π), topoisomerase II (topo II), multidrug resistance gene-associated protein (MRP), lung resistance-related protein (LRP), Ki-67, and p53 was determined by immunohistochemistry (IHC) in AGEJ tissues before neoadjuvant chemotherapy. Chemotherapeutic efficacy was evaluated according to RECIST 1.0 standards and histopathological results, and the relationship between the expression of the cellular proteins and chemotherapy efficacy was analyzed. The SOX regimen was associated with an overall response rate of 46.2%. The frequency of expression of the seven cancer-associated factors in the AGEJ tissues was as follows: P-gp, 64.5%; GST-π, 39.8%; topo II, 72.0%; MRP, 33.3%; LRP, 68.8%; Ki-67, 62.4%; and p53, 40.9%. Expression of Ki-67 (p = 0.003) and p53 (p = 0.009) was significantly correlated with chemotherapy sensitivity. Elevated Ki-67 expression and decreased p53 expression predict for SOX insensitivity in AGEJ, and the cellular expression of these respective proteins may provide a useful reference for designing individualized chemotherapy regimens for AGEJ patients in the future.
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14
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Wang Y. Transcriptional Regulatory Network Analysis for Gastric Cancer Based on mRNA Microarray. Pathol Oncol Res 2017; 23:785-791. [PMID: 28078605 DOI: 10.1007/s12253-016-0159-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 12/14/2016] [Indexed: 12/27/2022]
Abstract
We aimed to screen the differential expressed genes (DEGs) and transcriptional factors (TFs) related to gastric cancer. GSE19826 microarray data downloaded from Gene Expression Omnibus was used to identify the differentially expressed genes (DEGs) and PPI network of DEGs were constructed by the Retrieval of Interacting Genes database. Pathway enrichment analysis of DEGs were performed by Gene Set Enrichment Analysis. Then, the transcriptional regulatory network was constructed based on TRANSFAC database. Finally, regulatory impact factor (RIF) of TF was calculated. We identified 446 DEGs including 209 up- and 237 down-regulated genes. These DEGs were mainly significantly enriched in 5 pathways including ECM receptor interaction (p = 0.013899), spliceosome (p = 0.025591), bladder cancer (p = 0.026316), focal adhesion (p = 0.047809) and WNT signaling pathway (p = 0.048077). PPI network with 247 nodes and 913 edges were constructed and COL5A2 was the hub node. Transcriptional regulatory network with 6 differently expressed TFs, 58 non-differently expressed TFs, 44 DEGs and 735 non-DEGs was constructed. Finally, top 5 TFs including CRX, TFAP4, NKX2-1, MYB and RARG with higher ZRIF were screened. The identified DEGs such as COL5A2 and TOP2A, and TFs including EGR2, FOXM1, NKX2-1 and TFAP4 might be the critical genes and TFs for gastric cancer.
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Affiliation(s)
- Yan Wang
- Department of Gastroenterology, Shengjing Hospital, China Medical University, No.36 Sanhao Road, Shenyang, 110004, China.
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15
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Azarnezhad A, Mehdipour P. Cancer Genetics at a Glance: The Comprehensive Insights. CANCER GENETICS AND PSYCHOTHERAPY 2017:79-389. [DOI: 10.1007/978-3-319-64550-6_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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16
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Wu J, Li S, Ma R, Sharma A, Bai S, Dun B, Cao H, Jing C, She J, Feng J. Tumor profiling of co-regulated receptor tyrosine kinase and chemoresistant genes reveal different targeting options for lung and gastroesophageal cancers. Am J Transl Res 2016; 8:5729-5740. [PMID: 28078044 PMCID: PMC5209524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 09/10/2016] [Indexed: 06/06/2023]
Abstract
The expression of a number of genes can influence the response rates to chemotherapy while genes encoding receptor tyrosine kinases (RTKs) determine the response to most targeted cancer therapies currently used in clinics. In this study, we evaluated seven genes known to influence chemotherapeutic response (ERCC1, BRCA1, RRM1, TUBB3, STMN1, TYMS, and TOP2A) and five RTKs (EGFR, ERBB2, PDGFRB, VEGFR1 and VEGFR2) in non-small cell lung cancer (NSCLC) and esophagus cancer (EC) and the data are compared to gastric cancer (GC) data reported previously. We demonstrate significant differences in the expression profiles between different cancer types as well as heterogeneity among patients within the same cancer type. In all three cancer types, five chemoresistant genes (TOP2A, STMN1, TYMS, BRCA1 and RRM1) are coordinately up-regulated in almost all EC, approximately 90% of NSCLC and one third of GC patients. Most EC and nearly half of GC patients have increased expression of the three RTKs critical to angiogenesis (PDGFR, VEGFR1 and VEGFR2), while almost none of the NSCLC patients have elevated expression of angiogenic RTKs. A variable percentage of patients in the three cancer types show upregulation of the EGFR family RTKs, EGFR and/or ERBB2. It is of interest to note that approximately 10% of the NSCLC and GC patients are triple-negative for the chemosensitivity genes, angiogenic and EGFR RTK genes. The results suggest significant gene expression differences between different cancer types as well as heterogeneity within each cancer type and therefore different molecules should be targeted for future drug development and clinical trials.
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Affiliation(s)
- Jianzhong Wu
- Clinical Oncology Research Center, Jiangsu Cancer HospitalNanjing, Jiangsu Province, People’s Republic of China
| | - Shuchun Li
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta UniversityAugusta, GA, USA
| | - Rong Ma
- Clinical Oncology Research Center, Jiangsu Cancer HospitalNanjing, Jiangsu Province, People’s Republic of China
| | - Ashok Sharma
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta UniversityAugusta, GA, USA
| | - Shan Bai
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta UniversityAugusta, GA, USA
| | - Boying Dun
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta UniversityAugusta, GA, USA
| | - Haixia Cao
- Clinical Oncology Research Center, Jiangsu Cancer HospitalNanjing, Jiangsu Province, People’s Republic of China
| | - Changwen Jing
- Clinical Oncology Research Center, Jiangsu Cancer HospitalNanjing, Jiangsu Province, People’s Republic of China
| | - Jinxiong She
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta UniversityAugusta, GA, USA
| | - Jifeng Feng
- Clinical Oncology Research Center, Jiangsu Cancer HospitalNanjing, Jiangsu Province, People’s Republic of China
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17
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Shen GS, Zhao JD, Zhao JH, Ma XF, Du F, Kan J, Ji FX, Ma F, Zheng FC, Wang ZY, Xu BH. Association of HER2 status with prognosis in gastric cancer patients undergoing R0 resection: A large-scale multicenter study in China. World J Gastroenterol 2016; 22:5406-5414. [PMID: 27340357 PMCID: PMC4910661 DOI: 10.3748/wjg.v22.i23.5406] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 05/11/2016] [Accepted: 05/23/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether the positive status of human epidermal growth receptor 2 (HER2) can be regarded as an effective prognostic factor for patients with gastric cancer (GC) undergoing R0 resection.
METHODS: A total of 1562 GC patients treated by R0 resection were recruited. HER2 status was evaluated in surgically resected samples of all the patients using immunohistochemical (IHC) staining. Correlations between HER2 status and clinicopathological characteristics were retrospective analyzed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard model, stratified by age, gender, tumor location and tumor-node-metastasis (TNM) stage, with additional adjustment for potential prognostic factors.
RESULTS: Among 1562 patients, 548 (positive rate = 35.08%, 95%CI: 32.72%-37.45%) were HER2 positive. Positive status of HER2 was significantly correlated with gender (P = 0.004), minority (P < 0.001), tumor location (P = 0.001), pathological grade (P < 0.001), TNM stage (P < 0.001) and adjuvant radiotherapy (74.67% vs 23.53%, P = 0.011). No significant associations were observed between HER2 status and disease free survival (HR = 0.19, 95%CI: 0.96-1.46, P = 0.105) or overall survival (HR = 1.19, 95%CI: 0.96-1.48, P = 0.118) using multivariate analysis, although stratified analyses showed marginally statistically significant associations both in disease free survival and overall survival, especially among patients aged < 60 years or with early TNM stages (I and II). Categorical age, TNM stage, neural invasion, and adjuvant chemotherapy were, as expected, independent prognostic factors for both disease free survival and overall survival.
CONCLUSION: The positive status of HER2 based on IHC staining was not related to the survival in patients with GC among the Chinese population.
