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Pádua D, Figueira P, Ribeiro I, Almeida R, Mesquita P. The Relevance of Transcription Factors in Gastric and Colorectal Cancer Stem Cells Identification and Eradication. Front Cell Dev Biol 2020; 8:442. [PMID: 32626705 PMCID: PMC7314965 DOI: 10.3389/fcell.2020.00442] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 05/11/2020] [Indexed: 12/12/2022] Open
Abstract
Gastric and colorectal cancers have a high incidence and mortality worldwide. The presence of cancer stem cells (CSCs) within the tumor mass has been indicated as the main reason for tumor relapse, metastasis and therapy resistance, leading to poor overall survival. Thus, the elimination of CSCs became a crucial goal for cancer treatment. The identification of these cells has been performed by using cell-surface markers, a reliable approach, however it lacks specificity and usually differs among tumor type and in some cases even within the same type. In theory, the ideal CSC markers are those that are required to maintain their stemness features. The knowledge that CSCs exhibit characteristics comparable to normal stem cells that could be associated with the expression of similar transcription factors (TFs) including SOX2, OCT4, NANOG, KLF4 and c-Myc, and signaling pathways such as the Wnt/β-catenin, Hedgehog (Hh), Notch and PI3K/AKT/mTOR directed the attention to the use of these similarities to identify and target CSCs in different tumor types. Several studies have demonstrated that the abnormal expression of some TFs and the dysregulation of signaling pathways are associated with tumorigenesis and CSC phenotype. The disclosure of common and appropriate biomarkers for CSCs will provide an incredible tool for cancer prognosis and treatment. Therefore, this review aims to gather the new insights in gastric and colorectal CSC identification specially by using TFs as biomarkers and divulge promising drugs that have been found and tested for targeting these cells.
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Affiliation(s)
- Diana Pádua
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Paula Figueira
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Inês Ribeiro
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Raquel Almeida
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Biology, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Patrícia Mesquita
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
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Aberrant DNA Polymerase Beta Enhances H. pylori Infection Induced Genomic Instability and Gastric Carcinogenesis in Mice. Cancers (Basel) 2019; 11:cancers11060843. [PMID: 31216714 PMCID: PMC6627457 DOI: 10.3390/cancers11060843] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 06/11/2019] [Accepted: 06/14/2019] [Indexed: 11/16/2022] Open
Abstract
H. pylori is a significant risk factor of gastric cancer that induces chronic inflammation and oxidative DNA damage to promote gastric carcinoma. Base excision repair (BER) is required to maintain the genome integrity and prevent oxidative DNA damage. Mutation in DNA polymerase beta (Pol β) impacts BER efficiency and has been reported in approximately 30-40% of gastric carcinoma tumors. In this study, we examined whether reduced BER capacity associated with mutation in the POLB gene, along with increased DNA damage generated by H. pylori infection, accelerates gastric cancer development. By infecting a Pol β mutant mouse model that lacks dRP lyase with H. pylori, we show that reactive oxygen and nitrogen species (RONS) mediated DNA damage is accumulated in Pol β mutant mice (L22P). In addition, H. pylori infection in Leu22Pro (L22P) mice significantly increases inducible nitric oxide synthesis (iNOS) mediated chronic inflammation. Our data show that L22P mice exhibited accelerated H. pylori induced carcinogenesis and increased tumor incidence. This work shows that Pol β mediated DNA repair under chronic inflammation conditions is an important suppressor of H. pylori induced stomach carcinogenesis.
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Li FQ, Chiriboga L, Black MA, Takemaru KI, Raffaniello RD. Chibby is a weak regulator of β-catenin activity in gastric epithelium. J Cell Physiol 2018; 234:1871-1879. [PMID: 30063079 DOI: 10.1002/jcp.27062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 06/26/2018] [Indexed: 11/06/2022]
Abstract
The canonical Wnt-β-catenin pathway is important in normal development. Mutations in β-catenin or proteins involved with regulating its phosphorylation or localization result in its nuclear accumulation where it activates its target genes and stimulates cell proliferation. This pathway is dysregulated in many different types of cancer, including gastric cancer (GC). Chibby (Cby) is a 14-kDa protein that inhibits β-catenin localization to the nucleus and represses β-catenin-induced transcriptional activity. In the current study, we examined the expression and function of Cby in normal and cancerous human gastric tissue. Reverse-transcription polymerase chain reaction and immunohistochemistry revealed that Cby is expressed in human stomach and localized to glandular elements. Immunohistochemical staining intensity of Cby was decreased in GC tissue when compared with normal gastric epithelium. In AGS cells, a human gastric carcinoma cell line, Cby expression was low. Stable AGS cell transfectants overexpressing Cby were prepared. Cby overexpression did not affect proliferation rates or β-catenin levels. However, confocal microscopy and subcellular fractionation studies revealed that Cby overexpression resulted in a small decrease in nuclear β-catenin. Moreover, Cby overexpression caused a molecular weight shift in nuclear β-catenin and resulted in decreased β-catenin signaling in AGS cells as measured by the TopFlash assay. However, Cby overexpression did not affect c-Myc protein levels. To conclude, Cby expression was decreased in GC samples and Cby expression altered β-catenin localization in cultured GC cells. However, Cby did not affect cell proliferation rates or β-catenin-induced protein expression. Cby may be involved in the early events in the pathogenesis of GC.
