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Yan B, Dong X, Wu Z, Chen D, Jiang W, Cheng J, Chen G, Yan J. Association of proteomics with lymph node metastasis in early gastric cancer patients. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167773. [PMID: 40048938 DOI: 10.1016/j.bbadis.2025.167773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 01/13/2025] [Accepted: 02/28/2025] [Indexed: 04/15/2025]
Abstract
Surgical decision making for early gastric cancer (EGC) is heavily influenced by its metastasis into the lymph nodes. Currently, the clinicopathological features of EGC cannot be used to accurately distinguish between EGC patients with and without lymph node metastasis. Our retrospective case-matching study included a total of 132 samples from 66 pairs of EGC patients with or without lymph node metastasis and conducted proteomic assays. By comparing the lymph node metastasis group and the nonmetastasis group, we found that two proteins, GABARAPL2 and NAV1, were significantly associated with lymph node metastasis in EGC patients. Our prediction model using protein biomarkers had good prediction accuracy, with an area under the curve (AUC) of 0.87, a sensitivity of 0.78, a specificity of 0.89, and an accuracy of 0.84, which can help distinguish between EGC patients with and without lymph node metastasis and guide the decision-making process for performing tailored surgery.
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Affiliation(s)
- Botao Yan
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China
| | - Xiaoyu Dong
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China; Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, PR China
| | - Zaizeng Wu
- Department of Pathology, Fujian Cancer Hospital, Fujian Medical University, Fuzhou, Fujian 350001, PR China
| | - Dexin Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China; Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, PR China
| | - Wei Jiang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China; Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, PR China
| | - Jiaxin Cheng
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China; Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, PR China
| | - Gang Chen
- Department of Pathology, Fujian Cancer Hospital, Fujian Medical University, Fuzhou, Fujian 350001, PR China.
| | - Jun Yan
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China; Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, PR China.
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Sukri A, Hanafiah A, Kosai NR. The Roles of Immune Cells in Gastric Cancer: Anti-Cancer or Pro-Cancer? Cancers (Basel) 2022; 14:cancers14163922. [PMID: 36010915 PMCID: PMC9406374 DOI: 10.3390/cancers14163922] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/05/2022] [Accepted: 08/07/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Gastric cancer is still one of the leading causes of death caused by cancer in developing countries. The emerging role of immunotherapy in cancer treatment has led to more research to elucidate the roles of essential immune cells in gastric cancer prognosis. We reviewed the roles of immune cells including T cells, B cells, dendritic cells, macrophages and natural killer cells in gastric cancer. Although the studies conducted on the roles of immune cells in gastric cancer pathogenesis produced conflicting results, understanding the roles of immune cells in gastric cancer will help us to harness them for application in immunotherapy for better prognosis and management of gastric cancer patients. Abstract Despite the fact that the incidence of gastric cancer has declined over the last decade, it is still the world’s leading cause of cancer-related death. The diagnosis of early gastric cancer is difficult, as symptoms of this cancer only manifest at a late stage of cancer progression. Thus, the prognosis of gastric cancer is poor, and the current treatment for improving patients’ outcomes involves the application of surgery and chemotherapy. Immunotherapy is one of the most recent therapies for gastric cancer, whereby the immune system of the host is programmed to combat cancer cells, and the therapy differs based upon the patient’s immune system. However, an understanding of the role of immune cells, namely the cell-mediated immune response and the humoral immune response, is pertinent for applications of immunotherapy. The roles of immune cells in the prognosis of gastric cancer have yielded conflicting results. This review discusses the roles of immune cells in gastric cancer pathogenesis, specifically, T cells, B cells, macrophages, natural killer cells, and dendritic cells, as well as the evidence presented thus far. Understanding how cancer cells interact with immune cells is of paramount importance in designing treatment options for gastric cancer immunotherapy.
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Affiliation(s)
- Asif Sukri
- Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM), Bandar Puncak Alam, Shah Alam 43200, Malaysia
| | - Alfizah Hanafiah
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
- Correspondence:
| | - Nik Ritza Kosai
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
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Zhong X, Xuan F, Qian Y, Pan J, Wang S, Chen W, Lin T, Zhu H, Wang X, Wang G. A genomic-clinicopathologic Nomogram for the preoperative prediction of lymph node metastasis in gastric cancer. BMC Cancer 2021; 21:455. [PMID: 33892676 PMCID: PMC8066490 DOI: 10.1186/s12885-021-08203-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 04/16/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Preoperative evaluation of lymph node (LN) state is of pivotal significance for informing therapeutic decisions in gastric cancer (GC) patients. However, there are no non-invasive methods that can be used to preoperatively identify such status. We aimed at developing a genomic biosignature based model to predict the possibility of LN metastasis in GC patients. METHODS We used the RNA profile retrieving strategy and performed RNA expression profiling in a large GC cohort (GSE62254, n = 300) from Gene Expression Ominus (GEO). In the exploratory stage, 300 GC patients from GSE62254 were involved and the differentially expressed RNAs (DERs) for LN-status were determined using the R software. GC samples in GSE62254 were randomly allocated into a learning set (n = 210) and a verification set (n = 90). By using the Least absolute shrinkage and selection operator (LASSO) regression approach, a set of 23-RNA signatures were established and the signature based nomogram was subsequently built for distinguishing LN condition. The diagnostic efficiency, as well as the clinical performance of this model were assessed using the decision curve analysis (DCA). Metascape was used for bioinformatic analysis of the DERs. RESULTS Based on the genomic signature, we established a nomogram that robustly distinguished LN status in the learning (AUC = 0.916, 95% CI 0.833-0.999) and verification sets (AUC = 0.775, 95% CI 0.647-0.903). DCA demonstrated the clinical value of this nomogram. Functional enrichment analysis of the DERs was performed using bioinformatics methods which revealed that these DERs were involved in several lymphangiogenesis-correlated cascades. CONCLUSIONS In this study, we present a genomic signature based nomogram that integrates the 23-RNA biosignature based scores and Lauren classification. This model can be utilized to estimate the probability of LN metastasis with good performance in GC. The functional analysis of the DERs reveals the prospective biogenesis of LN metastasis in GC.
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Affiliation(s)
- Xin Zhong
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, East Qingchun Road 3, Zhejiang, 310016, Hangzhou, China.
| | - Feichao Xuan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, East Qingchun Road 3, Zhejiang, 310016, Hangzhou, China
| | - Yun Qian
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, East Qingchun Road 3, Zhejiang, 310016, Hangzhou, China
| | - Junhai Pan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, East Qingchun Road 3, Zhejiang, 310016, Hangzhou, China
| | - Suihan Wang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, East Qingchun Road 3, Zhejiang, 310016, Hangzhou, China
| | - Wenchao Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, East Qingchun Road 3, Zhejiang, 310016, Hangzhou, China
| | - Tianyu Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, East Qingchun Road 3, Zhejiang, 310016, Hangzhou, China
| | - Hepan Zhu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, East Qingchun Road 3, Zhejiang, 310016, Hangzhou, China
| | - Xianfa Wang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, East Qingchun Road 3, Zhejiang, 310016, Hangzhou, China.
| | - Guanyu Wang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, East Qingchun Road 3, Zhejiang, 310016, Hangzhou, China.
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Zhao Y, Li J, Li D, Wang Z, Zhao J, Wu X, Sun Q, Lin PP, Plum P, Damanakis A, Gebauer F, Zhou M, Zhang Z, Schlösser H, Jauch KW, Nelson PJ, Bruns CJ. Tumor biology and multidisciplinary strategies of oligometastasis in gastrointestinal cancers. Semin Cancer Biol 2020; 60:334-343. [PMID: 31445220 DOI: 10.1016/j.semcancer.2019.08.026] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 08/20/2019] [Indexed: 12/11/2022]
Abstract
More than 70% of gastrointestinal (GI) cancers are diagnosed with metastases, leading to poor prognosis. For some cancer patients with limited sites of metastatic tumors, the term oligometastatic disease (OMD) has been coined as opposed to systemic polymetastasis (PMD) disease. Stephan Paget first described an organ-specific pattern of metastasis in 1889, now known as the "seed and soil" theory where distinct cancer types are found to metastasize to different tumor-specific sites. Our understanding of the biology of tumor metastasis and specifically the molecular mechanisms driving their formation are still limited, in particular, as it relates to the genesis of oligometastasis. In the following review, we discuss recent advances in general understanding of this metastatic behavior including the role of specific signaling pathways, various molecular features and biomarkers, as well as the interaction of carcinoma cells with their tissue microenvironments (both primary and metastatic niches). The unique features that underlie OMD provide potential targets for localized therapy. As it relates to clinical practice, OMD is emerging as treatable with surgical resection and/or other local therapy options. Strategies currently being applied in the clinical management of OMD will be discussed including surgical, radiation-based therapy, ablation procedures, and the results of emerging clinical trials involving immunotherapy.
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Affiliation(s)
- Yue Zhao
- Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany; Department of General, Visceral und Vascular Surgery, Otto von Guericke University, Magdeburg, Germany.
| | - Jiahui Li
- Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany
| | - Dai Li
- Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany; Department of Anethesiology, Changhai Hospital, Naval Medical University, Shanghai, PR China
| | - Zhefang Wang
- Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany
| | - Jiangang Zhao
- Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany; Department of General, Visceral und Vascular Surgery, Ludwig-Maximilian-University (LMU), Munich, Germany
| | - Xiaolin Wu
- Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany
| | - Qiye Sun
- Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany
| | | | - Patrick Plum
- Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany; Institute for Pathology, University Hospital Cologne, Cologne, Germany
| | - Alexander Damanakis
- Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany
| | - Florian Gebauer
- Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany
| | - Menglong Zhou
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Hans Schlösser
- Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Center for Integrated Oncology (CIO) Achen, Bonn, Cologne and Düsseldorf, Cologne, Germany
| | - Karl-Walter Jauch
- Department of General, Visceral und Vascular Surgery, Ludwig-Maximilian-University (LMU), Munich, Germany
| | - Peter J Nelson
- Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Germany
| | - Christiane J Bruns
- Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany; Center for Integrated Oncology (CIO) Achen, Bonn, Cologne and Düsseldorf, Cologne, Germany.