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18
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Concordance rate between HER2 immunohistochemistry and in situ hybridization in gastric carcinoma: systematic review and meta-analysis. Int J Biol Markers 2016; 31:e1-10. [PMID: 26349670 DOI: 10.5301/jbm.5000171] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2015] [Indexed: 12/17/2022]
Abstract
PURPOSE The aim of this study was to investigate the diagnostic accuracy of HER2 immunohistochemistry (IHC) in gastric carcinoma (GC) through a systematic review, meta-analysis and diagnostic test accuracy review. METHOD The current study included 12,679 GC cases and 181 subsets in 45 eligible studies. We performed concordance analysis between HER2 IHC and in situ hybridization (ISH) in GC. Diagnostic test accuracy was analyzed and the area under the curve (AUC) on the summary receiver operating characteristic (SROC) curve was calculated. RESULTS HER2 amplification rates were 3.0%, 31.8%, and 93.0% in the IHC score 0/1+, 2+, and 3+ groups, respectively. The concordance rates between IHC and ISH were 0.969 (95% confidence interval [CI] 0.962-0.975), 0.393 (95% CI 0.331-0.458) and 0.915 (95% CI 0.882-0.939) in the HER2 IHC score 0/1+, 2+, and 3+ groups, respectively. For all the HER2 IHC score groups, the positive rates were higher in the silver ISH (SISH) subgroup than in the fluorescence ISH (FISH) and chromogenic ISH (CISH) subgroups. In diagnostic test accuracy review, the pooled sensitivity and specificity were 0.86 (95% CI 0.84-0.87) and 0.91 (95% CI 0.90-0.91). The AUC on SROC curve was 0.958. However, there was no significant difference in the values of AUC between the ISH methods. CONCLUSIONS Our results showed that HER2 IHC was well concordant with ISH in HER2 IHC score 0/1+ or 3+. Although this meta-analysis showed higher diagnostic accuracy of HER2 IHC, more detailed criteria for HER2 IHC score 2+ cases will be required to predict HER2 status.
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19
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Zhang F, Yang X, Li L, Sun L, Wang BO, Yu X. Epidermal growth factor receptor expression and gene copy number analysis in gastric carcinoma samples from Chinese patients. Oncol Lett 2016; 11:173-181. [PMID: 26870185 PMCID: PMC4727090 DOI: 10.3892/ol.2015.3875] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 09/09/2015] [Indexed: 12/26/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) expression and gene copy number have been observed to be associated with a positive clinical response to EGFR inhibitors. The present study aimed to evaluate EGFR expression and gene copy number in samples of gastric carcinoma (GC) from Chinese patients. EGFR expression and gene copy number were detected using immunohistochemistry and fluorescence in situ hybridization, in tissue array slides containing 150 individual samples of GC tissue. The association between EGFR status, clinicopathological features and overall patient survival was analyzed. Out of the 150 cases of GC evaluated, 63 (42.00%) demonstrated weak EGFR expression and 20 (13.33%) demonstrated EGFR overexpression. EGFR expression was observed to be associated with tumor location (P<0.05). Out of 104 cases of GC, which produced a clear FISH signal, 6 (5.77%) exhibited EGFR gene amplification and 5 (4.80%) exhibited balanced polysomy. Patients exhibiting GC, who demonstrated weak EGFR expression, EGFR overexpression or increased EGFR gene copy number, possessed an unfavorable prognosis. Multivariate analysis revealed that EGFR expression, tumor/node/metastasis stage and tumor location were potential independent unfavorable prognostic factors for GC patients. In conclusion, EGFR overexpression, gene amplification and polysomy were observed in GC patients and were associated with an unfavorable prognosis. Evaluation of EGFR status may therefore facilitate the identification of a subset of GC patients sensitive to treatment with EGFR-targeted therapies.
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Affiliation(s)
- Fan Zhang
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
| | - Xingwu Yang
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
| | - Lianhong Li
- Department of Pathology and Forensic Medicine, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Lei Sun
- Department of Pathology and Forensic Medicine, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - B O Wang
- Department of Pathology and Forensic Medicine, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Xiaotang Yu
- Department of Pathology and Forensic Medicine, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
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20
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The HER2 gene and HER2 protein status and chromosome 17 polysomy in gastric cancer cells in own material. Appl Immunohistochem Mol Morphol 2015; 23:113-7. [PMID: 25203430 DOI: 10.1097/pai.0000000000000070] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND The aims of the study were to assess the expression of HER2 protein, the amplification of the HER2 gene, and the occurrence of chromosome 17 polysomy in gastric cancer cells and to analyze the relation between the results of such a determination and the selected clinicopathologic parameters in patients treated for gastric cancer. METHODS Tissue samples of primary tumor from 83 consecutive patients who underwent gastric cancer resection were analyzed by immunohistochemical (IHC) analysis and fluorescence in situ hybridization (FISH). RESULTS A positive result of the IHC test, with a minimum score +, was obtained among 22.8% patients. The FISH test was carried out successfully among 58 patients, including 10.3% cases with a positive result, whereas the presence of chromosome 17 polysomy was confirmed among 13.8% patients. A statistically significant dependence was found between the presence of HER2 overexpression and: the lower stage of tumor infiltration, the higher grade of cancer differentiation, no mucinous component, and the intestinal type according to the Lauren classification. Statistically significant relation was found between chromosome 17 polysomy and the tumor location in the proximal part of the stomach, the performance of the palliative procedure, the presence of distant metastases, and a higher frequency of postoperative complications. CONCLUSIONS There is no complete coincidence in gastric cancer between the occurrence of the HER2 gene amplification and the HER2 receptor expression. The impact of the HER2 gene status and HER2 protein on prognosis in gastric cancer remains unclear. Chromosome 17 polysomy may be an important negative prognostic factor in gastric cancer.
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21
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Large-scale RNA-Seq Transcriptome Analysis of 4043 Cancers and 548 Normal Tissue Controls across 12 TCGA Cancer Types. Sci Rep 2015; 5:13413. [PMID: 26292924 PMCID: PMC4544034 DOI: 10.1038/srep13413] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 07/27/2015] [Indexed: 12/21/2022] Open
Abstract
The Cancer Genome Atlas (TCGA) has accrued RNA-Seq-based transcriptome data for more than 4000 cancer tissue samples across 12 cancer types, translating these data into biological insights remains a major challenge. We analyzed and compared the transcriptomes of 4043 cancer and 548 normal tissue samples from 21 TCGA cancer types, and created a comprehensive catalog of gene expression alterations for each cancer type. By clustering genes into co-regulated gene sets, we identified seven cross-cancer gene signatures altered across a diverse panel of primary human cancer samples. A 14-gene signature extracted from these seven cross-cancer gene signatures precisely differentiated between cancerous and normal samples, the predictive accuracy of leave-one-out cross-validation (LOOCV) were 92.04%, 96.23%, 91.76%, 90.05%, 88.17%, 94.29%, and 99.10% for BLCA, BRCA, COAD, HNSC, LIHC, LUAD, and LUSC, respectively. A lung cancer-specific gene signature, containing SFTPA1 and SFTPA2 genes, accurately distinguished lung cancer from other cancer samples, the predictive accuracy of LOOCV for TCGA and GSE5364 data were 95.68% and 100%, respectively. These gene signatures provide rich insights into the transcriptional programs that trigger tumorigenesis and metastasis, and many genes in the signature gene panels may be of significant value to the diagnosis and treatment of cancer.
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22
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Li SC, Ma R, Wu JZ, Xiao X, Wu W, Li G, Chen B, Sharma A, Bai S, Dun BY, She JX, Tang JH. Delineation of gastric cancer subtypes by co-regulated expression of receptor tyrosine kinases and chemosensitivity genes. Am J Transl Res 2015; 7:1429-1439. [PMID: 26396673 PMCID: PMC4568798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 06/22/2015] [Indexed: 06/05/2023]
Abstract
Chemotherapy plays a key role in improving disease-free survival and overall survival of gastric cancer (GC); however, response rates are variable and a non-negligible proportion of patients undergo toxic and costly chemotherapeutic regimens without a survival benefit. Several studies have shown the existence of GC subtypes which may predict survival and respond differently to chemotherapy. It is also known that the expression level of chemotherapy-related and target therapy-related genes correlates with response to specific antitumor drugs. Nevertheless, these genes have not been considered jointly to define GC subtypes. In this study, we evaluated seven genes known to influence chemotherapeutic response (ERCC1, BRCA1, RRM1, TUBB3, STMN1, TYMS and TOP2A) and five receptor tyrosine kinases (RTKs) (EGFR, ERBB2, PDGFRB, VEGFR1 and VEGFR2). We demonstrate significant heterogeneity of gene expression among GC patients and identified four GC subtypes using the expression profiles of eight genes in two co-regulation groups: chemosensitivity (BRCA1, STMN1, TYMS and TOP2A) and RTKs (EGFR, PDGFRB, VEGFR1 and VEGFR2). The results are of immediate translational value regarding GC diagnostics and therapeutics, as many of these genes are curently widely used in relevant clinical testing.