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Affiliation(s)
- Feng-Qian Li
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York
| | - Luis Chiriboga
- Department of Pathology, New York University Langone Medical Center, New York
| | - Margaret A Black
- Department of Pathology, New York University Langone Medical Center, New York
| | - Ken-Ichi Takemaru
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York
| | - Robert D Raffaniello
- Department of Medical Laboratory Sciences, Hunter College, School of Arts and Sciences, New York
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Sepulveda AR, J. Del Portillo A. Molecular Basis of Diseases of the Gastrointestinal Tract. MOLECULAR PATHOLOGY 2018:387-415. [DOI: 10.1016/b978-0-12-802761-5.00019-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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5
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Murakami T, Mitomi H, Yao T, Saito T, Shibuya T, Watanabe S. Epigenetic regulation of Wnt/β-catenin signal-associated genes in gastric neoplasia of the fundic gland (chief cell-predominant) type. Pathol Int 2017; 67:147-155. [PMID: 28105693 DOI: 10.1111/pin.12509] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 12/28/2016] [Indexed: 12/13/2022]
Abstract
Gastric neoplasia of the fundic gland (chief cell-predominant) type (GNCCP) is a rare variant of gastric tumor. This tumor is associated with activation of the Wnt/β-catenin signaling pathway; however, the mechanisms underlying this activation remain unknown. To elucidate potential roles of Wnt/β-catenin signal-associated gene methylation in GNCCP, we performed β-catenin immunostaining and methylation-specific polymerase chain reaction (PCR) for their associated genes, including SFRPs, APC, AXIN2, and MCC, in 26 GNCCPs [i.e., 11 intramucosal (GNCCP-Ms) and 15 submucosal tumors (GNCCP-SMs)], and compared with 27 fundic gland polyps (FGPs), 12 FGPs with dysplasia (FGP-Ds), 27 conventional gastric adenocarcinomas (CGAs). Nuclear β-catenin labeling indices were higher in GNCCPs and CGAs than in FGPs and FGP-Ds. SFRPs, APC, and AXIN2 were more frequently methylated in GNCCPs and CGAs (SFRP1, 88%/96%; SFRP2, 85%/93%; SFRP4, 73%/81%; APC, 81%/81%; AXIN2, 81%/85%; respectively) than in FGPs and FGP-Ds (37%/50%; 41%/42%; 41%/58%; 37%/33%; 41%/50%; respectively). A significant correlation was seen between nuclear β-catenin expression and methylation of SFRP1 in GNCCPs. Furthermore, nuclear β-catenin expression was significantly frequent in high-methylated GNCCPs than in low-methylated tumors. In conclusion, our results suggest that activation of this pathway, mediated by gene methylation, may be associated with progression of some GNCCP cases, similar to CGAs.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hiroyuki Mitomi
- Department of Pathology, Japan Labor Health and Welfare Organization, Kanto Rosai Hospital, Kanagawa, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tomoyoshi Shibuya
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Sumio Watanabe
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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Jin EH, Lee SI, Kim J, Seo EY, Lee SY, Hur GM, Shin S, Hong JH. Association between Promoter Polymorphisms of TFF1, TFF2, and TFF3 and the Risk of Gastric and Diffuse Gastric Cancers in a Korean Population. J Korean Med Sci 2015; 30:1035-41. [PMID: 26240479 PMCID: PMC4520932 DOI: 10.3346/jkms.2015.30.8.1035] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 04/17/2015] [Indexed: 01/26/2023] Open
Abstract
Gastric cancer is one of the most common cancers in the world. The aims of this study were to evaluate the association between polymorphisms in TFF gene family, TFF1, TFF2, and TFF3 and the risk of gastric cancer (GC) and GC subgroups in a Korean population via a case-control study. The eight polymorphisms in TFF gene family were identified by sequencing and genotyped with 377 GC patients and 396 controls by using TaqMan genotyping assay. The rs184432 TT genotype of TFF1 was significantly associated with a reduced risk of GC (odds ratio, [OR) = 0.45; 95% confidence interval, [CI] = 0.25-0.82; P = 0.009), more protective against diffuse-type GC (OR = 0.20; 95% CI = 0.05-0.89; P = 0.035) than GC (OR = 0.34; 95% CI = 0.14-0.82; P = 0.017) in subjects aged < 60 yr, and correlated with lymph node metastasis negative GC and diffuse-type GC (OR = 0.44; 95% CI = 0.23-0.86; P = 0.016 and OR = 0.20; 95% CI = 0.05-0.87; P = 0.031, respectively). In addition, a decreased risk of lymph node metastasis negative GC and diffuse-type GC was observed for rs225359 TT genotype of TFF1 (OR = 0.46, 95% CI = 0.24-0.88; P = 0.020 and OR = 0.21, 95% CI = 0.05-0.88; P = 0.033, respectively). These findings suggest that the rs184432 and rs225359 polymorphisms in TFF1 have protective effects for GC and contribute to the development of GC in Korean individuals.
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Affiliation(s)
- Eun-Heui Jin
- Clinical Trials Center, Chungnam National University Hospital, Daejeon, Korea
| | - Sang-Il Lee
- Department of Surgery, Chungnam National University Hospital, Daejeon, Korea
| | - JaeWoo Kim
- Clinical Trials Center, Chungnam National University Hospital, Daejeon, Korea
| | - Eun Young Seo
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea
| | - Su Yel Lee
- National Biobank of Korea, Chungnam National University Hospital, Daejeon, Korea
| | - Gang Min Hur
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, Korea
| | - Sanghee Shin
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, Korea
| | - Jang Hee Hong
- Clinical Trials Center, Chungnam National University Hospital, Daejeon, Korea
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, Korea
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Chiurillo MA. Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review. World J Exp Med 2015; 5:84-102. [PMID: 25992323 PMCID: PMC4436943 DOI: 10.5493/wjem.v5.i2.84] [Citation(s) in RCA: 244] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Revised: 12/05/2014] [Accepted: 03/20/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer remains one of the most common cancers worldwide and one of the leading cause for cancer-related deaths. Gastric adenocarcinoma is a multifactorial disease that is genetically, cytologically and architecturally more heterogeneous than other gastrointestinal carcinomas. The aberrant activation of the Wnt/β-catenin signaling pathway is involved in the development and progression of a significant proportion of gastric cancer cases. This review focuses on the participation of the Wnt/β-catenin pathway in gastric cancer by offering an analysis of the relevant literature published in this field. Indeed, it is discussed the role of key factors in Wnt/β-catenin signaling and their downstream effectors regulating processes involved in tumor initiation, tumor growth, metastasis and resistance to therapy. Available data indicate that constitutive Wnt signalling resulting from Helicobacter pylori infection and inactivation of Wnt inhibitors (mainly by inactivating mutations and promoter hypermethylation) play an important role in gastric cancer. Moreover, a number of recent studies confirmed CTNNB1 and APC as driver genes in gastric cancer. The identification of specific membrane, intracellular, and extracellular components of the Wnt pathway has revealed potential targets for gastric cancer therapy. High-throughput “omics” approaches will help in the search for Wnt pathway antagonist in the near future.
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Abstract
Gastric cancer is an aggressive disease that continues to have a daunting impact on global health. Despite an overall decline in incidence over the last several decades, gastric cancer remains the fourth most common type of cancer and is the second leading cause of cancer-related death worldwide. This review aims to discuss the global distribution of the disease and the trend of decreasing incidence of disease, delineate the different pathologic subtypes and their immunohistochemical (IHC) staining patterns and molecular signatures and mutations, explore the role of the pathogen H. pylori in tumorgenesis, discuss the increasing incidence of the disease in the young, western populations and define the role of biologic agents in the treatment of the disease.