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Izumi D, Gao F, Toden S, Sonohara F, Kanda M, Ishimoto T, Kodera Y, Wang X, Baba H, Goel A. A genomewide transcriptomic approach identifies a novel gene expression signature for the detection of lymph node metastasis in patients with early stage gastric cancer. EBioMedicine 2019; 41:268-275. [PMID: 30772302 PMCID: PMC6441863 DOI: 10.1016/j.ebiom.2019.01.057] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 01/29/2019] [Accepted: 01/30/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Although identification of lymph node (LN) metastasis is a well-recognized strategy for improving outcomes in patients with gastric cancer (GC), currently there is lack of availability of adequate molecular biomarkers that can identify such metastasis. Herein we have developed a robust gene-expression signature for detecting LN metastasis in early stage GC by using a transcriptome-wide biomarker discovery and subsequent validation in multiple clinical cohorts. METHODS A total of 532 patients with pathological T1 and T2 GC from 4 different cohorts were analyzed. Two independent datasets (n = 96, and n = 188) were used to establish a gene signature for the identification of LN metastasis in GC patients. The diagnostic performance of our gene-expression signature was subsequently assessed in two independent clinical cohorts using qRT-PCR assays (n = 101, and n = 147), and subsequently compared against conventional tumor markers and image-based diagnostics. FINDINGS We established a 15-gene signature by analyzing multiple high throughput datasets, which robustly distinguished LN status in both training (AUC = 0.765, 95% CI 0.667-0.863) and validation cohorts (AUC = 0.742, 95% CI 0.630-0.852). Notably, the 15-gene signature was significantly superior compared to the conventional tumor markers, CEA (P = .04) and CA19-9 (P = .005), as well as computed tomography-based imaging (P = .04). INTERPRETATION We have established and validated a 15-gene signature for detecting LN metastasis in GC patients, which offers a robust diagnostic tool for potentially improving treatment outcomes in gastric cancer patients. FUND: NIH: CA72851, CA181572, CA14792, CA202797, CA187956; CPRIT: RP140784: Baylor Sammons Cancer Center polot grants (AG), VPRT: 9610337, CityU 21101115, 11102317, 11103718; JCYJ20170307091256048 (XW).
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Affiliation(s)
- Daisuke Izumi
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA; Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Surgery, Kumamoto General Hospital, Kumamoto, Japan
| | - Feng Gao
- Department of Biomedical Sciences, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China
| | - Shusuke Toden
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Fuminori Sonohara
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA; Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takatsugu Ishimoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; The International Research Center for Medicine Sciences, Kumamoto University, Kumamoto, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Xin Wang
- Department of Biomedical Sciences, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, City University of Hong Kong, Shenzhen, China.
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Ajay Goel
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
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Abstract
Array comparative genomic hybridization (aCGH) is a high-throughput lab technique to measure genome-wide chromosomal copy numbers. Data from aCGH experiments require extensive pre-processing, which consists of three steps: normalization, segmentation and calling. Each of these pre-processing steps yields a different data set: normalized data, segmented data, and called data. Publications using aCGH base their findings on data from all stages of the pre-processing. Hence, there is no consensus on which should be used for further down-stream analysis. This consensus is however important for correct reporting of findings, and comparison of results from different studies. We discuss several issues that should be taken into account when deciding on which data are to be used. We express the believe that called data are best used, but would welcome opposing views.
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Affiliation(s)
- Wessel N. Van Wieringen
- Department of Mathematics, Vrije Universiteit De Boelelaan 1081a, 1081 HV Amsterdam, The Netherlands
| | - Mark A. Van De Wiel
- Department of Mathematics, Vrije Universiteit De Boelelaan 1081a, 1081 HV Amsterdam, The Netherlands
- VU University Medical Center, P.O. Box 7075, 1007 MB Amsterdam, The Netherlands
| | - Bauke Ylstra
- VU University Medical Center, P.O. Box 7075, 1007 MB Amsterdam, The Netherlands
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Li M, Hong G, Cheng J, Li J, Cai H, Li X, Guan Q, Tong M, Li H, Guo Z. Identifying Reproducible Molecular Biomarkers for Gastric Cancer Metastasis with the Aid of Recurrence Information. Sci Rep 2016; 6:24869. [PMID: 27109211 PMCID: PMC4843012 DOI: 10.1038/srep24869] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 04/06/2016] [Indexed: 01/17/2023] Open
Abstract
To precisely diagnose metastasis state is important for tailoring treatments for gastric cancer patients. However, the routinely employed radiological and pathologic tests for tumour metastasis have considerable high false negative rates, which may retard the identification of reproducible metastasis-related molecular biomarkers for gastric cancer. In this research, using three datasets, we firstly shwed that differentially expressed genes (DEGs) between metastatic tissue samples and non-metastatic tissue samples could hardly be reproducibly detected with a proper statistical control when the metastatic and non-metastatic samples were defined by TNM stage alone. Then, assuming that undetectable micrometastases are the prime cause for recurrence of early stage patients with curative resection, we reclassified all the “non-metastatic” samples as metastatic samples whenever the patients experienced tumour recurrence during follow-up after tumour resection. In this way, we were able to find distinct and reproducible DEGs between the reclassified metastatic and non-metastatic tissue samples and concordantly significant DNA methylation alterations distinguishing metastatic tissues and non-metastatic tissues of gastric cancer. Our analyses suggested that the follow-up recurrence information for patients should be employed in the research of tumour metastasis in order to decrease the confounding effects of false non-metastatic samples with undetected micrometastases.
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Affiliation(s)
- Mengyao Li
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou 350001, China
| | - Guini Hong
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou 350001, China
| | - Jun Cheng
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou 350001, China
| | - Jing Li
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou 350001, China
| | - Hao Cai
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou 350001, China
| | - Xiangyu Li
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou 350001, China
| | - Qingzhou Guan
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou 350001, China
| | - Mengsha Tong
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou 350001, China
| | - Hongdong Li
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou 350001, China
| | - Zheng Guo
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou 350001, China
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Lectin microarray technology identifies specific lectins related to lymph node metastasis of advanced gastric cancer. Gastric Cancer 2016; 19:531-542. [PMID: 25840959 DOI: 10.1007/s10120-015-0491-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2014] [Accepted: 03/13/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although various molecular profiling technologies have the potential to predict specific tumor phenotypes, the comprehensive profiling of lectin-bound glycans in human cancer tissues has not yet been achieved. METHODS We examined 242 advanced gastric cancer (AGC) patients without or with lymph node metastasis-N0 (n = 62) or N+ (n = 180)-by lectin microarray, and identified the specific lectins highly associated with AGC phenotypes. RESULTS In seven gastric cancer cell lines, in contrast to expressed-in-cancer lectins, not-expressed-in-cancer (NEC) lectins were tentatively designated by lectin microarray. Binding signals of the specific lectins were robustly reduced in AGC patients with N+ status as compared with those with N0 status. The receiver operating characteristic curve determined the optimal cutoff value to differentiate N0 status from N+ status, and subsequent profiling of NEC lectins identified Vicia villosa agglutinin (VVA) association with the significant other lectins involved in lymph node metastasis. VVA reaction was clearly found on cancer cells, suggesting that it may result from carcinoma-stroma interaction in primary AGC, because VVA is an NEC lectin. Most intriguingly, VVA reaction was remarkably attenuated in the tumor cells of the metastatic lymph nodes, even if it was recognized in primary AGC. In AGC, histological type was strongly associated with soybean agglutinin and Bauhinia purpurea lectin, whereas p53 mutation was the best correlated with Griffonia simplicifolia lectin II. CONCLUSIONS Lectin microarrays can be used to very accurately quantify the reaction of glycans with tumor tissues, and such profiles may represent the specific phenotypes, including N+ status, histological type, or p53 mutation of AGC.
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Suh YS, Yu J, Kim BC, Choi B, Han TS, Ahn HS, Kong SH, Lee HJ, Kim WH, Yang HK. Overexpression of Plasminogen Activator Inhibitor-1 in Advanced Gastric Cancer with Aggressive Lymph Node Metastasis. Cancer Res Treat 2015; 47:718-26. [PMID: 25687870 PMCID: PMC4614183 DOI: 10.4143/crt.2014.064] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 10/06/2014] [Indexed: 12/26/2022] Open
Abstract
Purpose The purpose of this study is to investigate differentially expressed genes using DNA microarray between advanced gastric cancer (AGC) with aggressive lymph node (LN) metastasis and that with a more advanced tumor stage but without LN metastasis. Materials and Methods Five sample pairs of gastric cancer tissue and normal gastric mucosa were taken from three patients with T3N3 stage (highN) and two with T4N0 stage (lowN). Data from triplicate DNA microarray experiments were analyzed, and candidate genes were identified using a volcano plot that showed ≥ 2-fold differential expression and were significant by Welch's t test (p < 0.05) between highN and lowN. Those selected genes were validated independently by reverse-transcriptase–polymerase chain reaction (RT-PCR) using five AGC patients, and tissue-microarray (TMA) comprising 47 AGC patients. Results CFTR, LAMC2, SERPINE2, F2R, MMP7, FN1, TIMP1, plasminogen activator inhibitor-1 (PAI-1), ITGB8, SDS, and TMPRSS4 were commonly up-regulated over 2-fold in highN. REG3A, CD24, ITLN1, and WBP5 were commonly down-regulated over 2-fold in lowN. Among these genes, overexpression of PAI-1 was validated by RT-PCR, and TMA showed 16.7% (7/42) PAI-1 expression in T3N3, but none (0/5) in T4N0 (p=0.393). Conclusion DNA microarray analysis and validation by RT-PCR and TMA showed that overexpression of PAI-1 is related to aggressive LN metastasis in AGC.
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Affiliation(s)
- Yun-Suhk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jieun Yu
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | | | - Boram Choi
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Tae-Su Han
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Seong Ahn
- Department of Surgery, SMG-SNU Boramae Medical Center, Seoul, Korea
| | - Seong-Ho Kong
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyuk-Joon Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Woo Ho Kim
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Han-Kwang Yang
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Mottaghi-Dastjerdi N, Soltany-Rezaee-Rad M, Sepehrizadeh Z, Roshandel G, Ebrahimifard F, Setayesh N. Identification of novel genes involved in gastric carcinogenesis by suppression subtractive hybridization. Hum Exp Toxicol 2014; 34:3-11. [PMID: 24812152 DOI: 10.1177/0960327114532386] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Gastric cancer (GC) is one of the most common and life-threatening types of malignancies. Identification of the differentially expressed genes in GC is one of the best approaches for establishing new diagnostic and therapeutic targets. Furthermore, these investigations could advance our knowledge about molecular biology and the carcinogenesis of this cancer. To screen for the overexpressed genes in gastric adenocarcinoma, we performed suppression subtractive hybridization (SSH) on gastric adenocarcinoma tissue and the corresponding normal gastric tissue, and eight genes were found to be overexpressed in the tumor compared with those of the normal tissue. The genes were ribosomal protein L18A, RNase H2 subunit B, SEC13, eukaryotic translation initiation factor 4A1, tetraspanin 8, cytochrome c oxidase subunit 2, NADH dehydrogenase subunit 4, and mitochondrially encoded ATP synthase 6. The common functions among the identified genes include involvement in protein synthesis, involvement in genomic stability maintenance, metastasis, metabolic improvement, cell signaling pathways, and chemoresistance. Our results provide new insights into the molecular biology of GC and drug discovery: each of the identified genes could be further investigated as targets for prognosis evaluation, diagnosis, treatment, evaluation of the response to new anticancer drugs, and determination of the molecular pathogenesis of GC.