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Affiliation(s)
- Shu-Chun Li
- Clinical Oncology Research Center, Jiangsu Cancer Hospital Nanjing, Jiangsu Province, People's Republic of China ; Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University Augusta, GA ; Sino-American Institute of Translational Medicine, Nanjing Tech University Nanjing, Jiangsu Province, People's Republic of China
| | - Rong Ma
- Clinical Oncology Research Center, Jiangsu Cancer Hospital Nanjing, Jiangsu Province, People's Republic of China
| | - Jian-Zhong Wu
- Clinical Oncology Research Center, Jiangsu Cancer Hospital Nanjing, Jiangsu Province, People's Republic of China
| | - Xia Xiao
- Sino-American Institute of Translational Medicine, Nanjing Tech University Nanjing, Jiangsu Province, People's Republic of China
| | - Wei Wu
- Zhenjiang Jintai Life Technologies Zhenjiang, Jiangsu Province, People's Republic of China
| | - Gang Li
- Clinical Oncology Research Center, Jiangsu Cancer Hospital Nanjing, Jiangsu Province, People's Republic of China
| | - Bo Chen
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University Augusta, GA ; Sino-American Institute of Translational Medicine, Nanjing Tech University Nanjing, Jiangsu Province, People's Republic of China
| | - Ashok Sharma
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University Augusta, GA
| | - Shan Bai
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University Augusta, GA
| | - Bo-Ying Dun
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University Augusta, GA
| | - Jin-Xiong She
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University Augusta, GA
| | - Jin-Hai Tang
- Clinical Oncology Research Center, Jiangsu Cancer Hospital Nanjing, Jiangsu Province, People's Republic of China
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Nagatsuma AK, Aizawa M, Kuwata T, Doi T, Ohtsu A, Fujii H, Ochiai A. Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma. Gastric Cancer 2015; 18:227-38. [PMID: 24626858 DOI: 10.1007/s10120-014-0360-4] [Citation(s) in RCA: 135] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 02/08/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Some tyrosine kinase receptors (RTKs) play critical roles in gastric cancer progression. Not only trastuzumab, but also several other agents targeting RTKs are being investigated for gastric cancer therapy. However, the simultaneous expression of multiple RTKs, which may interfere with the effectiveness of therapeutic agents, has not been evaluated in a large cohort with gastric adenocarcinoma (GAC). METHODS We performed a tissue microarray analysis in 950 patients with GAC who underwent a gastrectomy without preoperative chemotherapy. The protein expressions of HER2, EGFR, MET and FGFR2 were evaluated using immunohistochemistry, and the gene amplifications of HER2, EGFR and MET were examined using dual-color in situ hybridization. RESULTS The frequency of overexpression was 11.8% for HER2, 23.5% for EGFR, 24.9 % for MET and 31.1% for FGFR2. Whereas strong staining for each of the RTKs was heterogeneous, tumors with homogeneously strong staining areas often exhibited gene amplification. Strong EGFR expression was significantly associated with a poor outcome, but no prognostic correlations were observed in other RTKs. The overexpression of single and multiple RTKs was observed in 40.4 and 22.7% of the cases, respectively. HER2, EGFR, MET and FGFR2 predominance was observed in 10.1, 13.9, 16.1 and 22.9% of the GACs, respectively. CONCLUSIONS Approximately two-thirds of patients with GAC exhibited the expression of at least one RTK and would be candidates for targeted therapies. Moreover, one-third of at least one RTK overexspressing cases showed multiple RTKs expression. Our results may be useful for selecting the most suitable patients for each targeted therapy.
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Affiliation(s)
- Akiko Kawano Nagatsuma
- Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-city, Chiba, 277-8577, Japan
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Wang T, Amemiya Y, Henry P, Seth A, Hanna W, Hsieh ET. Multiplex Ligation-dependent Probe Amplification Can Clarify HER2 Status in Gastric Cancers with "Polysomy 17". J Cancer 2015; 6:403-8. [PMID: 25874002 PMCID: PMC4392047 DOI: 10.7150/jca.11424] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Accepted: 01/12/2015] [Indexed: 01/29/2023] Open
Abstract
Therapy with trastuzumab confers a survival benefit in HER2 positive advanced gastric and gastroesophageal adenocarcinoma. HER2 status is evaluated by immunohistochemistry (IHC) and in situ hybridization (ISH). An ISH ratio of HER2 to centromere 17 (CEP17) ≥2.0 is considered amplified. This assumes that CEP17 reflects chromosomal copy number. Cases where CEP17 exceeds 3 are classified as polysomic, but it's unknown if they represent true polysomy or centromeric amplification. This has implications on the validity of current ISH criteria. Multiplex ligation-dependent probe amplification (MLPA) allows simultaneous quantification of multiple loci and can distinguish between true polysomy and centromeric amplification. We selected 13 gastric cancers with CEP17 counts ≥3.0 (polyCEP17), and 8 non-polyCEP17 gastric cancer controls. Silver ISH for HER2 and CEP17 were performed and scored by manufacturer guidelines. We also performed an MLPA HER2 assay that evaluates 22 genes on chromosome 17. MLPA identified HER2 amplification in 7 polyCEP17 cases compared to 2 identified by ISH. Overall, 9 of 13 polyCEP17 cases had amplification of the peri-centromeric gene WSB1, compared to 1 of 8 non-polyCEP17 controls (p=0.02). This could account for ISH CEP17 counts ≥3.0. MLPA did not show any cases of complete chromosome 17 duplication and peri-centromeric amplification can explain most cases of ISH polyCEP17. Current ISH criteria may under-diagnose HER2 amplification in polyCEP17 cases due to flawed assumptions about polysomy. MLPA can detect HER2 amplification missed by IHC and ISH, and thus may be an effective ancillary technique in evaluating HER2 status.
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Affiliation(s)
- Tao Wang
- 1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Yutaka Amemiya
- 2. Genomics Core Facilities, Sunnybrook Research Institute, Toronto, Canada
| | - Pauline Henry
- 1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; ; 3. Department of Pathology, Toronto East General Hospital, Toronto, Canada
| | - Arun Seth
- 1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; ; 2. Genomics Core Facilities, Sunnybrook Research Institute, Toronto, Canada; ; 4. Department of Pathology, Sunnybrook Health Sciences Centre, Toronto, Canada
| | - Wedad Hanna
- 1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; ; 4. Department of Pathology, Sunnybrook Health Sciences Centre, Toronto, Canada
| | - Eugene T Hsieh
- 1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; ; 4. Department of Pathology, Sunnybrook Health Sciences Centre, Toronto, Canada
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25
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Sedef AM, Köse F, Sümbül AT, Doğan Ö, Beşen AA, Tatlı AM, Mertsoylu H, Sezer A, Muallaoğlu S, Özyılkan Ö, Abalı H. Patients with distal intestinal gastric cancer have superior outcome with addition of taxanes to combination chemotherapy, while proximal intestinal and diffuse gastric cancers do not: does biology and location predict chemotherapy benefit? Med Oncol 2015; 32:476. [DOI: 10.1007/s12032-014-0476-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 12/19/2014] [Indexed: 01/26/2023]
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26
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Gowryshankar A, Nagaraja V, Eslick GD. HER2 status in Barrett's esophagus & esophageal cancer: a meta analysis. J Gastrointest Oncol 2014; 5:25-35. [PMID: 24490040 DOI: 10.3978/j.issn.2078-6891.2013.039] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 06/07/2013] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The oncogenic potential of the Human Epidermal Growth Factor Receptor 2 (HER2) is well known in the context of breast cancer however; its relationship with the development of Barrett's Esophagus (BE) and Esophageal Cancer (EC) is unclear. The aim of this meta-analysis was to determine the overall prevalence and survival of HER2+ in BE & EC. PATIENTS AND METHODS Several databases were searched including article reference lists. Inclusion criteria required that studies measured HER2 positivity in subjects with BE or EC. RESULTS 33 studies were included in the meta-analysis (10 BE & 23 EC studies). The prevalence of HER2+ was found to be 24% (95% CI: 15-36%) in BE and 26% (95% CI: 19-34%) in EC. Squamous cell carcinoma (SCC) had a higher ER of 32% (95% CI: 20-48%) in comparison with adenocarcinoma (ADC) with an ER of 21% (95% CI: 14-32%). Sub group analyses showed a high geographical variance, Asia was found to be the highest prevalent area with an ER 42% (95% CI: 22-64%). The difference in survival rate between groups HER2- & HER2+ was found to be 7 months. CONCLUSIONS Our results highlight a high prevalence of HER2+ in subjects with adenocarcinoma. HER2+ appears to decrease the survival time of EC patients.