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Affiliation(s)
- Lauren Peirce Carcas
- Department of Hematology and Oncology Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA
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9
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Cho M, Eze O, Xu R. Molecular genetics of gastric adenocarcinoma in clinical practice. World J Med Genet 2014; 4:58-68. [DOI: 10.5496/wjmg.v4.i3.58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Accepted: 05/16/2014] [Indexed: 02/06/2023] Open
Abstract
The molecular genetics of gastric carcinoma (GC) dictates their biology and clinical behavior. The two morphologically distinct types of gastric carcinoma by Lauren classification, i.e., intestinal and diffuse cell types, have a significant difference in clinical outcome. These two types of GC have different molecular pathogenetic pathways with unique genetic alterations. In addition to environmental and other etiologies, intestinal type GC is associated with Helicobacter pylori (H. pylori) infection and involves a multistep molecular pathway driving the normal epithelium to intestinal metaplasia, dysplasia, and malignant transformation by chromosomal and/or microsatellite instability (MSI), mutation of tumor suppressor genes, and loss of heterozygosity among others. Diffuse type shows no clear causal relationship with H. pylori infection, but is commonly associated with deficiency of cell-cell adhesion due to mutation of the E-cadherin gene (CDH1), and a manifestation of the hereditary gastric cancer syndrome. Thus, detection of CDH1 mutation or loss of expression of E-cadherin may aid in early diagnosis or screening of diffuse type GC. Detection of certain genetic markers, for example, MSI and matrix metalloproteinases, may provide prognostic information, particularly for intestinal type. The common genetic alterations may offer therapeutic targets for treatment of GC. Polymorphisms in Thymidylate synthase to metabolize 5-fluorouracil, glutathione S-transferase for degradation of Cisplatin, and amplification/overexpression of human epidermal growth factor receptor 2 targeted by monoclonal antibody Trastuzumab, are a few examples. P13K/Akt/mTOR pathway, c-Met pathways, epidermal growth factor receptor, insulin-like growth factor receptor, vascular endothelial growth factor receptor fibroblast growth factor receptor, and micro RNAs are several potential therapeutic biomarkers for GC under investigation.
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Radulescu S, Ridgway RA, Cordero J, Athineos D, Salgueiro P, Poulsom R, Neumann J, Jung A, Patel S, Woodgett J, Barker N, Pritchard DM, Oien K, Sansom OJ. Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation. Oncogene 2013; 32:2048-57. [PMID: 22665058 PMCID: PMC3631308 DOI: 10.1038/onc.2012.224] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Revised: 04/13/2012] [Accepted: 04/22/2012] [Indexed: 02/08/2023]
Abstract
A role for WNT signalling in gastric carcinogenesis has been suggested due to two major observations. First, patients with germline mutations in adenomatous polyposis coli (APC) are susceptible to stomach polyps and second, in gastric cancer, WNT activation confers a poor prognosis. However, the functional significance of deregulated WNT signalling in gastric homoeostasis and cancer is still unclear. In this study we have addressed this by investigating the immediate effects of WNT signalling activation within the stomach epithelium. We have specifically activated the WNT signalling pathway within the mouse adult gastric epithelium via deletion of either glycogen synthase kinase 3 (GSK3) or APC or via expression of a constitutively active β-catenin protein. WNT pathway deregulation dramatically affects stomach homoeostasis at very short latencies. In the corpus, there is rapid loss of parietal cells with fundic gland polyp (FGP) formation and adenomatous change, which are similar to those observed in familial adenomatous polyposis. In the antrum, adenomas occur from 4 days post-WNT activation. Taken together, these data show a pivotal role for WNT signalling in gastric homoeostasis, FGP formation and adenomagenesis. Loss of the parietal cell population and corresponding FGP formation, an early event in gastric carcinogenesis, as well as antral adenoma formation are immediate effects of nuclear β-catenin translocation and WNT target gene expression. Furthermore, our inducible murine model will permit a better understanding of the molecular changes required to drive tumourigenesis in the stomach.
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Affiliation(s)
- S Radulescu
- CR-UK Beatson Institute of Cancer Research, Glasgow, UK
| | - R A Ridgway
- CR-UK Beatson Institute of Cancer Research, Glasgow, UK
| | - J Cordero
- CR-UK Beatson Institute of Cancer Research, Glasgow, UK
| | - D Athineos
- CR-UK Beatson Institute of Cancer Research, Glasgow, UK
| | - P Salgueiro
- CR-UK Beatson Institute of Cancer Research, Glasgow, UK
- Institute of Medical Biology, A*STAR, 8A Biomedical Grove, Immunos, Singapore
| | - R Poulsom
- Histopathology Lab, CR-UK London Research Institute, London, UK
| | - J Neumann
- Pathologisches Institut, Ludwig-Maximilians Universität München, München, Germany
| | - A Jung
- Pathologisches Institut, Ludwig-Maximilians Universität München, München, Germany
| | - S Patel
- Samuel Lunenfeld Research Institute, Toronto, ON, Canada
| | - J Woodgett
- Samuel Lunenfeld Research Institute, Toronto, ON, Canada
| | - N Barker
- Institute of Medical Biology, A*STAR, 8A Biomedical Grove, Immunos, Singapore
| | - D M Pritchard
- Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - K Oien
- Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - O J Sansom
- CR-UK Beatson Institute of Cancer Research, Glasgow, UK
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Abstract
Helicobacter pylori infection leads to long-lasting chronic inflammation and represents the most common risk factor underlying gastric cancer. Recently, new insights into the mechanisms through which H. pylori and mucosal inflammation lead to cancer development have emerged. H. pylori virulence factors, in particular specific CagA genotypes, represent main factors in gastric cancer, inducing altered intracellular signaling in epithelial cells. The chronic nature of H. pylori infection appears to relate to the VacA virulence factor and Th17/Treg mechanisms. A role of H. pylori infection in epigenetic and microRNA deregulation has been shown. Mutation of the epithelial cell genome, a hallmark of cancer, was demonstrated to accumulate in H. pylori infected stomach partly due to inadequate DNA repair. Gastric stem cells were shown to be targets of oxidative injury in the Helicobacter-inflammatory milieu. Recent advances emphasizing the contribution of bacterial factors, inflammatory mediators, and the host epithelial response in gastric carcinogenesis are reviewed.
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Yoon SN, Oh ST, Lim SB, Kim TW, Kim JH, Yu CS, Kim JC. Clinicopathologic characteristics of colorectal cancer patients with synchronous and metachronous gastric cancer. World J Surg 2010; 34:2168-76. [PMID: 20532772 DOI: 10.1007/s00268-010-0623-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND We investigated the characteristics of synchronous and metachronous gastric cancer in patients with colorectal cancer. METHODS We reviewed 8,680 patients who underwent operations for primary sporadic colorectal cancer from 1989 to 2008. Synchronous gastric cancer was defined as gastric cancer diagnosed within 6 months of a colorectal cancer diagnosis. Gastric cancer diagnosed more than 6 months before or after colorectal cancer was defined as metachronous. RESULTS The incidences of synchronous and metachronous gastric cancer were 0.93 and 1.4%, respectively (combined 2.4%). The standardized incidence ratio was 1.199 (95% confidence interval [CI] = 1.005-1.420) when the patients with premetachronous gastric cancer were excluded. Patients with synchronous and metachronous gastric cancer were 5 years older on average compared to the control population without gastric cancer. In addition, multivariate analysis revealed an odds ratio (OR) of 3.6 for being male, OR = 2 for positive family history of solid tumors, OR = 2.2 for colonic lesion, and OR = 4 for MSH2 expression loss compared to patients without gastric cancer. Patients with postmetachronous gastric cancer (when compared to synchronous and premetachronous gastric cancer), a preoperative CEA level of less than 6 ng/ml, and a relatively early stage of colorectal cancer had significantly higher overall (p = 0.016, 0.007, and 0.004, respectively) and disease-free survival rates (p = 0.046, 0.003, and 0.004, respectively), only on univariate analysis. Lymphovascular invasion of colorectal cancer and an advanced stage of gastric cancer were independent poor prognostic factors for both overall (p = 0.018) and disease-free survival (p = 0.028). CONCLUSIONS Gastric cancer surveillance is recommended for patients with colorectal cancer, especially when the patient is old and male, has a positive family history of solid tumors, has a colonic lesion, or lacks MSH2 expression.