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Affiliation(s)
- N Mottaghi-Dastjerdi
- Department of Pharmaceutical Biotechnology and Pharmaceutical Biotechnology Research Center, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran Pharmaceutical Sciences Research Center, Sari School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Islamic Republic of Iran
| | - M Soltany-Rezaee-Rad
- Department of Pharmaceutical Biotechnology and Pharmaceutical Biotechnology Research Center, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran Pharmaceutical Sciences Research Center, Sari School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Islamic Republic of Iran
| | - Z Sepehrizadeh
- Department of Pharmaceutical Biotechnology and Pharmaceutical Biotechnology Research Center, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - G Roshandel
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Golestan, Islamic Republic of Iran
| | - F Ebrahimifard
- Department of General Surgery, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - N Setayesh
- Department of Pharmaceutical Biotechnology and Pharmaceutical Biotechnology Research Center, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
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Tänzer M, Liebl M, Quante M. Molecular biomarkers in esophageal, gastric, and colorectal adenocarcinoma. Pharmacol Ther 2013; 140:133-47. [PMID: 23791941 DOI: 10.1016/j.pharmthera.2013.06.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Accepted: 06/06/2013] [Indexed: 02/06/2023]
Abstract
Cancers of the esophagus, stomach and colon contribute to a major health burden worldwide and over 20% of all cancer deaths. Biomarkers that should indicate pathogenic process and are measureable in an objective manner for these tumors are rare and not established in the clinical setting. In general biomarkers can be very useful for cancer management as they can improve clinical decision-making regarding diagnosis, surveillance, and therapy. Biomarkers can be different types of molecular entities (such as DNA, RNA or proteins), which can be detected, in different tissues or body fluids. However, more important is the type of biomarker itself, which allows diagnostic, prognostic or predictive analyses for different clinical problems. This review aims to systematically summarize the recent findings of genetic and epigenetic markers for gastrointestinal tumors within the last decade. While many biomarkers seem to be very promising, especially if used as panels, further development is urgently needed to address practical considerations of biomarkers in cancer treatment.
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Affiliation(s)
- Marc Tänzer
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany
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12
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Wang G, Hu N, Yang HH, Wang L, Su H, Wang C, Clifford R, Dawsey EM, Li JM, Ding T, Han XY, Giffen C, Goldstein AM, Taylor PR, Lee MP. Comparison of global gene expression of gastric cardia and noncardia cancers from a high-risk population in china. PLoS One 2013; 8:e63826. [PMID: 23717493 PMCID: PMC3661768 DOI: 10.1371/journal.pone.0063826] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 04/05/2013] [Indexed: 12/14/2022] Open
Abstract
Objective To profile RNA expression in gastric cancer by anatomic subsites as an initial step in identifying molecular subtypes and providing targets for early detection and therapy. Methods We performed transcriptome analysis using the Affymetrix GeneChip U133A in gastric cardia adenocarcinomas (n = 62) and gastric noncardia adenocarcinomas (n = 72) and their matched normal tissues from patients in Shanxi Province, and validated selected dysregulated genes with additional RNA studies. Expression of dysregulated genes was also related to survival of cases. Results Principal Component Analysis showed that samples clustered by tumor vs. normal, anatomic location, and histopathologic features. Paired t-tests of tumor/normal tissues identified 511 genes whose expression was dysregulated (P<4.7E-07 and at least two-fold difference in magnitude) in cardia or noncardia gastric cancers, including nearly one-half (n = 239, 47%) dysregulated in both cardia and noncardia, one-fourth dysregulated in cardia only (n = 128, 25%), and about one-fourth in noncardia only (n = 144, 28%). Additional RNA studies confirmed profiling results. Expression was associated with case survival for 20 genes in cardia and 36 genes in noncardia gastric cancers. Conclusions The dysregulated genes identified here represent a comprehensive starting point for future efforts to understand etiologic heterogeneity, develop diagnostic biomarkers for early detection, and test molecularly-targeted therapies for gastric cancer.
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Affiliation(s)
- Gangshi Wang
- Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland, United States of America
| | - Nan Hu
- Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland, United States of America
| | - Howard H. Yang
- Office of the Director, Center for Cancer Research, NCI, Bethesda, Maryland, United States of America
| | - Lemin Wang
- Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland, United States of America
| | - Hua Su
- Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland, United States of America
| | - Chaoyu Wang
- Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland, United States of America
| | - Robert Clifford
- Multidrug Resistant Organism Repository and Surveillance Network, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America
| | - Erica M. Dawsey
- Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland, United States of America
| | - Jian-Min Li
- Shanxi Cancer Hospital, Taiyuan, Shanxi, PR China
| | - Ti Ding
- Shanxi Cancer Hospital, Taiyuan, Shanxi, PR China
| | - Xiao-You Han
- Shanxi Cancer Hospital, Taiyuan, Shanxi, PR China
| | - Carol Giffen
- Information Management Services, Inc., Silver Spring, Maryland, United States of America
| | - Alisa M. Goldstein
- Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland, United States of America
| | - Philip R. Taylor
- Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland, United States of America
- * E-mail: (PRT); (MPL)
| | - Maxwell P. Lee
- Office of the Director, Center for Cancer Research, NCI, Bethesda, Maryland, United States of America
- * E-mail: (PRT); (MPL)
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Zhang SN, Sun HH, Jin YM, Piao LZ, Jin DH, Lin ZH, Shen XH. Identification of differentially expressed genes in gastric cancer by high density cDNA microarray. Cancer Genet 2012; 205:147-55. [PMID: 22559975 DOI: 10.1016/j.cancergen.2012.01.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2011] [Revised: 12/24/2011] [Accepted: 01/09/2012] [Indexed: 11/25/2022]
Abstract
The identification of molecular markers for diagnosis, treatment, and prognosis is a significant issue in the management of patients with gastric cancer. We compared the expression profiles of 23 gastric cancers and 22 normal gastric tissues using cDNA microarrays. We divided the samples into two sets, 11 pairs as a training set and 12 unpaired gastric cancer and 11 unpaired normal gastric tissues as a test set. We selected significant genes in the training set and validated the significance of the genes in the test set. We obtained 238 classifier genes that showed a maximum cross-validation probability and clear hierarchical clustering pattern in the training set, and showed excellent class prediction probability in the independent test set. The classifier genes consisted of known genes related to the biological features of cancer and 28% unknown genes. We obtained genome-wide molecular signatures of gastric cancer, which provides preliminary exploration data for the pathophysiology of gastric cancer.
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Affiliation(s)
- Song-Nan Zhang
- Department of Oncology, Affiliated Hospital of Yanbian University, Yanji, China
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14
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Jun KH, Kim SY, Yoon JH, Song JH, Park WS. Amplification of the UQCRFS1 Gene in Gastric Cancers. J Gastric Cancer 2012; 12:73-80. [PMID: 22792519 PMCID: PMC3392327 DOI: 10.5230/jgc.2012.12.2.73] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Revised: 05/07/2012] [Accepted: 05/09/2012] [Indexed: 11/28/2022] Open
Abstract
PURPOSE The specific aim of this study is to unravel a DNA copy number alterations, and to search for novel genes that are associated with the development of Korean gastric cancer. MATERIALS AND METHODS We investigated a DNA copy number changes in 23 gastric adenocarcinomas by array-comparative genomic hybridization and quantitative real-time polymerase chain reaction analyses. Besides, the expression of UQCRFS1, which shows amplification in array-CGH, was examined in 186 gastric cancer tissues by an immunohistochemistry, and in 9 gastric cancer cell lines, as well as 24 gastric cancer tissues by immunoblotting. RESULTS We found common gains at 48 different loci, and a common loss at 19 different loci. Amplification of UQCRFS1 gene at 19q12 was found in 5 (21.7%) of the 23 gastric cancers in an array-comparative genomic hybridization and DNA copy number were increased in 5 (20.0%) out of the 25 gastric cancer in quantitative real-time polymerase chain reaction. In immunohistochemistry, the overexpression of the protein was detected in 105 (56.5%) out of the 186 gastric cancer tissues. Statistically, there was no significant relationship between the overexpression of UQCRFS1 and clinicopathologic parameters (P>0.05). In parallel, the overexpression of UQCRFS1 protein was confirmed in 6 (66.7%) of the 9 gastric cancer cell lines, and 12 (50.0%) of the 24 gastric cancer tissues by immunoblotting. CONCLUSIONS These results suggest that the overexpression of UQCRFS1 gene may contribute to the development and/or progression of gastric cancer, and further supported that mitochondrial change may serve as a potential cancer biomarker.
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Affiliation(s)
- Kyong Hwa Jun
- Department of General Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Su Young Kim
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jung Hwan Yoon
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae Hwi Song
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Won Sang Park
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
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15
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Buffart TE, Carvalho B, van Grieken NCT, van Wieringen WN, Tijssen M, Kranenbarg EMK, Verheul HMW, Grabsch HI, Ylstra B, van de Velde CJH, Meijer GA. Losses of chromosome 5q and 14q are associated with favorable clinical outcome of patients with gastric cancer. Oncologist 2012; 17:653-62. [PMID: 22531355 DOI: 10.1634/theoncologist.2010-0379] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE To improve the clinical outcome of patients with gastric cancer, intensified combination strategies are currently in clinical development, including combinations of more extensive surgery, (neo)adjuvant chemotherapy, and radiotherapy. The present study used DNA copy number profiling to identify subgroups of patients with different clinical outcomes. We hypothesize that, by identification of subgroups, individual treatment strategies can be selected to improve clinical outcome and to reduce unnecessary treatment toxicity for patients with gastric cancer. EXPERIMENTAL DESIGN DNA from 206 gastric cancer patients was isolated and analyzed by genomewide array comparative genomic hybridization. DNA copy number profiles were correlated with lymph node status and patient survival. In addition, heat shock protein 90 (HSP90) expression was analyzed and correlated with survival in 230 gastric cancer patients. RESULTS Frequent (>20%) DNA copy number gains and losses were observed on several chromosomal regions. Losses on 5q11.2-q31.3 and 14q32.11-q32.33 (14% of patients) were correlated with good clinical outcome in univariate and multivariate analyses, with a median disease-free survival interval of 9.2 years. In addition, loss of expression of HSP90, located on chromosome 14q32.2, was correlated with better patient survival. CONCLUSION Genomewide DNA copy number profiling allowed the identification of a subgroup of gastric cancer patients, marked by losses on chromosomes 5q11.2-q31.3 and 14q32.11-q32.33 or low HSP90 protein expression, with an excellent clinical outcome after surgery alone. We hypothesize that this subgroup of patients most likely will not benefit from (neo)adjuvant systemic treatment and/or radiotherapy, whereas anti-HSP90 therapy may have clinical potential in patients with HSP90-expressing gastric cancer, pending validation in an independent dataset.