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Affiliation(s)
- Ashwini Gowryshankar
- The Whiteley-Martin Research Centre, The Discipline of Surgery, The University of Sydney, Sydney Medical School, Nepean, Penrith, New South Wales, Australia
| | - Vinayak Nagaraja
- The Whiteley-Martin Research Centre, The Discipline of Surgery, The University of Sydney, Sydney Medical School, Nepean, Penrith, New South Wales, Australia
| | - Guy D Eslick
- The Whiteley-Martin Research Centre, The Discipline of Surgery, The University of Sydney, Sydney Medical School, Nepean, Penrith, New South Wales, Australia
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27
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Labots M, Buffart TE, Haan JC, van Grieken NCT, Tijssen M, van de Velde CJH, Grabsch HI, Ylstra B, Carvalho B, Fijneman RJA, Verheul HMW, Meijer GA. High-level copy number gains of established and potential drug target genes in gastric cancer as a lead for treatment development and selection. Cell Oncol (Dordr) 2013; 37:41-52. [PMID: 24379144 DOI: 10.1007/s13402-013-0162-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2013] [Indexed: 01/20/2023] Open
Abstract
PURPOSE The overall survival rate of patients with advanced gastric cancer is poor. Therefore, there is an urgent need for new treatment options for these patients. The identification of drug target genes located on DNA regions exhibiting high-level copy number gains (CNG) may be an effective approach, as has e.g. previously been shown for HER2. The aim of the present study was to identify putative drug targets in patients with gastric cancer by applying this strategy. METHODS Genome-wide array comparative genomic hybridization (array CGH) data available from 183 primary gastric cancer samples were analyzed through Ingenuity Pathway Analysis (IPA) to assess whether any established or potential anticancer drug target genes showed high-level CNG, including focal amplifications. RESULTS A total of 147 high-level gained regions were identified in the gastric cancer samples, harboring 167 genes that had previously been annotated as drug target genes. Thirty (18 %) of these genes showed high-level gains in at least 2 % of the tumors. The identified drug target genes included those for drugs known to be active in advanced (gastric) cancer, targets for targeted therapies in clinical development, as well as targets for drugs currently used for other indications but of potential interest for anticancer treatment. In addition, 12 potential drug target genes were identified, including genes involved in growth factor signaling and cell cycle regulation. CONCLUSION The majority of gastric cancers carried one or more high-level CNGs or focal amplifications encompassing putative drug target genes. A number of the associated drugs are currently not being considered for treatment of gastric cancer. Based on these results we hypothesize that DNA copy number profiling may be a useful tool to identify new drug targets and to guide individualized treatment strategies in patients with gastric cancer.
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Affiliation(s)
- Mariette Labots
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
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28
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Davison JM, Pai RK. HER2 Assessment in Upper Gastrointestinal Tract Adenocarcinoma: A Practical, Algorithmic Approach. Surg Pathol Clin 2013; 6:391-403. [PMID: 26839094 DOI: 10.1016/j.path.2013.05.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Gastric and gastroesophageal junction adenocarcinomas constitute a major health problem. For localized disease, adjuvant treatment is multidisciplinary and usually includes a combination of surgery, radiation and chemotherapy. Recently, trastuzumab (Herceptin) has been approved for the treatment of metastatic upper gastrointestinal (GI) tract (gastric, esophageal, and gastroesophageal) adenocarcinomas. The purpose of this review is to provide pathologists with practical guidance in HER2 assessment of upper GI tract adenocarcinomas in order to accurately identify patients eligible for trastuzumab therapy.
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Affiliation(s)
- Jon M Davison
- Department of Pathology, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA
| | - Reetesh K Pai
- Department of Pathology, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
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29
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Abediankenari S, Jeivad F. Epidermal Growth Factor Receptor Gene Polymorphisms and Gastric Cancer in Iran. Asian Pac J Cancer Prev 2013; 14:3187-90. [DOI: 10.7314/apjcp.2013.14.5.3187] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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30
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Zhang EY, Cristofanilli M, Robertson F, Reuben JM, Mu Z, Beavis RC, Im H, Snyder M, Hofree M, Ideker T, Omenn GS, Fanayan S, Jeong SK, Paik YK, Zhang AF, Wu SL, Hancock WS. Genome wide proteomics of ERBB2 and EGFR and other oncogenic pathways in inflammatory breast cancer. J Proteome Res 2013; 12:2805-17. [PMID: 23647160 DOI: 10.1021/pr4001527] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
In this study we selected three breast cancer cell lines (SKBR3, SUM149 and SUM190) with different oncogene expression levels involved in ERBB2 and EGFR signaling pathways as a model system for the evaluation of selective integration of subsets of transcriptomic and proteomic data. We assessed the oncogene status with reads per kilobase per million mapped reads (RPKM) values for ERBB2 (14.4, 400, and 300 for SUM149, SUM190, and SKBR3, respectively) and for EGFR (60.1, not detected, and 1.4 for the same 3 cell lines). We then used RNA-Seq data to identify those oncogenes with significant transcript levels in these cell lines (total 31) and interrogated the corresponding proteomics data sets for proteins with significant interaction values with these oncogenes. The number of observed interactors for each oncogene showed a significant range, e.g., 4.2% (JAK1) to 27.3% (MYC). The percentage is measured as a fraction of the total protein interactions in a given data set vs total interactors for that oncogene in STRING (Search Tool for the Retrieval of Interacting Genes/Proteins, version 9.0) and I2D (Interologous Interaction Database, version 1.95). This approach allowed us to focus on 4 main oncogenes, ERBB2, EGFR, MYC, and GRB2, for pathway analysis. We used bioinformatics sites GeneGo, PathwayCommons and NCI receptor signaling networks to identify pathways that contained the four main oncogenes and had good coverage in the transcriptomic and proteomic data sets as well as a significant number of oncogene interactors. The four pathways identified were ERBB signaling, EGFR1 signaling, integrin outside-in signaling, and validated targets of C-MYC transcriptional activation. The greater dynamic range of the RNA-Seq values allowed the use of transcript ratios to correlate observed protein values with the relative levels of the ERBB2 and EGFR transcripts in each of the four pathways. This provided us with potential proteomic signatures for the SUM149 and 190 cell lines, growth factor receptor-bound protein 7 (GRB7), Crk-like protein (CRKL) and Catenin delta-1 (CTNND1) for ERBB signaling; caveolin 1 (CAV1), plectin (PLEC) for EGFR signaling; filamin A (FLNA) and actinin alpha1 (ACTN1) (associated with high levels of EGFR transcript) for integrin signalings; branched chain amino-acid transaminase 1 (BCAT1), carbamoyl-phosphate synthetase (CAD), nucleolin (NCL) (high levels of EGFR transcript); transferrin receptor (TFRC), metadherin (MTDH) (high levels of ERBB2 transcript) for MYC signaling; S100-A2 protein (S100A2), caveolin 1 (CAV1), Serpin B5 (SERPINB5), stratifin (SFN), PYD and CARD domain containing (PYCARD), and EPH receptor A2 (EPHA2) for PI3K signaling, p53 subpathway. Future studies of inflammatory breast cancer (IBC), from which the cell lines were derived, will be used to explore the significance of these observations.