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Affiliation(s)
- Sang Nam Yoon
- Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, 388-1 Poongnap-dong, Songpa-gu, Seoul 138-736, Korea.
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13
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Sepulveda AR, Aisner DL. Molecular Basis of Diseases of the Gastrointestinal Tract. MOLECULAR PATHOLOGY 2009:365-393. [DOI: 10.1016/b978-0-12-374419-7.00019-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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14
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Srivastava A, Lauwers GY. Gastric epithelial dysplasia: the Western perspective. Dig Liver Dis 2008; 40:641-9. [PMID: 18424243 DOI: 10.1016/j.dld.2008.02.039] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2008] [Revised: 02/25/2008] [Accepted: 02/26/2008] [Indexed: 12/11/2022]
Abstract
The need for early diagnosis of gastric cancer is emphasized by the fact that gastric cancer remains the second most common cause of cancer related deaths worldwide. The aggressive surveillance and definite therapy for low and high-grade dysplasia, which can be achieved endoscopic means, remains the cornerstone of clinical management. Although the precursor status of dysplasia is not contested, its classification is controversial and fraught with marked inter-observer variations. Most cases of gastric dysplasia have an "intestinal" phenotype referred to as adenomatous dysplasia. Hyperplastic (type II dysplasia) is another less common variant. The progression of dysplasia to carcinoma is paralleled by a stepwise accumulation of multiple, but yet uncertain, genetic abnormalities. There are no immunohistochemical or molecular assays that can stratify with certainty the risk of progression to cancer. Given the low rate of transformation of low-grade dysplasia, annual endoscopic surveillance with re-biopsy is advocated. A diagnosis of indefinite for dysplasia should also prompt endoscopic surveillance. A diagnosis of high-grade dysplasia is more ominous, since it progress to cancer in most cases. However, the novel imaging and endoscopic modalities have modified management strategies with mucosal lesions amenable to endoscopic resection, while surgical resection is reserved to invasive adenocarcinoma with submucosal invasion.
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Affiliation(s)
- A Srivastava
- Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
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15
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Lauwers GY, Srivastava A. Gastric preneoplastic lesions and epithelial dysplasia. Gastroenterol Clin North Am 2007; 36:813-29, vi. [PMID: 17996792 DOI: 10.1016/j.gtc.2007.08.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The incidence of gastric cancer is declining; however, it remains the second most common cause of cancer-related deaths worldwide. This article describes gastric preneoplastic lesions and epithelial dysplasia. The possible role of Helicobacter pylori infection is emphasized.
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Affiliation(s)
- Gregory Y Lauwers
- Department of Pathology, Massachusetts General Hospital, Gastrointestinal Pathology Service, 55 Fruit Street, Warren 2, Boston, MA 02114-2696, USA.
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16
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Vogiatzi P, Vindigni C, Roviello F, Renieri A, Giordano A. Deciphering the underlying genetic and epigenetic events leading to gastric carcinogenesis. J Cell Physiol 2007; 211:287-95. [PMID: 17238139 DOI: 10.1002/jcp.20982] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Gastric cancer is a common aggressive malignancy. Although its incidence shows considerable variation among different countries, gastric cancer is still a major health problem worldwide. The causes of stomach cancer are not completely understood. What is clear is that gastric cancer is a multi-stage process involving genetic and epigenetic factors. This review is an in-depth study of the known genetic and epigenetic processes in the development of this tumor, and delineates possible approaches in gene and epigenetic therapy.
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Affiliation(s)
- Paraskevi Vogiatzi
- Department of Molecular Biology, Medical Genetics, University of Siena, Siena, Italy
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Yamazaki K, Tajima Y, Makino R, Nishino N, Aoki S, Kato M, Sakamoto M, Morohara K, Kaetsu T, Kusano M. Tumor differentiation phenotype in gastric differentiated-type tumors and its relation to tumor invasion and genetic alterations. World J Gastroenterol 2006; 12:3803-9. [PMID: 16804962 PMCID: PMC4087925 DOI: 10.3748/wjg.v12.i24.3803] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To clarify the relations between tumor differentiation phenotype and tumor invasion or genetic alterations in gastric differentiated-type tumors.
METHODS: We examined the tumor differentiation phenotype, the presence of mutations in APC and p53, and the microsatellite instability (MSI) status in 48 gastric adenomas and 171 differentiated-type carcinomas. The tumor differentiation phenotype was determined by examining the expression of human gastric mucin (HGM), MUC6, MUC2 and CD10. The tumors were then classified into gastric- (G-), gastric and intestinal mixed- (GI-), or intestinal- (I-) phenotypes, according to the immunopositivity of the above markers. The presence of mutations in APC and p53 and the MSI status were also investigated in all the tumors.
RESULTS: Gastric adenomas were significantly associated with CD10 expression, I-phenotype tumors and the presence of APC mutations, compared with carcinomas (66.7% vs 25.1%, P < 0.0001; 56.3% vs 14.6%, P < 0.0001; 39.6% vs 14.0%, P < 0.0001, respectively) and inversely associated with expressions of HGM and MUC6 and the presence of p53 mutations (10.4% vs 62.6%, P < 0.0001; 39.6% vs 64.3%, P = 0.003; 2.0% vs 26.3%, P = 0.001, respectively). The frequency of APC mutations was significantly higher in HGM-negative tumors, MUC6-negative tumors, CD10-positive tumors and I-phenotype tumors than in HGM-positive tumors, MUC6-positive tumors, CD10-negative tumors and G-phenotype tumors (32.7% vs 7.1%, P < 0.0001; 27.8% vs 14.0%, P = 0.0182; 37.3% vs 10.4%, P < 0.0001; and 38.5% vs 9.5%, P = 0.0017, respectively). The frequency of MSI was significantly higher in MUC6-positive tumors, CD10-negative tumors and G-phenotype tumors than in MUC6-negative tumors, CD10-positive tumors and I-phenotype tumors (24.8% vs 6.7%, P = 0.0009; 22.2% vs 8.0%, P = 0.0143; and 28.6% vs 9.6%, P = 0.0353, respectively).
CONCLUSION: The tumor differentiation phenotype is closely related to tumor invasion and genetic alterations in gastric differentiated-type tumors.