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Affiliation(s)
- Tineke E Buffart
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
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16
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Fan B, Dachrut S, Coral H, Yuen ST, Chu KM, Law S, Zhang L, Ji J, Leung SY, Chen X. Integration of DNA copy number alterations and transcriptional expression analysis in human gastric cancer. PLoS One 2012; 7:e29824. [PMID: 22539939 PMCID: PMC3335165 DOI: 10.1371/journal.pone.0029824] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2011] [Accepted: 12/03/2011] [Indexed: 12/16/2022] Open
Abstract
Background Genomic instability with frequent DNA copy number alterations is one of the key hallmarks of carcinogenesis. The chromosomal regions with frequent DNA copy number gain and loss in human gastric cancer are still poorly defined. It remains unknown how the DNA copy number variations contributes to the changes of gene expression profiles, especially on the global level. Principal Findings We analyzed DNA copy number alterations in 64 human gastric cancer samples and 8 gastric cancer cell lines using bacterial artificial chromosome (BAC) arrays based comparative genomic hybridization (aCGH). Statistical analysis was applied to correlate previously published gene expression data obtained from cDNA microarrays with corresponding DNA copy number variation data to identify candidate oncogenes and tumor suppressor genes. We found that gastric cancer samples showed recurrent DNA copy number variations, including gains at 5p, 8q, 20p, 20q, and losses at 4q, 9p, 18q, 21q. The most frequent regions of amplification were 20q12 (7/72), 20q12–20q13.1 (12/72), 20q13.1–20q13.2 (11/72) and 20q13.2–20q13.3 (6/72). The most frequent deleted region was 9p21 (8/72). Correlating gene expression array data with aCGH identified 321 candidate oncogenes, which were overexpressed and showed frequent DNA copy number gains; and 12 candidate tumor suppressor genes which were down-regulated and showed frequent DNA copy number losses in human gastric cancers. Three networks of significantly expressed genes in gastric cancer samples were identified by ingenuity pathway analysis. Conclusions This study provides insight into DNA copy number variations and their contribution to altered gene expression profiles during human gastric cancer development. It provides novel candidate driver oncogenes or tumor suppressor genes for human gastric cancer, useful pathway maps for the future understanding of the molecular pathogenesis of this malignancy, and the construction of new therapeutic targets.
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Affiliation(s)
- Biao Fan
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America
- Department of Surgery, Beijing Cancer Hospital & Institute, Peking University School of Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China
| | - Somkid Dachrut
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Ho Coral
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America
| | - Siu Tsan Yuen
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Kent Man Chu
- Department of Surgery; The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Simon Law
- Department of Surgery; The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Lianhai Zhang
- Department of Surgery, Beijing Cancer Hospital & Institute, Peking University School of Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China
| | - Jiafu Ji
- Department of Surgery, Beijing Cancer Hospital & Institute, Peking University School of Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China
- * E-mail: (XC); (SYL); (JFJ)
| | - Suet Yi Leung
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
- * E-mail: (XC); (SYL); (JFJ)
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America
- * E-mail: (XC); (SYL); (JFJ)
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van Essen HF, Ylstra B. High-resolution copy number profiling by array CGH using DNA isolated from formalin-fixed, paraffin-embedded tissues. Methods Mol Biol 2012; 838:329-341. [PMID: 22228020 DOI: 10.1007/978-1-61779-507-7_16] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
We describe protocols to acquire high-quality DNA from formalin-fixed, paraffin-embedded (FFPE) tissues for the use in array comparative genome hybridization (CGH). Formalin fixation combined with paraffin embedding is routine procedure for solid malignancies in the diagnostic practice of the pathologist. As a consequence, large archives of FFPE tissues are available in pathology institutes across the globe. This archival material is for many research questions an invaluable resource, with long-term clinical follow-up and survival data available. FFPE is, thus, highly attractive for large genomics studies, including experiments requiring samples for test/learning and validation. Most larger array CGH studies have, therefore, made use of FFPE material and show that CNAs have tumor- and tissue-specific traits (Chin et al. Cancer Cell 10: 529-541, 2006; Fridlyand et al. BMC Cancer 6: 96, 2006; Weiss et al. Oncogene 22: 1872-1879, 2003; Jong et al. Oncogene 26: 1499-1506, 2007). The protocols described are tailored to array CGH of FFPE solid malignancies: from sectioning FFPE blocks to specific cynosures for pathological revisions of sections, DNA isolation, quality testing, and amplification. The protocols are technical in character and elaborate up to the labeling of isolated DNA while further processes and interpretation and data analysis are beyond the scope.
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Abstract
Gastric cancer is the most common cancer in Korea, with an age-standardized rate of 61.2 in males and 23.9 in females (in 2007), one of the highest in the world. Using a large gastric tissue depository and the extensive clinical experience gained from gastric cancer surgery, we work as a 'translational researcher' to apply basic research tools and results to the clinical field. We are also interested in providing answers to the questions in the operating room using the methods of basic research. I would like to introduce our research activities in this review paper.
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Affiliation(s)
- Han-Kwang Yang
- Department of Surgery, Seoul National University College of Medicine and Gastric Cancer Center, Seoul National University Cancer Hospital, Korea.
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López F, Llorente JL, García-Inclán C, Alonso-Guervós M, Cuesta-Albalad MP, Fresno MF, Alvarez-Marcos C, Suárez C, Hermsen MA. Genomic profiling of sinonasal squamous cell carcinoma. Head Neck 2011; 33:145-53. [PMID: 20848437 DOI: 10.1002/hed.21417] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Sinonasal squamous cell carcinomas (SCCs) are rare tumors with no etiologic link to tobacco and alcohol, as opposed to other SCCs of the head and neck (HNSCC). Little is known about the genetic changes in sinonasal SCC. METHODS DNA copy number changes of sinonasal SCC were analyzed by multiplex ligation-dependent probe amplification (MLPA) and microarray comparative genomic hybridization (maCGH), and results were related to clinicopathologic features. RESULTS Copy number losses most frequently included genes at 9p21, 13q14, 17p13, 17q21, and 18q11. Frequent gains were observed on 8q24, 11q13, 17q12, 19p13, and 20q11-q13. CONCLUSION The genomic profile of sinonasal SCC showed a number of chromosomal regions with copy number changes similar to those known in HNSCC, in spite of the differences in etiology.
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Affiliation(s)
- Fernando López
- Department of Otolaryngology, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain
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20
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Cho JY, Lim JY, Cheong JH, Park YY, Yoon SL, Kim SM, Kim SB, Kim H, Hong SW, Park YN, Noh SH, Park ES, Chu IS, Hong WK, Ajani JA, Lee JS. Gene expression signature-based prognostic risk score in gastric cancer. Clin Cancer Res 2011; 17:1850-7. [PMID: 21447720 DOI: 10.1158/1078-0432.ccr-10-2180] [Citation(s) in RCA: 278] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE Despite continual efforts to develop a prognostic model of gastric cancer by using clinical and pathologic parameters, a clinical test that can discriminate patients with good outcomes from those with poor outcomes after gastric cancer surgery has not been established. We aim to develop practical biomarker-based risk score that can predict relapse of gastric cancer after surgical treatment. EXPERIMENTAL DESIGN Microarray technologies were used to generate and analyze gene expression profiling data from 65 gastric cancer patients to identify biomarker genes associated with relapse. The association of expression patterns of identified genes with relapse and overall survival was validated in independent gastric cancer patients. RESULTS We uncovered two subgroups of gastric cancer that were strongly associated with the prognosis. For the easy translation of our findings into practice, we developed a scoring system based on the expression of six genes that predicted the likelihood of relapse after curative resection. In multivariate analysis, the risk score was an independent predictor of relapse in a cohort of 96 patients. We were able to validate the robustness of the six-gene signature in an additional independent cohort. CONCLUSIONS The risk score derived from the six-gene set successfully prognosticated the relapse of gastric cancer patients after gastrectomy.
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Affiliation(s)
- Jae Yong Cho
- Department of Systems Biology, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77054, USA
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Zhang D, Wang Z, Luo Y, Xu Y, Liu Y, Yang W, Zhang X. Analysis of DNA copy number aberrations by multiple ligation-dependent probe amplification on 50 intestinal type gastric cancers. J Surg Oncol 2010; 103:124-32. [PMID: 21259245 DOI: 10.1002/jso.21792] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2010] [Accepted: 09/26/2010] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND OBJECTIVES The molecular genetic alterations leading to gastric malignancy are largely unknown. This study aimed to unravel the genomic DNA copy number aberrations (CNAs) profile during gastric tumorigenesis. METHODS In this study, we performed genomic profiling in a set of 50 intestinal type gastric carcinomas by a PCR-based relative quantification method, multiple ligation-dependent probe amplification (MLPA) with 112 cancer-related gene loci selected throughout each human chromosome as probes of MLPA assay. RESULTS Numerous chromosomal DNA CNAs, including gains of 3p22, 4q25, 8q24, 11p13, and 20q13, and losses of 1p36 and 9p21, were identified by MLPA assay as recurrent DNA CNAs in gastric cancer. Moreover, we found the median numbers of gains, losses, and total CNAs were significantly higher in lymph node metastasis positive patients than in cases without metastasis. And gain of 11p13 and losses of 9p21.3, 11q13.3, 17q25.3, and 22q11.23 were associated with lymph node metastasis (P < 0.05). Finally, two major groups, including G1 + 2 with a large number of CNAs and G3 + 4 with a small number of CNAs, can be successfully distinguished by hierarchical cluster analysis. CONCLUSIONS Our results proved MLPA is a reliable and efficient method to evaluate DNA copy number changes in gastric cancers.