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Affiliation(s)
- Emma Yue Zhang
- Barnett Institute and Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States
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31
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Zhang J, Yang YC, Zhu JS, Zhou Z, Chen WX. Clinicopathologic characteristics of YES-associated protein 1 overexpression and its relationship to tumor biomarkers in gastric cancer. Int J Immunopathol Pharmacol 2013; 25:977-87. [PMID: 23298488 DOI: 10.1177/039463201202500415] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Yes-associated protein 1 (YAP1), a downstream effector of the Hippo pathway, plays an important role in the development and progression of multiple malignancies, including human gastric cancer (GC). However, the clinical significance of YAP1 expression in GC needs to be comprehensively explored. Based on the pivotal role of YAP1 in the hippo pathway, we explored the clinicopathologic characteristics of YAP1 overexpression and its relationship to some tumor biomarkers in GC. Ninety cases of GC, chronic gastritis (CG) and CG with dysplasia samples were collected, and clinical data of all patients with GC were analyzed. The expression of YAP1 was assessed using immunohistochemical assay in biopsy samples. As a result, almost all the GC samples, but few CG and dysplasia samples showed YAP1 positive staining mainly in the nucleus. The expression of YAP1 was found in GC tissues with higher strong reactivity rate, compared with dysplasia and CG tissues (79.2 percent vs 47.1 percent and 15 percent, each P<0.001), and its expression level was elevated with the ascending order of GC malignancy. However, no significant correlation was found between the expression of YAP1 and epidermal growth factor receptor (EGFR) with gender, age, gross stage, degree of differentiation, tumor size, TNM staging, perineural infiltration, vascular invasion, lymphatic vessel invasion and lymph node metastases in patients with GC (each P>0.05). Furthermore, Spearman rank correlation analysis also showed no correlation of YAP1 with EGFR, Ki-67, CD34 and topoisomerase II (TOP II). Taken together, YAP1 is highly expressed in GC tissues compared with the dysplasia and CG tissues and its expression level is elevated with the ascending order of tumor malignancy; but, YAP1 expression does not correlate with the clinicopathologic characteristics and the expression of EGFR, Ki-67, CD34 and TOP II in GC.
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Affiliation(s)
- J Zhang
- Department of Gastroenterology, Shanghai Jiao Tong University, Shanghai, China
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32
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Cruz-Reyes C, Gamboa-Dominguez A. HER2 amplification in gastric cancer is a rare event restricted to the intestinal phenotype. Int J Surg Pathol 2013; 21:240-6. [PMID: 23564704 DOI: 10.1177/1066896913481055] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The objectives of this study were to identify HER2 prevalence in gastric cancer and correlate it with location, phenotype, and follow-up. Consecutive gastric cancer patients with tissue blocks, gross data, and follow-up data, were submitted to immunohistochemistry (IHC) with HercepTest. Chromogenic and fluorescence in situ hybridization was performed in IHC-positive tumors. A total of 269 patients were included with a median age of 61 years. In 172 gastrectomized patients, histotypes were diffuse (72, 41.8%), intestinal (63, 36.6%), and mixed (37, 21.5%). HER2 IHC expression was 0 in 167, 2+ in 2, and 3+ in 3 tumors. Only endoscopic biopsies were available in 97 patients and HER2 IHC expression was 0 in 88, 1+ in 3, 2+ in 4, and 3+ in 2 patients. In all, 10/269 (3.7%) had HER2 amplification. Amplified tumors were intestinal adenocarcinomas located throughout the different regions of the stomach. Heterogeneity was documented in 4 widely sampled tumors. HER2 amplification was restricted to the intestinal phenotype. It is a rare event and its screening should be driven by gastric cancer histotype.
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Affiliation(s)
- Carolina Cruz-Reyes
- Departamento de Patología, National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico City, Mexico
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33
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El Fatemi H, Hammas N, Idrissi K, Mellas N, Bennani A, Amarti A, Cayre A, Penault-llorca F, Mesbahi O. [The search for protein overexpression and HER2 gene amplification in gastric cancer by immunohistochemistry and in situ hybridization: experience of the CHU Hassan II of Fez]. Pan Afr Med J 2012; 13:79. [PMID: 23397021 PMCID: PMC3567406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Accepted: 11/26/2012] [Indexed: 11/06/2022] Open
Abstract
La surexpression de l'Her2 a été détectée dans plusieurs cancers et a été particulièrement étudiée dans le cancer du sein. Elle est décrite dans 10 à 30% des adénocarcinomes gastriques. Un statut HER2 positif est un facteur de mauvais pronostic et un facteur prédictif de la réponse à l'herceptine (trastuzumab). Cet article présente les résultats d'une étude préliminaire portant sur 31 cas de tumeurs gastriques, et dont le but est d’évaluer la surexpression de l’ HER2 dans les adénocarcinomes gastriques avancés tout en comparant nos résultats avec ceux de la littérature. Le taux des cas surexprimant l'Her2 dans notre étude (35.5%) est proche de celui noté par Aoyaji et al (34%), mais il est supérieur à celui noté dans la plupart des séries de la littérature notamment une vaste étude baptisée TOGA. La poursuite de cette étude par un échantillon plus large est nécessaire afin de mieux comprendre les particularités de ce cancer dans notre contexte.
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Affiliation(s)
- Hinde El Fatemi
- Laboratoire d'anatomie et cytologie pathologique, CHU HASSAN II, FES, Maroc,Corresponding author: El Fatemi Hinde, Laboratoire d'anatomie et cytologie pathologique, CHU HASSAN II, FES, Maroc
| | - Nawal Hammas
- Laboratoire d'anatomie et cytologie pathologique, CHU HASSAN II, FES, Maroc
| | - Karima Idrissi
- Laboratoire d'anatomie et cytologie pathologique, CHU HASSAN II, FES, Maroc
| | - Nawfel Mellas
- Laboratoire d'anatomie et cytologie pathologique, Jean Perrin, Clermont Ferrand, France
| | - Amal Bennani
- Laboratoire d'anatomie et cytologie pathologique, CHU HASSAN II, FES, Maroc
| | - Afaf Amarti
- Laboratoire d'anatomie et cytologie pathologique, CHU HASSAN II, FES, Maroc
| | - Anne Cayre
- Service d'oncologie médicale, CHU HASSAN II, FES, Maroc
| | | | - Omar Mesbahi
- Laboratoire d'anatomie et cytologie pathologique, Jean Perrin, Clermont Ferrand, France
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34
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Bria E, De Manzoni G, Beghelli S, Tomezzoli A, Barbi S, Di Gregorio C, Scardoni M, Amato E, Frizziero M, Sperduti I, Corbo V, Brunelli M, Bersani S, Tortora G, Scarpa A. A clinical-biological risk stratification model for resected gastric cancer: prognostic impact of Her2, Fhit, and APC expression status. Ann Oncol 2012; 24:693-701. [PMID: 23131390 DOI: 10.1093/annonc/mds506] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND To obtain a prognostic stratification model for resected gastric cancer patients. PATIENTS AND METHODS Clinicopathological and molecular data (expression of Cdx2, Apc, β-catenin, E-cadherin, Fhit, p53, and human epidermal growth factor receptor-2 (Her2); HER2 and TOPO2A gene copy number; PIK3CA mutations; microsatellite instability) were correlated to cancer-specific/overall survival (CSS/OS) using a Cox model. Individual patient probability (IPP) was estimated by logistic equation. A continuous score to identify risk-classes was derived according to the model ratios. RESULTS Two-hundred eight patients were studied (median follow-up 20 months). At multivariate analysis, sex, stage, margins, location, nodes, Apc, and Fhit were independent predictors for CSS; the same factors (and age and Her2, except Fhit) predicted OS. Multivariate model predicted IPP with high prognostic accuracy (0.90 for CSS; 0.91 for OS). A two-class model significantly separated low- and high-risk patients for CSS (23.4% and 85.6%, P < 0.0001) and OS (21.4% and 82.0%, P < 0.0001). A three-class model differentiated low-, intermediate-, and high-risk patients for CSS (6.3%, 35.3%, and 88.0%, P < 0.0001) and OS (6.1%, 34.6%, and 86.5%, P < 0.0001). CONCLUSIONS A risk classification system comprising the immunohistochemical expression of three proteins (Apc, Fhit, and Her2) and five clinicopathological parameters (stage, resected nodes, margins, location, and sex) accurately separates the resected gastric cancer patients into three classes of risk.