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Affiliation(s)
- Kimiyasu Yamazaki
- Department of Surgery, Division of General and Gastroenterological Surgery, Showa University, School of Medicine, Tokyo, Japan
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18
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Abstract
Gastric cancer remains a global killer with a shifting burden from the developed to the developing world. The cancer develops along a multistage process that is defined by distinct histological and pathophysiological phases. Several genetic and epigenetic alterations mediate the transition from one stage to another and these include mutations in oncogenes, tumour suppressor genes and cell cycle and mismatch repair genes. The most significant advance in the fight against gastric caner came with the recognition of the role of Helicobacter pylori (H pylori) as the most important acquired aetiological agent for this cancer. Recent work has focussed on elucidating the complex host/microbial interactions that underlie the neoplastic process. There is now considerable insight into the pathogenesis of this cancer and the prospect of preventing and eradicating the disease has become a reality. Perhaps more importantly, the study of H pylori-induced gastric carcinogenesis offers a paradigm for understanding more complex human cancers. In this review, we examine the molecular and cellular events that underlie H pylori-induced gastric cancer.
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Affiliation(s)
- Malcolm-G Smith
- Department of Medicine and Therapeutics, Institute of Medical Sciences, Aberdeen University, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom
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19
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Abstract
Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes, have been extensively studied in gastric carcinoma and play important roles in gastric carcinogenesis. This review will briefly discuss the basic aspects of DNA methylation and CpG island methylation, in particular the epigenetic alterations of certain critical genes implicated in gastric carcinogenesis and its relevance of clinical implications.
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Affiliation(s)
- In Seon Choi
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA
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20
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Gologan A, Graham DY, Sepulveda AR. Molecular markers in Helicobacter pylori-associated gastric carcinogenesis. Clin Lab Med 2005; 25:197-222. [PMID: 15749238 DOI: 10.1016/j.cll.2004.12.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Helicobacter pylori infection is a known risk factor of gastric carcino-genesis. This article presents early molecular alterations associated with H. pylori chronic gastritis and advances in the molecular characterization of preneoplastic intestinal metaplasia (IM) and premalignant gastric mucosal lesions. H. pylori infection induces changes in gene expression, genomic instability and accumulation of gene mutations in the stomach epithelium. Mutations, including LOH and microsatellite instability, and gene hypermethylation are seen not only in gastric cancer, but are already detectable in IM and gastric dysplasia/adenoma. Recent reports using microarray expression analysis identified several gastric epithelial genes that are regulated by H. pylori. Among the many genes showing altered epithelial expression in response to H. pylori, some might be useful as markers to assess gastric cancer risk. Profiles of mutagenesis and gene expression in IM and dysplasia/adenoma have been characterized and represent potential markers of preneoplastic and premalignant lesions during gastric carcinogenesis.
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Affiliation(s)
- Adrian Gologan
- Department of Pathology, University of Pittsburgh Medical Center, PUH-A610, 200 Lothrop Street, Pittsburgh, PA 15213-2582, USA
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21
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Smith GV, Feakins R, Farthing MJ, Ballinger A. Cyclooxygenase 2, p53, beta-catenin, and APC protein expression in gastric adenomatous polyps. Am J Clin Pathol 2005. [PMID: 15716238 DOI: 10.1309/263a4pq83r9qcruf] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Gastric adenomatous polyps are rare findings in upper gastrointestinal endoscopy; however, they are associated strongly with malignant transformation. Few series describe the oncogenic characteristics of gastric adenomas. In the present study, we immunohisto-chemically assessed the expression of cyclooxygenase (COX)-2, beta-catenin, p53, and adenomatous polyposis coli (APC) in paraffin-embedded specimens of 14 gastric adenomas. Control samples of normal gastric tissue and gastric adenocarcinoma also were analyzed. Of the adenomas, 7 demonstrated overexpression of COX-2, and all demonstrated nuclear p53 accumulation. Accumulation of beta-catenin in the nucleus and cytoplasm was detected in 38% (3/8) of specimens. Loss of APC staining was observed in 50% (4/8). Similar alterations in oncoprotein expression were seen in gastric cancers but not in normal control sections. Gastric adenomas display alterations in the expression of COX-2, beta-catenin, and APC similar to those seen in adenocarcinomas; however, accumulation of p53 was significantly more common in adenomas than in cancers.
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22
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Lee JH, Park SJ, Abraham SC, Seo JS, Nam JH, Choi C, Juhng SW, Rashid A, Hamilton SR, Wu TT. Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas. Oncogene 2004; 23:4646-54. [PMID: 15064707 DOI: 10.1038/sj.onc.1207588] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gastric carcinogenesis involves multiple genetic and epigenetic alterations. Epigenetic silencing of tumor-related genes due to CpG island methylation (CIM) has been recently reported in gastric cancer, but the role in precursor lesions is not well understood. We analysed the methylation status of the tumor suppressor gene p16, the DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using methylation-specific polymerase chain reaction in 35 polypoid adenomas and 46 flat dysplasias unassociated with carcinoma, 34 early adenocarcinomas (T1N0M0) and associated adenomas/dysplasias, and corresponding adjacent non-neoplastic mucosa. The extent of CIM was defined by the fraction of methylated loci (methylation index), and compared with previously characterized genetic alterations (microsatellite instability (MSI) and APC gene mutation). We found that methylation of p16 was more frequent in adenocarcinoma-associated dysplasias/adenomas (29%) and adenocarcinomas (44%) as compared to flat dysplasias (4%) and adenomas (18%) unassociated with adenocarcinoma (P=0.001). The mean methylation index increased from normal/chronic gastritis (CG) mucosa (0.09) to intestinal metaplasia (IM) (0.16), flat dysplasias (0.40) or polypoid adenomas (0.41) unassociated with carcinoma, dysplasias/adenomas associated with carcinoma (0.44), and adenocarcinomas (0.44). There was no difference in frequencies of high-level CpG island methylation (CIM-H, methylation index > or =0.5) among flat dysplasias (50%) and polypoid adenomas (51%) unassociated with carcinoma, dysplasias/adenomas associated with adenocarcinoma (47%), and adenocarcinoma (47%). CIM-H was present in 15% of IM, but not in normal/CG mucosa. There was a significant correlation between methylation of hMLH1 and high-level of microsatellite instability (MSI-H): methylation of hMLH1 was present in 71% of MSI-H tumors, but only 8% of MSI-low tumors and 13% of microsatellite-stable tumors (P=0.0001). There was no statistical difference between methylation index and APC mutation. Our results indicate that concurrent promoter methylation is an early and frequent event in gastric tumorigenesis, including both MSI-H and microsatellite-stable neoplasms. Methylation of the p16 gene may contribute to the malignant transformation of gastric precursor lesions.