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Affiliation(s)
- Dai Zhang
- McKusick-Zhang Center for Genetic Medicine and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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22
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Tomioka N, Morita K, Kobayashi N, Tada M, Itoh T, Saitoh S, Kondo M, Takahashi N, Kataoka A, Nakanishi K, Takahashi M, Kamiyama T, Ozaki M, Hirano T, Todo S. Array comparative genomic hybridization analysis revealed four genomic prognostic biomarkers for primary gastric cancers. ACTA ACUST UNITED AC 2010; 201:6-14. [PMID: 20633762 DOI: 10.1016/j.cancergencyto.2010.04.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2009] [Revised: 03/29/2010] [Accepted: 04/21/2010] [Indexed: 12/14/2022]
Abstract
Unlike the case with some other solid tumors, whole genome array screening has not revealed prognostic genetic aberrations in primary gastric cancer. Comparative genomic hybridization (CGH) using bacterial artificial chromosome (BAC) arrays for 56 primary gastric cancers resulted in identification of four prognostic loci in this study: 6q21 (harboring FOXO3A; previously FKHRL1), 9q32 (UGCG), 17q21.1 approximately q21.2 (CASC3), and 17q21.32 (HOXB3 through HOXB9). If any one of these four loci was deleted, the prognosis of the patient was significantly worse (P = 0.0019). This was true even for advanced tumors (stage IIIA, IIB, or IV, n = 39) (P = 0.0113), whereas only 1 of the 17 patients with less advanced tumors (stage IA, IB, or II; n = 17) died of disease after surgery. Multivariate analysis according to the status of four BACs or pathological stage based on the Japanese Classification of Gastric Carcinoma (stages IA, IB, and II vs. stages IIIA, IIIB, and IV) demonstrated that the BAC clone status was also an independent prognostic factor (P = 0.006). These findings may help predict which patients with malignant potential need more intensive therapy, or may point to new therapeutic approaches especially for advanced tumors. The parameter here termed the integrated genomic prognostic biomarker may therefore be of clinical utility as a prognostic biomarker.
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Affiliation(s)
- Nobumoto Tomioka
- Department of General Surgery, Hokkaido University Graduate School of Medicine, N-15 W-7 Kita-ku, Sapporo, Japan.
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van Houte BPP, Heringa J. Accurate confidence aware clustering of array CGH tumor profiles. ACTA ACUST UNITED AC 2009; 26:6-14. [PMID: 19846437 DOI: 10.1093/bioinformatics/btp603] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
MOTIVATION Chromosomal aberrations tend to be characteristic for given (sub)types of cancer. Such aberrations can be detected with array comparative genomic hybridization (aCGH). Clustering aCGH tumor profiles aids in identifying chromosomal regions of interest and provides useful diagnostic information on the cancer type. An important issue here is to what extent individual aCGH tumor profiles can be reliably assigned to clusters associated with a given cancer type. RESULTS We introduce a novel evolutionary fuzzy clustering (EFC) algorithm, which is able to deal with overlapping clusterings. Our method assesses these overlaps by using cluster membership degrees, which we use here as a confidence measure for individual samples to be assigned to a given tumor type. We first demonstrate the usefulness of our method using a synthetic aCGH dataset and subsequently show that EFC outperforms existing methods on four real datasets of aCGH tumor profiles involving four different cancer types. We also show that in general best performance is obtained using 1- Pearson correlation coefficient as a distance measure and that extra preprocessing steps, such as segmentation and calling, lead to decreased clustering performance. AVAILABILITY The source code of the program is available from http://ibi.vu.nl/programs/efcwww
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Affiliation(s)
- Bart P P van Houte
- Centre for Integrative Bioinformatics VU (IBIVU), Faculty of Sciences and Faculty of Earth and Life Sciences, VU University Amsterdam, De Boelelaan 1081A, 1081 HV Amsterdam, The Netherlands
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Buffart TE, van Grieken NCT, Tijssen M, Coffa J, Ylstra B, Grabsch HI, van de Velde CJH, Carvalho B, Meijer GA. High resolution analysis of DNA copy-number aberrations of chromosomes 8, 13, and 20 in gastric cancers. Virchows Arch 2009; 455:213-23. [PMID: 19697059 PMCID: PMC2744787 DOI: 10.1007/s00428-009-0814-y] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2009] [Revised: 07/12/2009] [Accepted: 07/16/2009] [Indexed: 02/06/2023]
Abstract
DNA copy-number gains of chromosomes 8q, 13q, and 20q are frequently observed in gastric cancers. Moreover gain of chromosome 20q has been associated with lymph node metastasis. The aim of this study was to correlate DNA copy-number changes of individual genes on chromosomes 8q, 13q, and 20q in gastric adenocarcinomas to clinicopathological data. DNA isolated from 63 formalin-fixed and paraffin-embedded gastric adenocarcinoma tissue samples was analyzed by whole-genome microarray comparative genomic hybridization and by multiplex ligation-dependent probe amplification (MLPA), targeting 58 individual genes on chromosomes 8, 13, and 20. Using array comparative genomic hybridization, gains on 8q, 13q, and 20q were observed in 49 (77.8%), 25 (39.7%), and 49 (77.8%) gastric adenocarcinomas, respectively. Gain of chromosome 20q was significantly correlated with lymph node metastases (p = 0.05) and histological type (p = 0.02). MLPA revealed several genes to be frequently gained in DNA copy number. The oncogene c-myc on 8q was gained in 73% of the cancers, while FOXO1A and ATP7B on 13q were both gained in 28.6% of the cases. Multiple genes on chromosome 20q showed gains in more than 60% of the cancers. DNA copy-number gains of TNFRSF6B (20q13.3) and ZNF217 (20q13.2) were significantly associated with lymph node metastasis (p = 0.02) and histological type (p = 0.02), respectively. In summary, gains of chromosomes 8q, 13q, and 20q in gastric adenocarcinomas harbor DNA copy-number gains of known and putative oncogenes. ZNF217 and TNFRSF6B are associated with important clinicopathological variables, including lymph node status.
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Affiliation(s)
- Tineke E Buffart
- Department of Pathology, VU University Medical Center, PO Box 7057, 1007, Amsterdam, The Netherlands
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Abstract
Gastric cancer is the second most frequent cause of cancer death worldwide, although much geographical variation in incidence exists. Prevention and personalised treatment are regarded as the best options to reduce gastric cancer mortality rates. Prevention strategies should be based on specific risk profiles, including Helicobacter pylori genotype, host gene polymorphisms, presence of precursor lesions, and environmental factors. Although adequate surgery remains the cornerstone of gastric cancer treatment, this single modality treatment seems to have reached its maximum achievable effect for local control and survival. Minimally invasive techniques can be used for treatment of early gastric cancers. Achievement of locoregional control for advanced disease remains very difficult. Extended resections that are standard practice in some Asian countries have not been shown to be as effective in other developed countries. We present an update of the incidence, causes, pathology, and treatment of gastric cancer, consisting of surgery, new strategies with neoadjuvant and adjuvant chemotherapy or radiotherapy, or both, novel treatment strategies using gene signatures, and the effect of caseload on patient outcomes.
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Affiliation(s)
- Henk H Hartgrink
- Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
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26
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Hartgrink HH, Jansen EPM, van Grieken NCT, van de Velde CJH. Gastric cancer. LANCET (LONDON, ENGLAND) 2009. [PMID: 19625077 DOI: 10.1016/s0140-6736(09)] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Gastric cancer is the second most frequent cause of cancer death worldwide, although much geographical variation in incidence exists. Prevention and personalised treatment are regarded as the best options to reduce gastric cancer mortality rates. Prevention strategies should be based on specific risk profiles, including Helicobacter pylori genotype, host gene polymorphisms, presence of precursor lesions, and environmental factors. Although adequate surgery remains the cornerstone of gastric cancer treatment, this single modality treatment seems to have reached its maximum achievable effect for local control and survival. Minimally invasive techniques can be used for treatment of early gastric cancers. Achievement of locoregional control for advanced disease remains very difficult. Extended resections that are standard practice in some Asian countries have not been shown to be as effective in other developed countries. We present an update of the incidence, causes, pathology, and treatment of gastric cancer, consisting of surgery, new strategies with neoadjuvant and adjuvant chemotherapy or radiotherapy, or both, novel treatment strategies using gene signatures, and the effect of caseload on patient outcomes.
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Affiliation(s)
- Henk H Hartgrink
- Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
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27
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Buffart TE, Tijssen M, El-Bchiri J, Duval A, van de Wiel MA, Ylstra B, Meijer GA, Carvalho B. NMD inhibition fails to identify tumour suppressor genes in microsatellite stable gastric cancer cell lines. BMC Med Genomics 2009; 2:39. [PMID: 19563644 PMCID: PMC2709900 DOI: 10.1186/1755-8794-2-39] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2008] [Accepted: 06/29/2009] [Indexed: 12/05/2022] Open
Abstract
Background Gastric cancers frequently show chromosomal alterations which can cause activation of oncogenes, and/or inactivation of tumour suppressor genes. In gastric cancer several chromosomal regions are described to be frequently lost, but for most of the regions, no tumour suppressor genes have been identified yet. The present study aimed to identify tumour suppressor genes inactivated by nonsense mutation and deletion in gastric cancer by means of GINI (gene identification by nonsense mediated decay inhibition) and whole genome copy number analysis. Methods Two non-commercial gastric cancer cell lines, GP202 and IPA220, were transfected with siRNA directed against UPF1, to specifically inhibit the nonsense mediated decay (NMD) pathway, and with siRNA directed against non-specific siRNA duplexes (CVII) as a control. Microarray expression experiments were performed in triplicate on 4 × 44 K Agilent arrays by hybridizing RNA from UPF1-transfected cells against non-specific CVII-transfected cells. In addition, array CGH of the two cell lines was performed on 4 × 44K agilent arrays to obtain the DNA copy number profiles. Mutation analysis of GINI candidates was performed by sequencing. Results UPF1 expression was reduced for >70% and >80% in the GP202 and IPA220 gastric cancer cell lines, respectively. Integration of array CGH and microarray expression data provided a list of 134 and 50 candidate genes inactivated by nonsense mutation and deletion for GP202 and IPA220, respectively. We selected 12 candidate genes for mutation analysis. Of these, sequence analysis was performed on 11 genes. One gene, PLA2G4A, showed a silent mutation, and in two genes, CTSA and PTPRJ, missense mutations were detected. No nonsense mutations were detected in any of the 11 genes tested. Conclusion Although UPF1 was substantially repressed, thus resulting in the inhibition of the NMD system, we did not find genes inactivated by nonsense mutations. Our results show that the GINI strategy leads to a high number of false positives.
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Affiliation(s)
- Tineke E Buffart
- Dept Pathology, VU University Medical Center, Amsterdam, The Netherlands.