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Affiliation(s)
- E Bria
- ARC-NET the Miriam Cherubini Loro, Applied Research on Cancer Center
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Zhang F, Tang JM, Wang L, Shen JY, Zheng L, Wu PP, Zhang M, Yan ZW. Phosphorylation of epidermal growth factor receptor and chromosome 7 polysomy in gastric adenocarcinoma. J Dig Dis 2012; 13:350-9. [PMID: 22713084 DOI: 10.1111/j.1751-2980.2012.00597.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate the phosphorylation of epidermal growth factor receptor (EGFR) and its potentially associated chromosomal aberrations in gastric adenocarcinoma. METHODS Phosphorylated EGFR (pEGFR) was detected by immunohistochemistry on 145 specimens including 60 tumoral, 60 non-tumoral, 12 tumor-adjacent intramucosal dysplasia from patients with gastric adenocarcinoma and 13 mucosae from cancer-free patients. EGFR gene amplification and chromosome 7 (Chr-7) polysomy were detected by fluorescence in situ hybridization. RESULTS Positivity of pEGFR was found in 50 tumoral (83.3%) and 42 non-tumoral specimens (70.0%). There was an association between tumoral and non-tumoral zones on immunostains of pEGFR (r = 0.353, P = 0.006). Nuclear pEGFR usually presented in mucosae with Helicobacter pylori infection, stromal reaction or vascular invasion. Cytoplasmic pEGFR was correlated with local cancer extension (r = 0.337, P = 0.014) and inversely related with gastrokine 2, which had been previously detected in the same specimens. Eleven intramucosal dysplastic specimens were also positive for pEGFR while 13 mucosae from cancer-free patients were all negative. No EGFR gene amplification was observed. However, seven tumor specimens showed Chr-7 polysomy (11.7%) in which 5 were strongly positive for pEGFR. CONCLUSIONS EGFR phosphorylation may be one of the mechanisms that promote tumor initiation and expansion in gastric adenocarcinoma. Detection of pEGFR with analysis of its nuclear or cytoplasmic patterns could be clinicopathologically valuable. Chr-7 polysomy may partially contribute to EGFR activation in gastric adenocarcinoma, although its role does not predominate.
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Affiliation(s)
- Fan Zhang
- Department of Pathology, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
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Khattak MA, Martin HL, Karapetis CS. Targeted therapy for esophagogastric cancers: a review. Onco Targets Ther 2012; 5:91-102. [PMID: 22719211 PMCID: PMC3377432 DOI: 10.2147/ott.s25117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The incidence of esophagogastric cancers is increasing rapidly in the Western population. Despite better understanding of the biology and intense research in the treatment of these cancers, the long-term survival remains poor both in the locally advanced and metastatic settings. The addition of combined modality strategies has resulted in modest improvement in 5-year survival rates. A number of biologic agents targeting epidermal-derived growth factor receptor, vascular endothelial derived growth factor and its receptor, and mammalian target of rapamycin (mTOR) are being currently evaluated in Phase II and III clinical trials. Some of these, like trastuzumab, cetuximab, and bevacizumab, have shown promising results. This review provides a brief overview of the recent developments in biologic agents for the treatment of esophagogastric cancers.
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Affiliation(s)
| | | | - Christos S Karapetis
- Flinders Medical Centre, Adelaide, South Australia
- Flinders University, Adelaide, SA, Australia
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37
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Abu Hejleh T, Deyoung BR, Engelman E, Deutsch JM, Zimmerman B, Halfdanarson TR, Berg DJ, Parekh KR, Lynch WR, Iannettoni MD, Bhatia S, Clamon G. Relationship between HER-2 overexpression and brain metastasis in esophageal cancer patients. World J Gastrointest Oncol 2012; 4:103-8. [PMID: 22645633 PMCID: PMC3360103 DOI: 10.4251/wjgo.v4.i5.103] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2011] [Revised: 01/19/2012] [Accepted: 03/10/2012] [Indexed: 02/05/2023] Open
Abstract
AIM: To study if HER-2 overexpression by locally advanced esophageal cancers increase the chance of brain metastasis following esophagectomy.
METHODS: We retrospectively reviewed the medical records of esophageal cancer patients who underwent esophagectomy at University of Iowa Hospitals and Clinics between 2000 and 2010. Data analyzed consisted of demographic and clinical variables. The brain metastasis tissue was assayed for HER-2 overexpression utilizing the FDA approved DAKO Hercept Test®.
RESULTS: One hundred and forty two patients were reviewed. Median age was 64 years (36-86 years). Eighty eight patients (62%) received neoadjuvant chemoradiotherapy. Pathological complete and partial responses were achieved in 17 (19%) and 71 (81%) patients. Cancer relapsed in 43/142 (30%) patients. The brain was the first site of relapse in 9/43 patients (21%, 95% CI: 10%-36%). HER-2 immunohistochemistry testing of the brain metastasis tissue showed that 5/9 (56%) cases overexpressed HER-2 (3+ staining).
CONCLUSION: HER-2 overexpression might be associated with increased risk of brain metastasis in esophageal cancer patients following esophagectomy. Further studies will be required to validate this observation.
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Affiliation(s)
- Taher Abu Hejleh
- Taher Abu Hejleh, Eric Engelman, Jeremy M Deutsch, Thorvardur R Halfdanarson, Daniel J Berg, Gerald Clamon, Division of Hematology, Oncology and Marrow Transplantation, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, C32 GH, Iowa City, IA 52242-1081, United States
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38
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Kneissl J, Keller S, Lorber T, Heindl S, Keller G, Drexler I, Hapfelmeier A, Höfler H, Luber B. Association of amphiregulin with the cetuximab sensitivity of gastric cancer cell lines. Int J Oncol 2012; 41:733-44. [PMID: 22614881 DOI: 10.3892/ijo.2012.1479] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2011] [Accepted: 03/02/2012] [Indexed: 01/22/2023] Open
Abstract
The therapeutic activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab in gastric cancer is currently being investigated in clinical studies. Reliable biomarkers for the identification of patients who are likely to benefit from this treatment are not available. In this study, we assessed the activity of cetuximab in five gastric cancer cell lines (AGS, AZ521, Hs746T, LMSU and MKN1). The viability of two of these cell lines, AZ521 and MKN1, was significantly reduced by cetuximab treatment. High expression and secretion levels of the EGFR-binding ligand, amphiregulin (AREG), were associated with cetuximab responsiveness. MET activation and mutations in Kirsten-Ras gene (KRAS) were associated with cetuximab resistance. By introducing a hierarchy between these markers, we established a model that facilitated the correct classification of all five gastric cancer cell lines as cetuximab responsive or non-responsive. The highest priority was allocated to activating KRAS mutations, followed by MET activation and finally by the levels of secreted AREG. In order to validate these results, we used three additional human gastric cancer cell lines (KATOIII, MKN28 and MKN45). In conclusion, we propose that our model allows the response of gastric cancer cell lines to cetuximab treatment to be predicted.
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Affiliation(s)
- Julia Kneissl
- Institute of Pathology, Technische Universität München, Klinikum rechts der Isar, Munich, Germany
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39
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García-García E, Gómez-Martín C, Angulo B, Conde E, Suárez-Gauthier A, Adrados M, Perna C, Rodríguez-Peralto JL, Hidalgo M, López-Ríos F. Hybridization for human epidermal growth factor receptor 2 testing in gastric carcinoma: a comparison of fluorescence in-situ hybridization with a novel fully automated dual-colour silver in-situ hybridization method. Histopathology 2011; 59:8-17. [PMID: 21771023 PMCID: PMC3166662 DOI: 10.1111/j.1365-2559.2011.03894.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Aims: Amplification of the human epidermal growth factor receptor 2 (HER2) gene has been reported in gastric carcinoma (GC). Accordingly, trastuzumab plus chemotherapy has recently become the new standard treatment for HER2-positive advanced GCs. The aim was to compare the alleged gold standard for hybridization [fluorescence in-situ hybridization (FISH)] with a novel, fully automated brightfield dual-colour silver-enhanced in-situ hybridization (SISH) method. Methods and results: The studies series was comprised of 166 GC samples. Additionally, tumours with discordant results obtained by FISH and SISH were analysed by real-time quantitative polymerase chain reaction (PCR) with the LightMix kit HER-2/neu. Of the samples, 17.5% and 21% were amplified by FISH and SISH, respectively. Heterogeneity was identified in up to 52% of cases. In 96.4% of cases, FISH showed the same results as SISH. All six discordant cases were positive by SISH and negative by FISH. On review of the FISH slides, all contradictory cases were polysomic and were confirmed to be negative for amplification by real-time PCR. Interestingly, all ratios in this latter group were between 2.06 and 2.50, so setting the cut-off for amplification at ≥3 resulted in perfect concordance. Conclusions: Dual-colour SISH represents a novel method for the determination of HER2 status in GC.