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Affiliation(s)
- Jae-Hyuk Lee
- Department of Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA
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23
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Kitayama Y, Igarashi H, Watanabe F, Maruyama Y, Kanamori M, Sugimura H. Nonrandom chromosomal numerical abnormality predicting prognosis of gastric cancer: a retrospective study of 51 cases using pathology archives. J Transl Med 2003; 83:1311-1320. [PMID: 13679439 DOI: 10.1097/01.lab.0000087622.80751.c5] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Chromosomal or centromerical numerical abnormality (CNA) is a well-known characteristic of human cancer, but the extensive and specific documentation of CNA in gastric cancer is still sparse, partly because of difficulty in obtaining cytogenetic information. Taking advantage of a recently developed fluorescence in situ hybridization protocol for formalin-fixed paraffin-embedded tissues, we investigated CNA of 51 gastric cancer cases with a panel of 18 chromosome-specific alpha-satellite probes (for chromosomes 1-4, 6-12, 15-18, 20, X and Y) and region specific probes (c-myc and p53) to enumerate respective chromosome numbers in interphase nuclei. The involved chromosomes exhibiting CNA were nonrandom in gastric cancer. Aberrations of chromosomes 1, 8, 17, 20, and X were frequent regardless of histologic types, whereas aberrations chromosomes 10, 15, and 18 occurred less often (p < 0.001). From a histopathologic standpoint, the mucocellular type had stable CNA in comparison with the tubular type (mucocellular type vs tubular type carcinoma: 21.0 +/- 10.63% vs 62.8 +/- 12.79%, p < 0.001). Interestingly, there was less extensive CNA in women (men vs women: 54.3 +/- 9.49% versus 24.9 +/- 12.23%, p < 0.001). A dramatic difference in the outcome was detected according to the involvement of chromosomes 3, 10, 11, 12, 17, and Y; that is, the cases with CNA of these chromosomes had worse prognosis.
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Affiliation(s)
- Yasuhiko Kitayama
- First Department of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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24
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Sepulveda AR, Graham DY. Role of Helicobacter pylori in gastric carcinogenesis. Hematol Oncol Clin North Am 2003. [DOI: 10.1016/s0889-8588(03)00021-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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25
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Fang DC, Luo YH, Yang SM, Li XA, Ling XL, Fang L. Mutation analysis of APC gene in gastric cancer with microsatellite instability. World J Gastroenterol 2002; 8:787-91. [PMID: 12378616 PMCID: PMC4656562 DOI: 10.3748/wjg.v8.i5.787] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.4] [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 evaluate the role of APC mutation in gastric carcinogenesis and to correlate APC mutation with microsatellite instability (MSI) in gastric carcinomas.
METHODS: APC mutation was measured with multiplex PCR, denaturing gradient gel electrophoresis and DNA sequencing; and MSI was analyzed by PCR-based methods.
RESULTS: Sixty-eight cases of sporadic gastric carcinoma were studied for APC mutation at exon 15 and MSI. APC mutaions were detected in 15 (22.1%) gastric cancers. Frequence of APC mutation (33.3%) in intestinal type of gastric cancer was significantly higher than that in diffuse type (13.1%, P < 0.05). On the contrary, no association was observed between APC mutation and tumor size, differentiation, depth of invasion, metastasis or clinical stages. Using five microsatellite markers, MSI in at least one locus was detected in 17 of 68 (25%) of the tumors analyzed. APC mutations were all detected in MSI-L (only one locus, n = 9) or MSS (tumor lacking MSI or stable, n = 51), but no mutation was found in MSI-H (≥ 2 loci, n = 8).
CONCLUSION: APC mutation is involved in carcinogenesis of intestinal type of gastric cancer and is independent of MSI phenotype but related to the LOH pathway in gastric cancer.
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Affiliation(s)
- Dian-Chun Fang
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
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26
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Lee JH, Abraham SC, Kim HS, Nam JH, Choi C, Lee MC, Park CS, Juhng SW, Rashid A, Hamilton SR, Wu TT. Inverse relationship between APC gene mutation in gastric adenomas and development of adenocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2002; 161:611-8. [PMID: 12163385 PMCID: PMC1850731 DOI: 10.1016/s0002-9440(10)64216-2] [Citation(s) in RCA: 101] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Gastric cancer is common among the world, but genetic mechanisms of gastric carcinogenesis are not well understood. Gastric polypoid adenomas and flat dysplasias are regarded as precursor lesions. However, a detailed molecular study of these lesions has not been done to determine their role as precancerous lesions. We investigated mutations of the APC, beta-catenin, and K-ras genes, and microsatellite instability (MSI) status in 35 adenomas and 47 flat dysplasias without adenocarcinoma, 35 adenomas/dysplasias associated with adenocarcinomas, and 39 adenocarcinomas (20 diffuse type and 19 intestinal type). Somatic APC gene mutations were identified in 76% (59 of 78) of adenomas or flat dysplasias without associated adenocarcinoma, but in only 3% (1 of 30) of adenomas/dysplasias associated with adenocarcinoma, and in only 4% (3 of 69) of adenocarcinomas (P < 0.000001). No mutations of beta-catenin were found in adenocarcinomas, or adenomas/dysplasia without APC mutation. K-ras mutations were detected in 5% (4 of 82) of gastric adenomas/dysplasia without carcinoma, 3% (1 of 39) of adenocarcinomas without associated adenoma/dysplasia, and not in 32 adenocarcinomas with associated adenoma/dysplasia. High level of MSI (MSI-H) was more frequent in gastric adenoma/dysplasia associated with carcinoma (17%, 6 of 35) than in adenomas/dysplasia without carcinoma (3%, 2 of 75; P = 0.01). MSI-H was also more frequent in intestinal type adenocarcinoma (20%, 11 of 54) than in diffuse type (0%, 0 of 20; P = 0.03). APC gene mutations were present in six of nine (67%) of gastric adenomas/dysplasias with low level of MSI, but in none of the eight adenomas/dysplasia with MSI-H phenotype (P = 0.009). Our results indicate that somatic mutation of the APC gene plays an important role in the pathogenesis of gastric adenoma and dysplasia but has a limited role in neoplastic progression to adenocarcinoma. Gastric adenomas or dysplasias without APC mutations but with or without MSI may have a different biological behavior, and are precursors of intestinal-type of gastric adenocarcinomas.
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Affiliation(s)
- Jae-Hyuk Lee
- Department of Pathology, MD Anderson Cancer Center, Houston, Texas 77030, USA
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27
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Abstract
Peptic ulcers and gastric malignancies are the two major complication of the course of Helicobacter pylori-associated chronic gastritis. Both gastric adenocarcinomas and MALT lymphomas occur in association with H. pylori infection, and studies support an etiological association. This article discusses the natural history of H. pylori-related gastric carcinogenesis and criteria to identify people susceptible to H. pylori infection-associated gastric cancer. It then reviews the molecular and genetic mechanisms underlying the malignant transformation of the gastric mucosa associated with H. pylori.
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Affiliation(s)
- Antonia R Sepulveda
- Department of Pathology, PUH-A610, University of Pittsburgh Medical Center, 200 Lothrop St., Pittsburgh, PA 15213-2582, USA.
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28
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Minamoto T, Ronai Z. Gene mutation as a target for early detection in cancer diagnosis. Crit Rev Oncol Hematol 2001; 40:195-213. [PMID: 11738944 DOI: 10.1016/s1040-8428(01)00098-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The increasing number of genetic aberrations implicated in the development of human cancer has prompted a search to detect them at the earliest possible stage of their formation. Of the many such genetic changes identified thus far, relatively few meet the standard for markers in early diagnosis and prognosis, namely that the genetic modifications occur during the early onset phase of cancer development. Parallel to the increasing number of such genes is the growing availability of technologies using more powerful and cost-efficient methods that enable mass screening for genetic alterations. The purpose of this review is to summarize the currently available genes that can serve as markers for early detection of cancers and methods that allow their detection.