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Predicting node positivity in gastric cancer from gene expression profiles. Biotechnol Lett 2009; 31:1381-8. [DOI: 10.1007/s10529-009-0035-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2009] [Accepted: 05/07/2009] [Indexed: 01/25/2023]
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Mesenchymal stem cells from multiple myeloma patients display distinct genomic profile as compared with those from normal donors. Leukemia 2009; 23:1515-27. [PMID: 19357701 DOI: 10.1038/leu.2009.65] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
It is an open question whether in multiple myeloma (MM) bone marrow stromal cells contain genomic alterations, which may contribute to the pathogenesis of the disease. We conducted an array-based comparative genomic hybridization (array-CGH) analysis to compare the extent of unbalanced genomic alterations in mesenchymal stem cells from 21 myeloma patients (MM-MSCs) and 12 normal donors (ND-MSCs) after in vitro culture expansion. Whereas ND-MSCs were devoid of genomic imbalances, several non-recurrent chromosomal gains and losses (>1 Mb size) were detected in MM-MSCs. Using real-time reverse transcription PCR, we found correlative deregulated expression for five genes encoded in regions for which genomic imbalances were detected using array-CGH. In addition, only MM-MSCs showed a specific pattern of 'hot-spot' regions with discrete (<1 Mb) genomic alterations, some of which were confirmed using fluorescence in situ hybridization (FISH). Within MM-MSC samples, unsupervised cluster analysis did not correlate with particular clinicobiological features of MM patients. We also explored whether cytogenetic abnormalities present in myelomatous plasma cells (PCs) were shared by matching MSCs from the same patients using FISH. All MM-MSCs were cytogenetically normal for the tested genomic alterations. Therefore we cannot support a common progenitor for myeloma PCs and MSCs.
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Abstract
T-lymphocyte maturation associated protein, MAL, has been described as a tumour-suppressor gene with diagnostic value in colorectal and oesophageal cancers, and can be inactivated by promoter hypermethylation. The aim of this study was to analyse the prevalence of MAL promoter hypermethylation and the association with mRNA expression in gastric cancers and to correlate methylation status to clinicopathological data. Bisulphite-treated DNA isolated from formalin-fixed and paraffin-embedded samples of 202 gastric adenocarcinomas and 22 normal gastric mucosae was subjected to real-time methylation-specific PCR (Q-MSP). Two regions within the MAL promoter (M1 and M2) were analysed. In addition, 17 frozen gastric carcinomas and two gastric cancer cell lines were analysed both by Q-MSP and real-time RT–PCR. Methylation of M1 and M2 occurred in 71 and 80% of the gastric cancers, respectively, but not in normal gastric mucosa tissue. Hypermethylation of M2, but not M1, correlated with significantly better disease-free survival in a univariate (P=0.03) and multivariate analysis (P=0.03) and with downregulation of expression (P=0.01). These results indicate that MAL has a putative tumour-suppressor gene function in gastric cancer, and detection of promoter hypermethylation may be useful as a prognostic marker.
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31
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Panani AD. Cytogenetic and molecular aspects of gastric cancer: clinical implications. Cancer Lett 2008; 266:99-115. [PMID: 18381231 DOI: 10.1016/j.canlet.2008.02.053] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2007] [Revised: 02/05/2008] [Accepted: 02/22/2008] [Indexed: 12/13/2022]
Abstract
Gastric cancer is of major importance world-wide being the second most common cause of cancer-related death in the world. According to Lauren's histological classification gastric cancer is divided in two groups, the better differentiated intestinal carcinomas and the poorly differentiated diffuse-type cancers. The genetic changes underlying the initiation and progression of gastric cancer are not well defined. Gastric carcinogenesis is a multistep process involving a number of genetic and epigenetic factors. Although it has been proposed that different genetic pathways exist for differentiated and undifferentiated carcinomas, the two histological subtypes of gastric cancer share some common genetic alterations. Currently, tumor histology and pathologic stage are the major prognostic variables used in the clinical practice for gastric cancer patients. However, it is known that tumors with similar morphology may differ in biological aggressiveness, prognosis and response to treatment. Molecular genetic analysis of gastric cancer revealed a number of associations of certain genetic changes with pathological features, tumor biological behavior and prognosis of gastric cancer patients, suggesting that these genetic abnormalities might play an important role in gastric tumorigenesis. Increasing evidence suggests that the molecular genetic changes could be helpful in the clinical setting, contributing to prognosis and management of patients. Regarding epigenetic events in gastric tumorigenesis, a number of methylating markers have been proposed for risk assessment, prognostic evaluation and as therapeutic targets. However, further research is required in order to systematically investigate the genetic changes in gastric cancer estimating also their usefulness in the clinical practice. A good understanding of the genetic changes underlying gastric carcinogenesis may provide new perspectives for prognosis and screening of high risk individuals. Some of the genetic alterations could definitely improve tumor classification and management of gastric cancer patients. Also, based on molecular data identified in gastric cancer novel therapeutics might help to improve the treatment of this disease.
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Affiliation(s)
- Anna D Panani
- Critical Care Department, Medical School of Athens University, Cytogenetics Unit, Evangelismos Hospital, Ipsilandou 45-47, Athens 10676, Greece
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32
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Costa JL, Meijer G, Ylstra B, Caldas C. Array Comparative Genomic Hybridization Copy Number Profiling: A New Tool for Translational Research in Solid Malignancies. Semin Radiat Oncol 2008; 18:98-104. [DOI: 10.1016/j.semradonc.2007.10.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Chan P, Anguiano A, Hensley K, Keo N, Liu Y, Sarno R, Strom CM, Owen R. Clinical array comparative genomic hybridization: a new paradigm. EXPERT OPINION ON MEDICAL DIAGNOSTICS 2008; 2:449-459. [PMID: 23495710 DOI: 10.1517/17530059.2.4.449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
BACKGROUND Although the clinical utility of array comparative genomic hybridization (aCGH) is undisputed, the implementation of this technology is a unique experience for each laboratory. OBJECTIVE Endeavors to construct a bacterial artificial chromosome (BAC)-based CGH microarray targeting microdeletion and duplication syndromes related to mental retardation and developmental delay are described. METHOD Covering each chromosome at the 650-band level, the array comprises 1360 BAC clones with emphasis on the subtelomeric and pericentromeric regions and enrichment of genomic hot spots containing genes associated with specific constitutional disorders. During development of the array, fluorescence in situ hybridization (FISH) and end-sequencing analysis eliminated 24% of BACs that were mismapped or cross-hybridized, underscoring the need rigorously to assess arrayed elements. Performance of the BACs was tested further with chromosome-specific add-in experiments. CONCLUSION Of the first 500 clinical cases, 54 (11%) showed chromosome abnormalities, which were confirmed by FISH with BACs from the aberrant loci or by conventional cytogenetics. Array CGH is a powerful tool that is now being implemented in the realm of diagnostic testing.
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Affiliation(s)
- Patricia Chan
- Senior Scientist Quest Diagnostics Nichols Institute, Department of Cytogenetics, 33608 Ortega Highway San Juan Capistrano, CA 92675, USA +1 949 728 4805 ; +1 949 728 4979 ;
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Rivenbark AG, Coleman WB. Dissecting the molecular mechanisms of cancer through bioinformatics-based experimental approaches. J Cell Biochem 2007; 101:1074-86. [PMID: 17372928 DOI: 10.1002/jcb.21283] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Cancer is a disease of aberrant gene expression characterized by inappropriate (temporal or quantitative) expression of positive mediators of cell proliferation in conjunction with diminished expression of negative mediators of cell growth. Alteration of the normal balance of these positive and negative mediators leads to the abnormal growth of cells and tissues that typify neoplastic disease. Development of a better understanding of the genetic and epigenetic mechanisms that induce neoplastic transformation and drive the cancer phenotype is essential for continued progress towards the design of practical molecular diagnostics and effective treatment strategies. Over the past decades, molecular techniques that facilitate the assessment of gene expression, identification of gene mutations, and characterization of chromosome abnormalities (numeric and structural) have been established and applied to cancer research. However, many of these techniques are slow and labor-intensive. More recently, high-throughput technologies have emerged that generate large volumes of data related to the genetics and epigenetics of cancer (or other disorders). These advances in molecular genetic technology required the development of sophisticated bioinformatic tools to manage the large datasets generated. The combination of high-throughput molecular assays and bioinformatic-based data mining strategies has significantly impacted our understanding of the molecular pathogenesis of cancer, classification of tumors, and now the management of cancer patients in the clinic. This article will review basic molecular techniques and bioinformatic-based experimental approaches used to dissect the molecular mechanisms of carcinogenesis.
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Affiliation(s)
- Ashley G Rivenbark
- Department of Pathology and Laboratory Medicine, Curriculum in Toxicology, University of North Carolina Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
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Buffart TE, Carvalho B, Mons T, Reis RM, Moutinho C, Silva P, van Grieken NCT, Vieth M, Stolte M, van de Velde CJH, Schrock E, Matthaei A, Ylstra B, Carneiro F, Meijer GA. DNA copy number profiles of gastric cancer precursor lesions. BMC Genomics 2007; 8:345. [PMID: 17908304 PMCID: PMC2147033 DOI: 10.1186/1471-2164-8-345] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2007] [Accepted: 10/01/2007] [Indexed: 02/08/2023] Open
Abstract
Background Chromosomal instability (CIN) is the most prevalent type of genomic instability in gastric tumours, but its role in malignant transformation of the gastric mucosa is still obscure. In the present study, we set out to study whether two morphologically distinct categories of gastric cancer precursor lesions, i.e. intestinal-type and pyloric gland adenomas, would carry different patterns of DNA copy number changes, possibly reflecting distinct genetic pathways of gastric carcinogenesis in these two adenoma types. Results Using a 5K BAC array CGH platform, we showed that the most common aberrations shared by the 11 intestinal-type and 10 pyloric gland adenomas were gains of chromosomes 9 (29%), 11q (29%) and 20 (33%), and losses of chromosomes 13q (48%), 6(48%), 5(43%) and 10 (33%). The most frequent aberrations in intestinal-type gastric adenoma were gains on 11q, 9q and 8, and losses on chromosomes 5q, 6, 10 and 13, whereas in pyloric gland gastric adenomas these were gains on chromosome 20 and losses on 5q and 6. However, no significant differences were observed between the two adenoma types. Conclusion The results suggest that gains on chromosomes 8, 9q, 11q and 20, and losses on chromosomes 5q, 6, 10 and 13, likely represent early events in gastric carcinogenesis. The phenotypical entities, intestinal-type and pyloric gland adenomas, however, do not differ significantly (P = 0.8) at the level of DNA copy number changes.