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Affiliation(s)
- Elena García-García
- Laboratorio de Dianas Terapeuticas, Centro Integral Oncologico Clara Campal, Hospital Universitario Madrid Sanchinarro, C ⁄ On˜a, 10. 28050 Madrid, Spain
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40
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Huang SF, Cheng SD, Chien HT, Liao CT, Chen IH, Wang HM, Chuang WY, Wang CY, Hsieh LL. Relationship between epidermal growth factor receptor gene copy number and protein expression in oral cavity squamous cell carcinoma. Oral Oncol 2011; 48:67-72. [PMID: 21831696 DOI: 10.1016/j.oraloncology.2011.06.511] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Revised: 06/21/2011] [Accepted: 06/26/2011] [Indexed: 12/24/2022]
Abstract
This study was designed to explore the relationship between epidermal growth factor receptor (EGFR) copy number and EGFR protein expression in oral cavity squamous cell carcinoma (OSCCs) in Taiwan. A total of 160 oral cavity squamous cell carcinomas were examined for EGFR protein overexpression using immunohistochemistry and for copy number using a fluorescence in situ hybridization (FISH) assay. Overexpression and increased gene copy numbers of EGFR were found in 75 (46.88%) and 50 (31.25%) cases, respectively. The concordance rate for EGFR gene amplification and protein overexpression was 100%. EGFR overexpression was associated with a poor prognosis both in terms of disease-free survival (DFS) and overall survival (OS). On the other hand, the association between an increase in EGFR gene copies and DFS or OS was insignificant. This was despite the observed significant associations between gene copy number and tumor stage, depth of tumor invasion, lymph node metastasis, bone invasion and perineural invasion. EGFR protein overexpression is closely related to EGFR copy number. Standard methodological and interpretation criteria need to be established that allows EGFR copy number combined with EGFR protein expression to be determined in a manner that allows individualized EGFR targeted therapy in OSCC patients.
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Affiliation(s)
- Shiang-Fu Huang
- Department of Otolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
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Balassiano K, Lima S, Jenab M, Overvad K, Tjonneland A, Boutron-Ruault MC, Clavel-Chapelon F, Canzian F, Kaaks R, Boeing H, Meidtner K, Trichopoulou A, Laglou P, Vineis P, Panico S, Palli D, Grioni S, Tumino R, Lund E, Bueno-de-Mesquita HB, Numans ME, Peeters PHM, Ramon Quirós J, Sánchez MJ, Navarro C, Ardanaz E, Dorronsoro M, Hallmans G, Stenling R, Ehrnström R, Regner S, Allen NE, Travis RC, Khaw KT, Offerhaus GJA, Sala N, Riboli E, Hainaut P, Scoazec JY, Sylla BS, Gonzalez CA, Herceg Z. Aberrant DNA methylation of cancer-associated genes in gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Cancer Lett 2011; 311:85-95. [PMID: 21831520 DOI: 10.1016/j.canlet.2011.06.038] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Revised: 06/27/2011] [Accepted: 06/29/2011] [Indexed: 12/20/2022]
Abstract
Epigenetic events have emerged as key mechanisms in the regulation of critical biological processes and in the development of a wide variety of human malignancies, including gastric cancer (GC), however precise gene targets of aberrant DNA methylation in GC remain largely unknown. Here, we have combined pyrosequencing-based quantitative analysis of DNA methylation in 98 GC cases and 64 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and in cancer tissue and non-tumorigenic adjacent tissue of an independent series of GC samples. A panel of 10 cancer-associated genes (CHRNA3, DOK1, MGMT, RASSF1A, p14ARF, CDH1, MLH1, ALDH2, GNMT and MTHFR) and LINE-1 repetitive elements were included in the analysis and their association with clinicopathological characteristics (sex, age at diagnosis, anatomical sub-site, histological sub-type) was examined. Three out of the 10 genes analyzed exhibited a marked hypermethylation, whereas two genes (ALDH2 and MTHFR) showed significant hypomethylation, in gastric tumors. Among differentially methylated genes, we identified new genes (CHRNA3 and DOK1) as targets of aberrant hypermethylation in GC, suggesting that epigenetic deregulation of these genes and their corresponding cellular pathways may promote the development and progression of GC. We also found that global demethylation of tumor cell genomes occurs in GC, consistent with the notion that abnormal hypermethylation of specific genes occurs concomitantly with genome-wide hypomethylation. Age and gender had no significant influence on methylation states, but an association was observed between LINE-1 and MLH1 methylation levels with histological sub-type and anatomical sub-site. This study identifies aberrant methylation patters in specific genes in GC thus providing information that could be exploited as novel biomarkers in clinics and molecular epidemiology of GC.
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Affiliation(s)
- Karen Balassiano
- International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69008 Lyon, France
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42
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Begnami MD, Fukuda E, Fregnani JHTG, Nonogaki S, Montagnini AL, da Costa WL, Soares FA. Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. J Clin Oncol 2011; 29:3030-6. [PMID: 21709195 DOI: 10.1200/jco.2010.33.6313] [Citation(s) in RCA: 198] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE The human epidermal growth factor receptor (HER) family consists of four members: ErbB-1 (HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4). These receptors activate numerous downstream pathways in response to extracellular ligands, regulating diverse processes that include differentiation, migration, proliferation, and survival. Alterations in these genes play a role in the development and progression of many human cancers. In gastric carcinomas (GCs), expression of HER1 and HER2 is thought to be a prognostic factor and target of novel biologic agents. The effect of HER3 or HER4 expression in GC has not been sufficiently studied. In this study, we explored the gene and protein expression of the HER family in GC to establish new potential prognostic factors. PATIENTS AND METHODS Immunohistochemistry and fluorescence in situ hybridization were performed in 221 patients with GC using tissue microarray. Correlation between the expression or amplification of HER genes and the clinicopathologic parameters was statistically analyzed. RESULTS Alterations of members of the HER family were significantly associated with the parameters involved in tumor progression, including depth of tumor invasion, involved lymph nodes, and tumor stage. In addition, HER2 amplification and HER3 expression were significantly related to worse survival. CONCLUSION These results reveal that all members of the HER family are expressed in GC. Furthermore, expression of HER2 and HER3 is a significant predictor of poor survival in GC. Therefore, the development of HER-targeted agents and agents targeting downstream signaling pathways provides new possibilities in the treatment of GC.
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Affiliation(s)
- Maria D Begnami
- Department of Pathology, Hospital A.C. Camargo, Rua Professor Antonio Prudente 211, Liberdade, Sã Paulo, Brazil.
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Tu JH, Yu YH. Role of epidermal growth factor receptor inhibitors in the treatment of gastric carcinoma. Shijie Huaren Xiaohua Zazhi 2011; 19:1150-1155. [DOI: 10.11569/wcjd.v19.i11.1150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is one of the most common digestive system malignancies. Traditional chemoradiotherapy has modest efficacy in the treatment of gastric cancer. The epidermal growth factor receptor (EGFR) signal transduction pathway plays an important role in tumor proliferation, angiogenesis, invasion, and migration. EGFR inhibitors have been and are being developed to treat gastric carcinoma. In this paper, we review the role of EGFR inhibitors in the treatment of gastric carcinoma.