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Affiliation(s)
- T Minamoto
- Cancer Research Institute, Kanazawa University, Kanazawa, Japan
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29
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30
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Yokozaki H, Yasui W, Tahara E. Genetic and epigenetic changes in stomach cancer. INTERNATIONAL REVIEW OF CYTOLOGY 2001; 204:49-95. [PMID: 11243597 DOI: 10.1016/s0074-7696(01)04003-7] [Citation(s) in RCA: 81] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Genetic and epigenetic alterations of multiple cancer-related genes and molecules are implicated in the development and progression of human gastric carcinomas. Reactivation of telomerase, inactivation of p53 tumor suppressor gene, overexpression of cyclin E, and reduced expression of p27 KIP1 by disorganized degradation in proteasome are common events of both well-differentiated and poorly differentiated gastric adenocarcinomas. Inactivation of hMLH1 mismatch repair gene by CpG hypermethylation resulting in microsatellite instability, amplification of c-erbB2 oncogene, inactivation of APC tumor suppressor gene, and K-ras mutations are preferentially associated with well-differentiated gastric cancer. Conversely, reduction or loss of E-cadherin and catenins by both mutation and CpG hypermethylation and K-sam and c-met oncogene amplification are necessary for the development and progression of poorly differentiated or scirrhous gastric carcinomas. Interaction between cancer cells expressing c-met and hepatocyte growth factor from stromal cells is implicated in morphogenesis of gastric cancer.
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Affiliation(s)
- H Yokozaki
- First Department of Pathology, Hiroshima University School of Medicine, Japan
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31
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Sepulveda AR. Molecular testing of Helicobacter pylori-associated chronic gastritis and premalignant gastric lesions: clinical implications. J Clin Gastroenterol 2001; 32:377-82. [PMID: 11319306 DOI: 10.1097/00004836-200105000-00004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Helicobacter pylori-associated gastritis may progress or be complicated by peptic ulcer and gastric malignancy, including gastric carcinoma and mucosa-associated lymphoid tissue lymphoma. Predicting who develops malignancy remains a clinical challenge. The molecular understanding of pathways that are associated with progression of the normal gastric epithelium to malignancy together with classic histologic parameters are promising ways of tackling this problem. Ideally, molecular tools used for screening should be available as noninvasive tests, such as examination of markers detectable in blood samples, but these are not currently available. In contrast, molecular markers that correlate with cancer risk can be examined in the epithelium after endoscopic biopsy and can be of importance in identifying individuals at risk, especially if combined with other parameters of gastric cancer risk.
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Affiliation(s)
- A R Sepulveda
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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32
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Ebert MP, Yu J, Miehlke S, Fei G, Lendeckel U, Ridwelski K, Stolte M, Bayerdörffer E, Malfertheiner P. Expression of transforming growth factor beta-1 in gastric cancer and in the gastric mucosa of first-degree relatives of patients with gastric cancer. Br J Cancer 2000; 82:1795-800. [PMID: 10839293 PMCID: PMC2363226 DOI: 10.1054/bjoc.1999.1107] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Transforming growth factors beta (TGF-beta) constitute a family of polypeptide growth factors that control cell growth, cell differentiation and migration, as well as the formation of the extracellular matrix. Recent analyses revealed the overexpression of TGF-beta1 in human gastric cancers and demonstrated increased cell proliferation in the stomach of patients with gastric cancer and their first-degree relatives. Using human gastric tissues obtained from patients with gastric cancer (n = 19), biopsies from healthy first-degree relatives of gastric cancer patients (n = 18) and healthy individuals (n = 19), we analysed the expression of TGF-beta1 using the reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Fifteen of 19 patients with gastric cancer expressed TGF-beta1 in the tumour. In 11 of these 15 cases TGF-beta1 mRNA was also detectable in the non-tumourous stomach. Interestingly, all but two individuals with a first-degree relative diagnosed with gastric cancer exhibited TGF-beta1 expression in either the antrum or corpus biopsy or both. In contrast, only one of 19 individuals without a family history of gastric cancer expressed TGF-beta1 in the stomach (P< 0.0001). TGF-beta1 expression is detectable in a large proportion of gastric cancers and in the stomach of healthy first-degree relatives of gastric cancer patients. Since individuals without gastric cancers in their family express TGF-beta1 only in one of 19 cases, the induction of TGF-beta1 expression in first-degree relatives of patients with gastric cancer points to the presence of specific molecular alterations in a subgroup of individuals with an increased risk of developing gastric cancer that may precede the development of gastric cancers.
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Affiliation(s)
- M P Ebert
- Department of Gastroenterolgy, Otto-von-Guericke University Magdeburg, Germany
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33
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Bevilacqua RA, Corvello CM, Duarte AP, Simpson AJ. Detection of microsatellite instability but not truncating APC mutations in gastric adenocarcinomas in Brazilian patients. Genet Mol Biol 2000. [DOI: 10.1590/s1415-47572000000200001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
A crucial role for the adenomatous polyposis colonic (APC) gene in colorectal carcinogenesis has been conclusively established, but, the role of APC in gastric tumors remains controversial. APC mutations have been detected at a relatively high frequency in gastric tumors of Japanese patients, yet such mutations have been reported to be extremely rare in British patients and patients from north-central-Italy. We here report the analysis of 40 primary sporadic gastric adenocarcinomas and 35 primary sporadic colon adenocarcinomas (from patients resident in São Paulo, Brazil), for mutations in the APC gene between codons 686 and 1693 using the protein truncation test. Although 19 truncating mutations were detected in 35 colon adenocarcinomas (54.2%) none were found in any of the gastric adenocarcinomas. As an internal control the tumor samples were also evaluated for microsatellite alterations, which are also common features of both tumor types. Microsatellite instability was present in 1 colon and 7 gastric tumor samples. This suggests that in relation to APC mutations gastric adenocarcinomas from Brazilian patients are similar to those that occur in Europe, and support a fundamental difference both between gastric carcinomas that occur in different geographical regions and between the molecular etiology of gastric and colorectal adenocarcinomas occurring in São Paulo, Brazil.