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Affiliation(s)
- Tineke E Buffart
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
| | - Beatriz Carvalho
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
- Institute of Pathology and Molecular Immunology of University of Porto – IPATIMUP, Porto, Portugal
| | - Thomas Mons
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
| | - Rui M Reis
- Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, Portugal
| | - Cátia Moutinho
- Institute of Pathology and Molecular Immunology of University of Porto – IPATIMUP, Porto, Portugal
| | - Paula Silva
- Institute of Pathology and Molecular Immunology of University of Porto – IPATIMUP, Porto, Portugal
| | | | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | - Manfred Stolte
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | | | - Evelin Schrock
- Institute of Clinical Genetics, University of Technology, Dresden, Dresden, Germany
| | - Anja Matthaei
- Institute of Clinical Genetics, University of Technology, Dresden, Dresden, Germany
| | - Bauke Ylstra
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
| | - Fátima Carneiro
- Institute of Pathology and Molecular Immunology of University of Porto – IPATIMUP, Porto, Portugal
- Faculty of Medicine, University of Porto and Hospital, S. Joao, Porto, Portugal
| | - Gerrit A Meijer
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
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Shaikh TH. Oligonucleotide arrays for high-resolution analysis of copy number alteration in mental retardation/multiple congenital anomalies. Genet Med 2007; 9:617-25. [PMID: 17873650 DOI: 10.1097/gim.0b013e318148bb81] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Genetic diseases arising from microdeletions and microduplications lead to copy number alterations of genomic regions containing one or more genes. Clinically, these rearrangements may be detected by routine cytogenetic testing, which may include karyotype analysis, subtelomeric analysis with fluorescence in situ hybridization, and/or fluorescence in situ hybridization directed at known chromosomal rearrangement-based disorders. The major limitations of these tests are low resolution and limited coverage of the genome. Array-based comparative genomic hybridization has recently become a widely used approach in the genome-wide analysis of copy number alterations in children with mental retardation and/or multiple congenital anomalies. Oligonucleotide-based arrays provide a genome-wide coverage at a much higher resolution than microarrays currently used in clinical diagnostics, greatly improving the rate of detection of submicroscopic copy number alterations in children with mental retardation and/or multiple congenital anomalies.
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Affiliation(s)
- Tamim H Shaikh
- Division of Human Genetics, The Children's Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
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Kleivi K, Lind GE, Diep CB, Meling GI, Brandal LT, Nesland JM, Myklebost O, Rognum TO, Giercksky KE, Skotheim RI, Lothe RA. Gene expression profiles of primary colorectal carcinomas, liver metastases, and carcinomatoses. Mol Cancer 2007; 6:2. [PMID: 17201907 PMCID: PMC1770935 DOI: 10.1186/1476-4598-6-2] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2006] [Accepted: 01/03/2007] [Indexed: 01/27/2023] Open
Abstract
Background Despite the fact that metastases are the leading cause of colorectal cancer deaths, little is known about the underlying molecular changes in these advanced disease stages. Few have studied the overall gene expression levels in metastases from colorectal carcinomas, and so far, none has investigated the peritoneal carcinomatoses by use of DNA microarrays. Therefore, the aim of the present study is to investigate and compare the gene expression patterns of primary carcinomas (n = 18), liver metastases (n = 4), and carcinomatoses (n = 4), relative to normal samples from the large bowel. Results Transcriptome profiles of colorectal cancer metastases independent of tumor site, as well as separate profiles associated with primary carcinomas, liver metastases, or peritoneal carcinomatoses, were assessed by use of Bayesian statistics. Gains of chromosome arm 5p are common in peritoneal carcinomatoses and several candidate genes (including PTGER4, SKP2, and ZNF622) mapping to this region were overexpressed in the tumors. Expression signatures stratified on TP53 mutation status were identified across all tumors regardless of stage. Furthermore, the gene expression levels for the in vivo tumors were compared with an in vitro model consisting of cell lines representing all three tumor stages established from one patient. Conclusion By statistical analysis of gene expression data from primary colorectal carcinomas, liver metastases, and carcinomatoses, we are able to identify genetic patterns associated with the different stages of tumorigenesis.
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Affiliation(s)
- Kristine Kleivi
- Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway
- Medical Biotechnology VTT, Turku, Finland
| | - Guro E Lind
- Department of Cancer Prevention, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway
| | - Chieu B Diep
- Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway
| | - Gunn I Meling
- Surgical Department, Faculty Division Akershus University Hospital, Norway
| | - Lin T Brandal
- Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway
- Division of Infectious Disease Control, Norwegian Institute of Public Health, Oslo, Norway
| | - Jahn M Nesland
- Department of Pathology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway
| | - Ola Myklebost
- Department of Tumor Biology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway
- Department of Molecular Biosciences, University of Oslo, Norway
| | - Torleiv O Rognum
- Institute of Forensic Medicine, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway
| | - Karl-Erik Giercksky
- Department of Surgical Oncology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway
| | - Rolf I Skotheim
- Department of Cancer Prevention, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway
| | - Ragnhild A Lothe
- Department of Cancer Prevention, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway
- Department of Molecular Biosciences, University of Oslo, Norway
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Marchet A, Mocellin S, Belluco C, Ambrosi A, DeMarchi F, Mammano E, Digito M, Leon A, D'Arrigo A, Lise M, Nitti D. Gene expression profile of primary gastric cancer: towards the prediction of lymph node status. Ann Surg Oncol 2006; 14:1058-64. [PMID: 17106627 DOI: 10.1245/s10434-006-9090-0] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2006] [Revised: 06/05/2006] [Accepted: 06/05/2006] [Indexed: 12/17/2022]
Abstract
BACKGROUND The identification of gastric tumors associated with a higher risk of lymph node metastasis could help surgeons select patients who may benefit from extended lymph node dissection. The aim of this study was to screen the genome in the search of primary gastric cancer gene expression profiles that might predict lymph node status. METHODS The gene expression profile was evaluated in frozen tumor samples obtained from 32 patients with primary gastric adenocarcinomas. The array consisted of a duplicated spot panel of 5,541 human genes. To classify node-positive (N+) and node-negative (N-) cases, a logistic regression model was fitted optimizing the Akaike Information Criteria after a stepwise gene selection. The accuracy was evaluated by means of leave-one-out cross validation. RESULTS All patients underwent radical gastrectomy and extended lymphadenectomy. Of all the cases, 21 were N+ and 11 demonstrated no lymph node involvement (N-). After quality filtering, the analysis of variance selected a set of 136 genes potentially correlated with nodal involvement (P value <.05). Of these 136 genes, 5 were differentially expressed (adjusted P value <.05). After a stepwise gene selection, only three genes (Bik, aurora kinase B, eIF5A2) were retained in the logistic model, which could correctly predict lymph node status in 30 of 32 cases. CONCLUSIONS If our findings were confirmed, the identified gene pattern might be used to tailor the extent of lymph node dissection on a single patient basis.
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Affiliation(s)
- Alberto Marchet
- Clinica Chirurgica II, Dipartimento di Scienze Oncologiche e Chirurgiche, Istituto Oncologico Veneto IRCCS and University of Padova, Padova, Italy
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Abstract
Surgical resection with lymphadenectomy is the mainstay of treatment for all resectable esophagogastric junction tumors, prior to systemic generalization of the disease. This makes accurate pre-treatment staging and classification of the tumors most demanding. A well-established and internationally accepted classification for adenocarcinomas of the esophagogastric junction (AEG) helps to choose the appropriate surgical approach and to make results from different institutions comparable. Distal esophageal adenocarcinomas (AEGI) are distinguished from true cardia carcinomas (AEG II) and subcardiac gastric cancers (AEG III). Substantial advancements in this surgical field during the preceding decades have clearly revealed that individualization of the surgical strategy is the key to successfully approaching these entities. In this review we discuss the surgical management of esophagogastric junction tumors with a tailored surgical strategy.
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Affiliation(s)
- Burkhard H A von Rahden
- Department of Surgery, Technische Universitat Munchen, Ismaningerstr 22, Munchen D-81675, Germany.
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40
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The Signature from Messenger RNA Expression Profiling Can Predict Lymph Node Metastasis with High Accuracy for Non-small Cell Lung Cancer. J Thorac Oncol 2006. [DOI: 10.1016/s1556-0864(15)30373-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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41
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The Signature from Messenger RNA Expression Profiling Can Predict Lymph Node Metastasis with High Accuracy for Non-small Cell Lung Cancer. J Thorac Oncol 2006. [DOI: 10.1097/01243894-200609000-00005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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42
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Kubben FJGM, Sier CFM, Meijer MJW, van den Berg M, van der Reijden JJ, Griffioen G, van de Velde CJH, Lamers CBHW, Verspaget HW. Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer. Br J Cancer 2006; 95:744-51. [PMID: 16940985 PMCID: PMC2360506 DOI: 10.1038/sj.bjc.6603307] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Gastric cancers express enhanced levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Single-nucleotide polymorphisms (SNPs) in MMP and TIMP genes may be associated with disease susceptibility and might also affect their antigen expression. We studied the genotype distribution and allele frequencies of SNPs of MMP-2, -7, -8 and -9 and TIMP-1 and -2 in gastric cancer patients in relation to tumour progression, patient survival and tissue antigen expression. The genotype distribution and allele frequencies were similar in gastric cancer patients and controls, except for MMP-7−181A>G. In addition, the genotype distribution of MMP-7−181A>G was associated with Helicobacter pylori status (χ2 7.8, P=0.005) and tumour-related survival of the patients. Single-nucleotide polymorphism TIMP-2303C>T correlated significantly with the WHO classification (χ2 5.9, P=0.03) and also strongly with tumour-related survival (log rank 11.74, P=0.0006). Single-nucleotide polymorphisms of MMP-2, -8, -9 and TIMP-1 were not associated with tumour-related survival. Only the gene promoter MMP-2−1306C>T polymorphism correlated significantly with the protein level within the tumours. First-order dendrogram cluster analysis combined with Cox analysis identified the MMP-7−181A>G and TIMP-2303C>T polymorphism combination to have a major impact on patients survival outcome. We conclude that MMP-related SNPs, especially MMP-7−181A>G and TIMP-2303C>T, may be helpful in identifying gastric cancer patients with a poor clinical outcome.
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Affiliation(s)
- F J G M Kubben
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - C F M Sier
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - M J W Meijer
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - M van den Berg
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - J J van der Reijden
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - G Griffioen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - C J H van de Velde
- Department of Oncologic Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - C B H W Lamers
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - H W Verspaget
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
- E-mail:
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43
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Jong K, Marchiori E, van der Vaart A, Chin SF, Carvalho B, Tijssen M, Eijk PP, van den Ijssel P, Grabsch H, Quirke P, Oudejans JJ, Meijer GA, Caldas C, Ylstra B. Cross-platform array comparative genomic hybridization meta-analysis separates hematopoietic and mesenchymal from epithelial tumors. Oncogene 2006; 26:1499-506. [PMID: 16936777 DOI: 10.1038/sj.onc.1209919] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
A series of studies have been published that evaluate the chromosomal copy number changes of different tumor classes using array comparative genomic hybridization (array CGH); however, the chromosomal aberrations that distinguish the different tumor classes have not been fully characterized. Therefore, we performed a meta-analysis of different array CGH data sets in an attempt to classify samples tested across different platforms. As opposed to RNA expression, a common reference is used in dual channel CGH arrays: normal human DNA, theoretically facilitating cross-platform analysis. To this aim, cell line and primary cancer data sets from three different dual channel array CGH platforms obtained by four different institutes were integrated. The cell line data were used to develop preprocessing methods, which performed noise reduction and transformed samples into a common format. The transformed array CGH profiles allowed perfect clustering by cell line, but importantly not by platform or institute. The same preprocessing procedures used for the cell line data were applied to data from 373 primary tumors profiled by array CGH, including controls. Results indicated that there is no apparent feature related to the institute or platform and that array CGH allows for unambiguous cross-platform meta-analysis. Major clusters with common tissue origin were identified. Interestingly, tumors of hematopoietic and mesenchymal origins cluster separately from tumors of epithelial origin. Therefore, it can be concluded that chromosomal aberrations of tumors from hematopoietic and mesenchymal origin versus tumors of epithelial origin are distinct, and these differences can be picked up by meta-analysis of array CGH data. This suggests the possibility of prospectively using combined analysis of diverse copy number data sets for cancer subtype classification.