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44
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Delektorskaya VV, Chemeris GY, Zavalishina LE, Ryazantseva AA, Grigorchuk AY, Kononets PV, Davydov MI. Squamous cell carcinoma of the esophagus: evaluation of the status of epidermal growth factor receptors (EGFR and HER-2) by immunohistochemistry and in situ hybridization. Bull Exp Biol Med 2011; 149:615-20. [PMID: 21165401 DOI: 10.1007/s10517-010-1007-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
We performed a parallel evaluation of the status of epidermal growth factor receptors EGFR and HER-2 in tumor samples from 31 patients with squamous cell carcinoma of the esophagus. Hyperexpression of proteins was detected by immunohistochemical methods and gene amplification and other chromosome abnormalities were studied using FISH reaction. Evaluation of EGFR status showed that amplification of EGFR gene was present in 25% cases and chromosome 7 polysomy was detected in 29.2% cases positive by protein expression (2+/3+). Immunohistochemically positive EGFR status was confirmed by the results of FISH reaction for gene amplification and chromosome 7 polysomy in 54.2% cases (p=0.002). During evaluation of HER-2 status in the tumor, hyperexpression of the protein detected histochemically was not confirmed by FISH reaction for detection of amplification of the corresponding gene in 16.1% cases. In 22.6% patients, chromosome 7 polysomy was detected; it was not accompanied by amplification of HER-2 gene, but was related to immunohistochemically positive status of the tumor. Hyperexpression of EGFR protein significantly correlated with the presence of intravascular invasion (p=0.006) and increased depth of invasion (p=0.044), while amplification of EGFR gene (≥2.2) correlated with low differentiation degree of the tumor (p=0.006). The outcome of the disease was not associated with EGFR status at the gene and protein levels, whereas clinical course of the disease in patients with immunohistochemically negative expression of HER-2 protein was more favorable than in patients with positive expression (p=0.004). The results of this study suggest that hyperexpression/amplification of EGFR and hyperexpression of HER-2 are important clinical markers for evaluation of disease prognosis and development of new regimens of targeted therapy for patients with squamous cells carcinoma of the esophagus.
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Affiliation(s)
- V V Delektorskaya
- N. N. Blokhin Cancer Research Center, Russian Academy of Medical Sciences Russia.
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45
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Al-Batran SE, Al-Batran SE, Ruppert M, Ruppert M, Jäger E, Jäger E. Trastuzumab plus Chemotherapy in Gastric Cancer Overexpressing HER-2 and EGFR: A Case Report. ACTA ACUST UNITED AC 2011; 34:42-5. [DOI: 10.1159/000323345] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Kulka J, Szirtes I, Szász AM, Kupcsulik P, Kenessey I, Lotz G, Tímár J. [Pathology background of targeted therapy; quality control in pathology]. Magy Onkol 2010; 54:343-50. [PMID: 21163765 DOI: 10.1556/monkol.54.2010.4.8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The administration of targeted therapy of gastric carcinoma is a very important recent improvement of its treatment and prognosis. The basis of the successful treatment is the excellent quality of pathology, now including HER2 testing: the use of validated methods and strict criteria. This is especially important if we consider that many gastric cancers are diagnosed in small biopsy material, in which HER2 testing is challenging. This requires standardized, validated methods and experienced pathologists. Being of diagnostic and predictive significance, high quality of both the technique and the interpretation of the test is mandatory. In order to achieve general high quality in this field, technical and interpretation external quality control of HER2 testing is necessary. Hungarian pathologists with the help of Roche Hungary Ltd. completed an external quality control round which showed that most of the participating laboratories are able. Kulka J, Szirtes I, Szász AM, Kupcsulik P, Kenessey I, Lotz G, Tímár J. Pathology background of targeted therapy; quality control in pathology.
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Affiliation(s)
- Janina Kulka
- Semmelweis Egyetem II. sz. Patológiai Intézet 1091 Budapest Üllői út 93.
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47
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Detección de aneuploidías del cromosoma 17 y deleción del gen TP53 en una amplia variedad de tumores sólidos mediante hibridación in situ fluorescente bicolor. BIOMEDICA 2010. [DOI: 10.7705/biomedica.v30i3.273] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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48
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Lu Y, Liu P, Wen W, Grubbs CJ, Townsend RR, Malone JP, Lubet RA, You M. Cross-species comparison of orthologous gene expression in human bladder cancer and carcinogen-induced rodent models. Am J Transl Res 2010; 3:8-27. [PMID: 21139803 PMCID: PMC2981423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2010] [Accepted: 09/15/2010] [Indexed: 05/30/2023]
Abstract
Genes differentially expressed by tumor cells represent promising drug targets for anti-cancer therapy. Such candidate genes need to be validated in appropriate animal models. This study examined the suitability of rodent models of bladder cancer in B6D2F1 mice and Fischer-344 rats to model clinical bladder cancer specimens in humans. Using a global gene expression approach cross-species analysis showed that 13-34% of total genes in the genome were differentially expressed between tumor and normal tissues in each of five datasets from humans, rats, and mice. About 20% of these differentially expressed genes overlapped among species, corresponding to 2.6 to 4.8% of total genes in the genome. Several genes were consistently dysregulated in bladder tumors in both humans and rodents. Notably, CNN1, MYL9, PDLIM3, ITIH5, MYH11, PCP4 and FM05 were found to commonly down-regulated; while T0P2A, CCNB2, KIF20A and RRM2 were up-regulated. These genes are likely to have conserved functions contributing to bladder carcinogenesis. Gene set enrichment analysis detected a number of molecular pathways commonly activated in both humans and rodent bladder cancer. These pathways affect the cell cycle, HIF-1 and MYC expression, and regulation of apoptosis. We also compared expression changes at mRNA and protein levels in the rat model and identified several genes/proteins exhibiting concordant changes in bladder tumors, including ANXA1, ANXA2, CA2, KRT14, LDHA, LGALS4, SERPINA1, KRT18 and LDHB. In general, rodent models of bladder cancer represent the clinical disease to an extent that will allow successful mining of target genes and permit studies on the molecular mechanisms of bladder carcinogenesis.
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Affiliation(s)
- Yan Lu
- Department of Surgery and the Alvin J. Siteman Cancer Center, Washington University School of MedicineSt. Louis, MO 63110, USA
- Department of Physiology and the Cancer Center, Medical college of WisconsinMilwaukee, WI 53226, USA
| | - Pengyuan Liu
- Department of Surgery and the Alvin J. Siteman Cancer Center, Washington University School of MedicineSt. Louis, MO 63110, USA
- Department of Physiology and the Cancer Center, Medical college of WisconsinMilwaukee, WI 53226, USA
| | - Weidong Wen
- Department of Surgery and the Alvin J. Siteman Cancer Center, Washington University School of MedicineSt. Louis, MO 63110, USA
| | - Clinton J Grubbs
- Departments of Surgery, Genetics, and Medicine, University of Alabama at BirminghamBirmingham, AL 35294, USA
| | - Reid R Townsend
- Department of Internal Medicine, Washington University School of MedicineSt. Louis, MO 63110, USA
| | - James P Malone
- Department of Internal Medicine, Washington University School of MedicineSt. Louis, MO 63110, USA
| | - Ronald A Lubet
- Chemoprevention Agent Development Research Group, National Cancer InstituteRockville, MD 20892, USA
| | - Ming You
- Department of Surgery and the Alvin J. Siteman Cancer Center, Washington University School of MedicineSt. Louis, MO 63110, USA
- Department of Pharmacology and Toxicology and the Cancer Center, Medical college of WisconsinMilwaukee, WI 53226, USA
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Hwang MK, Bode AM, Byun S, Song NR, Lee HJ, Lee KW, Dong Z. Cocarcinogenic Effect of Capsaicin Involves Activation of EGFR Signaling but Not TRPV1. Cancer Res 2010; 70:6859-69. [DOI: 10.1158/0008-5472.can-09-4393] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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50
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Sánchez-Pérez I, García Alonso P, Belda Iniesta C. Clinical impact of aneuploidy on gastric cancer patients. Clin Transl Oncol 2010; 11:493-8. [PMID: 19661021 DOI: 10.1007/s12094-009-0393-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Gastric cancer is a leading cause of death worldwide. Nowadays, complete surgical resection and TNM at diagnosis are the main prognostic factors. In spite of this, many patients will have a recurrence after surgery and die within a few months or years. That means that we need more accurate prognostic factors to design specific approaches for individual patients. Chromosome instability is a feature of gastric cancer commonly associated to chromosomal aberrations that leads to major modifications of DNA content globally termed as aneuploidy. In this regard, many authors' opinions diverge regarding the clinical impact of aneuploidy. This review will summarise data on the clinical impact of aneuploidy on clinical practice, the biological mechanisms that underlie chromosomal instability that induces aneuploidy and the relevance of specific chromosomal aneuploidy to cancer biology.
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Affiliation(s)
- Isabel Sánchez-Pérez
- Translational Oncology Unit CSIC/UAM, Instituto de Investigaciones Biomédicas CSIC/UAM, Madrid, Spain.
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