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Affiliation(s)
- K Jong
- Faculty of Sciences, Vrije Universiteit (VU), Amsterdam, The Netherlands
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44
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Abstract
Gastric and gastro-oesophageal cancers represent a global health problem. In recent years, there has been a marked increase in the incidence of proximal gastric and distal oesophageal adenocarcinomas. Surgery is the primary therapy for localised gastric or gastro-oesophageal cancer; however, patients treated with surgery have high rates of local and distant relapse as well as an unacceptably low 5-year survival rate. Chemoradiation and preoperative chemotherapy can play an important role for these patients. The outcome of patients with metastatic disease is very poor but a number of newer chemotherapy agents, such as docetaxel, oxaliplatin and S-1, have been identified and some have shown promising results. This article reviews recent trials on localised and metastatic gastric and gastro-oesophageal cancers.
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Affiliation(s)
- Prajnan Das
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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45
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Leung SY, Ho C, Tu IP, Li R, So S, Chu KM, Yuen ST, Chen X. Comprehensive analysis of 19q12 amplicon in human gastric cancers. Mod Pathol 2006; 19:854-63. [PMID: 16575401 DOI: 10.1038/modpathol.3800593] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Amplification at 19q12 has been observed in multiple tumor types, while cyclin E1 (CCNE1) has been considered to be the key oncogene within this amplicon. We have previously applied cDNA microarray analysis to systematically characterize gene expression patterns of gastric tumor and nontumor samples. We identified a cluster of five tightly coregulated genes all located at chromosome 19q12, including CCNE1. We found that the 19q12 gene cluster is highly expressed in gastric tumors compared to nontumor gastric samples. Array based comparative genomic hybridization and real-time PCR was used to define the boundary of the 19q12 amplicon to a region of approximately 200 kb. Interestingly, we found that in some cases amplification at 19q12 was not associated with DNA copy number gain at CCNE1, suggesting that some other genes within the 19q12 amplicon may also have important function during gastric tumorigenesis. We found high expression of the 19q12 gene cluster to be statistically correlated with the cell proliferation gene signature. Using the SAM software, we identified a set of 577 genes whose expression levels positively correlated with the 19q12 gene cluster. GO term analysis revealed that this genelist is enriched with genes involved in cell cycle regulation and cell proliferation. In conclusion, expression array analysis combined with array comparative genomic hybridization and real-time PCR provides a new and powerful tool to identify clusters of genes which may be regulated by genomic DNA aberrations. In addition, our study indicates that amplification at 19q12 is associated with cell proliferation in vivo.
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Affiliation(s)
- Suet Yi Leung
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
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46
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Lee CIP, Leong SH, Png AEH, Choo KW, Syn C, Lim DTH, Law HY, Kon OL. An isothermal method for whole genome amplification of fresh and degraded DNA for comparative genomic hybridization, genotyping and mutation detection. DNA Res 2006; 13:77-88. [PMID: 16766515 DOI: 10.1093/dnares/dsi029] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Molecular genotyping has important biomedical and forensic applications. However, limiting amounts of human biological material often yield genomic DNA (gDNA) in insufficient quantity and of poor quality for a reliable analysis. This motivated the development of an efficient whole genome amplification method with quantitatively unbiased representation usable on fresh and degraded gDNA. Amplification of fresh frozen, formalin-fixed paraffin-embedded (FFPE) and DNase-degraded DNA using degenerate oligonucleotide-primed PCR or primer extension amplification using a short primer sequence bioinformatically optimized for coverage of the human genome was compared with amplification using current primers by chromosome-based and BAC-array comparative genomic hybridization (CGH), genotyping at short tandem repeats (STRs) and single base mutation detection. Compared with current primers, genome amplification using the bioinformatically optimized primer was significantly less biased on CGH in self-self hybridizations, and replicated tumour genome copy number aberrations, even from FFPE tissue. STR genotyping could be performed on degraded gDNA amplified using our technique but failed with multiple displacement amplification. Of the 18 different single base mutations 16 (89.5%) were correctly identified by sequencing gDNA amplified from clinical samples using our technique. This simple and efficient isothermal method should be helpful for genetic research and clinical and forensic applications.
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Affiliation(s)
- Cheryl I P Lee
- Division of Medical Sciences, National Cancer Centre 11 Hospital Drive, Singapore 169610
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47
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Wu MS, Lin YS, Chang YT, Shun CT, Lin MT, Lin JT. Gene expression profiling of gastric cancer by microarray combined with laser capture microdissection. World J Gastroenterol 2006; 11:7405-12. [PMID: 16437709 PMCID: PMC4725172 DOI: 10.3748/wjg.v11.i47.7405] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To examine the gene expression profile of gastric cancer (GC) by combination of laser capture microdissection (LCM) and microarray and to correlate the profiling with histological subtypes. METHODS Using LCM, pure cancer cells were procured from 45 cancerous tissues. After procurement of about 5000 cells, total RNA was extracted and the quality of RNA was determined before further amplification and hybridization. One microgram of amplified RNA was converted to cDNA and hybridized to cDNA microarray. RESULTS Among 45 cases, only 21 were qualified for their RNAs. A total of 62 arrays were performed. These included 42 arrays for cancer (21 cases with dye-swab duplication) and 20 arrays for non-tumorous cells (10 cases with dye-swab duplication) with universal reference. Analyzed data showed 504 genes were differentially expressed and could distinguish cancerous and non-cancerous groups with more than 99% accuracy. Of the 504 genes, trefoil factors 1, 2, and 3 were in the list and their expression patterns were consistent with previous reports. Immunohistochemical staining of trefoil factor 1 was also consistent with the array data. Analyses of the tumor group with these 504 genes showed that there were 3 subgroups of GC that did not correspond to any current classification system, including Lauren's classification. CONCLUSION By using LCM, linear amplification of RNA, and cDNA microarray, we have identified a panel of genes that have the power to discriminate between GC and non-cancer groups. The new molecular classification and the identified novel genes in gastric carcinogenesis deserve further investigations to elucidate their clinicopathological significance.
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Affiliation(s)
- Ming-Shiang Wu
- Department of Internal Medicine and Primary Care Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, China
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48
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Ylstra B, van den Ijssel P, Carvalho B, Brakenhoff RH, Meijer GA. BAC to the future! or oligonucleotides: a perspective for micro array comparative genomic hybridization (array CGH). Nucleic Acids Res 2006; 34:445-50. [PMID: 16439806 PMCID: PMC1356528 DOI: 10.1093/nar/gkj456] [Citation(s) in RCA: 162] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The array CGH technique (Array Comparative Genome Hybridization) has been developed to detect chromosomal copy number changes on a genome-wide and/or high-resolution scale. It is used in human genetics and oncology, with great promise for clinical application. Until recently primarily PCR amplified bacterial artificial chromosomes (BACs) or cDNAs have been spotted as elements on the array. The large-scale DNA isolations or PCR amplifications of the large-insert clones necessary for manufacturing the arrays are elaborate and time-consuming. Lack of a high-resolution highly sensitive (commercial) alternative has undoubtedly hindered the implementation of array CGH in research and diagnostics. Recently, synthetic oligonucleotides as arrayed elements have been introduced as an alternative substrate for array CGH, both by academic institutions as well as by commercial providers. Oligonucleotide libraries or ready-made arrays can be bought off-the-shelf saving considerable time and efforts. For RNA expression profiling, we have seen a gradual transition from in-house printed cDNA-based expression arrays to oligonucleotide arrays and we expect a similar transition for array CGH. This review compares the different platforms and will attempt to shine a light on the ‘BAC to the future’ of the array CGH technique.
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Affiliation(s)
- Bauke Ylstra
- Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
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49
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Buffart TE, Carvalho B, Hopmans E, Brehm V, Kranenbarg EK, Schaaij-Visser TBM, Eijk PP, van Grieken NCT, Ylstra B, van de Velde CJH, Meijer GA. Gastric cancers in young and elderly patients show different genomic profiles. J Pathol 2006; 211:45-51. [PMID: 17117405 DOI: 10.1002/path.2085] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Although most gastric cancers occur in elderly patients, a substantial number of cases of this common disease occur in young patients. Gastric cancer is a heterogeneous disease at the genomic level and different patterns of DNA copy number alterations are associated with different clinical behaviour. The aim of the present study was to explore differences in DNA copy number alterations in relation to age of onset of gastric cancer. DNA isolated from 46 paraffin-embedded gastric cancer tissue samples from 17 patients less than 50 years of age [median 43 (21-49) years] and 29 patients greater than or equal to 70 years of age [median 75 (70-83) years] was analysed by genome-wide microarray comparative genomic hybridization (array CGH) using an array of 5000 BAC clones. Patterns of DNA copy number aberrations were analysed by hierarchical cluster analysis of the mode-normalized and smoothed log(2) ratios of tumour to normal reference fluorescence signal intensities using TMEV software, after which cluster membership was correlated with age group. In addition, supervised analysis was performed using CGH Multi-array. Hierarchical cluster analysis of the array CGH data revealed three clusters with different genomic profiles that correlated significantly with age (p = 0.006). Cluster 1 mainly contained young patients, while elderly patients were divided over clusters 2 and 3. Chromosome regions 11q23.3 and 19p13.3 contributed most to age-related differences in tumour profiles. Gastric cancers of young and old patients belong to groups with different genomic profiles, which likely reflect different pathogenic mechanisms of the disease.
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Affiliation(s)
- T E Buffart
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
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50
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Abstract
Chromosome abnormalities have long been recognised as an important cause of learning disability and multiple malformation syndromes; 0.8% of live born infants have numerical or structural chromosomal anomalies resulting in an abnormal phenotype. The identification of such anomalies is important, both clinically and for accurate genetic counselling. Recently, the human genome sequence has enabled higher resolution screens for chromosome anomalies using both molecular cytogenetic and array based techniques. This review suggests a simple algorithm for the targeted use of diagnostic cytogenetic tools in specific patient groups commonly seen in paediatric practice.
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