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34
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Leung WK, Kim JJ, Kim JG, Graham DY, Sepulveda AR. Microsatellite instability in gastric intestinal metaplasia in patients with and without gastric cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2000; 156:537-43. [PMID: 10666383 PMCID: PMC1850057 DOI: 10.1016/s0002-9440(10)64758-x] [Citation(s) in RCA: 117] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The role and significance of microsatellite instability (MSI) in gastric carcinogenesis remain unknown. This study determined the chronology of MSI in gastric carcinogenesis by examining intestinal metaplasia (IM) from patients with and without gastric cancer. DNA was obtained from gastric specimens of 75 patients with gastric IM (30 cancer, 26 peptic ulcer, and 19 chronic gastritis patients) and was amplified with a set of eight microsatellite markers. Eight (26. 7%) tumors and seven (9.3%) IM samples (three from cancer-free patients) displayed high-level MSI (three or more loci altered). Low-level MSI (one or two loci altered) was detected in 50% of the tumors, in 40% of IM samples coexisting with cancer, and in 38% of IM tissues of cancer-free individuals. Among the 30 cancer patients, microsatellites were more frequently altered in IM coexisting with tumors that showed MSI (P = 0.003). In addition, patients with low-level MSI in the tumor tissues were more likely to have active Helicobacter pylori infection than those with stable tumors (P = 0.02). In conclusion, this study indicates that MSI occurs not only in gastric IM of patients with gastric carcinoma, but also in IM of cancer-free individuals. These data suggest that the progressive accumulation of MSI in areas of IM may contribute to gastric cancer development, representing an important molecular event in the multistep gastric carcinogenesis cascade.
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Affiliation(s)
- W K Leung
- Department of Medicine, Veterans Affairs Medical Center, Houston, Texas, USA
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35
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Yamamoto N, Kato Y, Yanagisawa A, Ohta H, Takahashi T, Kitagawa T. Predictive value of genetic diagnosis for cancer micrometastasis: histologic and experimental appraisal. Cancer 1997; 80:1393-8. [PMID: 9338462 DOI: 10.1002/(sici)1097-0142(19971015)80:8<1393::aid-cncr5>3.0.co;2-g] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The recently introduced genetic diagnosis of cancer micrometastasis is quite attractive because of its high detection sensitivity. Not infrequently, however, there are marked discrepancies between genetic and conventional histologic diagnoses, especially concerning lymph nodes from colon carcinoma patients. Because the histologic approach has long been relied on in the clinic, the reasons for the differences in results need to be elucidated. METHODS Serial sections of genetic diagnosis positive but histologic negative lymph nodes of colon carcinoma patients were prepared for histologic and immunohistochemical studies. To investigate the possible contaminating influence of DNA sequences derived from degraded carcinoma cells from the primary site through the lymphatics, the authors also injected purified DNA of human colon carcinoma cells (SW480) into the foot pads of rats and sequentially examined lymph nodes using genetic diagnosis methodology. RESULTS Careful histologic examination of genetic diagnosis positive, histologically negative lymph nodes of colon carcinoma patients confirmed the absence of cancer cells, whereas p53 protein was immunohistochemically demonstrated to be present in the cytoplasm of sinus histiocytes. In the rat experiment, positive reactions were obtained with the inguinal lymph nodes beginning 30 minutes after the injection, and lymph nodes at various sites were subsequently affected, even after a 72-hour period. CONCLUSIONS The current study thus suggests that positive results with genetic diagnosis may simply indicate the presence of tumor DNA and do not necessarily mean that viable cancer cells are present. Although the genetic approach may still hold promise for the detection of cancer micrometastases, its predictive value should be carefully assessed clinicopathologically, because its supersensitivity may be associated with a greatly increased false-positive rate.
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Affiliation(s)
- N Yamamoto
- Department of Pathology, Cancer Institute of Tokyo, Japan
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36
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Shoemaker AR, Gould KA, Luongo C, Moser AR, Dove WF. Studies of neoplasia in the Min mouse. BIOCHIMICA ET BIOPHYSICA ACTA 1997; 1332:F25-48. [PMID: 9141462 DOI: 10.1016/s0304-419x(96)00041-8] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- A R Shoemaker
- Laboratory of Genetics, University of Wisconsin Medical School, Madison 53706, USA
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37
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Sanz-Ortega J, Sanz-Esponera J, Caldes T, Gomez de la Concha E, Sobel ME, Merino MJ. LOH at the APC/MCC gene (5Q21) in gastric cancer and preneoplastic lesions. Prognostic implications. Pathol Res Pract 1996; 192:1206-10. [PMID: 9182290 DOI: 10.1016/s0344-0338(96)80152-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The APC/MCC gene (Familial Adenomatous Polyposis) at 5q21 plays a role in colon cancer carcinogenesis. LOH at this locus has also been described in gastric cancer and preneoplastic lesions. The APC locus has been recently related to a cell surface adhesion molecule and its alteration may favour metastatic dissemination. LOH at 5q21 has been associated with poor prognosis in other tumors such as lung cancer. Thirty-six gastric cancers were evaluated for LOH at 5q21 with 2 polymorphic markers from microdissected paraffin-embedded material. All tumors were classified by stage, histologic type, degree of differentiation and survival rates. In 4 cases, intestinal metaplasia cells in the adjacent mucosae were also microdissected. Six cases of moderate-severe gastric dysplasia were also added to the study. LOH was determined in 84% of the informative cases of GC, affecting both early and advanced stages of disease. Genomic instability was assessed in 5 cases, 3 of them associated with LOH. The only case of gastric cancer that did not show LOH or instability at 5q21 was a stage II, poorly differentiated intestinal carcinoma without evidence of recurrence after a 36 month follow-up period (the mean survival rate in our series was 28.3% at 36 months). We also found LOH in 2/6 dysplastic lesions and 1/4 intestinal metaplasias. Our data show that LOH at 5q21 is frequent in gastric cancer and is also present in intestinal metaplasia and dysplastic lesions. LOH at this locus is not a prognostic factor in GC in our study, due to the high incidence of LOH that we found.
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Affiliation(s)
- J Sanz-Ortega
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA
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38
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Abstract
Advances in molecular biology have revealed a consistent set of genetic alterations that may correspond to multistep tumor development. The pathogenesis of adenoma and differentiated adenocarcinoma of the stomach are reviewed from a genetic perspective with reference to the colorectal adenoma-carcinoma sequence. The sequential accumulation of genetic alterations characteristic of the colorectal adenoma-carcinoma sequence does not occur between adenoma and differentiated adenocarcinoma of the stomach, although adenomatous polyposis coll (APC) mutation in adenoma, and p53 mutation and loss of heterozygosity (LOH) of DCC (deleted in colorectal cancer) gene in carcinoma are prevalent genetic alterations. Allelotype, LOH and microsatellite analyses have revealed several chromosomal regions of deletion, as well as genetic instability, that accumulate during the development and progression of differentiated adenocarcinomas. However, these alterations are rarely found in adenomas of the stomach. These findings suggest that the adenoma-carcinoma sequence is relatively rare in gastric carcinogenesis, and that most differentiated adenocarcinomas of the stomach develop through a de novo pathway.
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Affiliation(s)
- G Tamura
- Department of Pathology, Iwate Medical University School of Medicine, Morioka, Japan
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39
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Sud R, Talbot IC, Delhanty JD. Infrequent alterations of the APC and MCC genes in gastric cancers from British patients. Br J Cancer 1996; 74:1104-8. [PMID: 8855982 PMCID: PMC2077127 DOI: 10.1038/bjc.1996.497] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
We examined 26 gastric carcinomas from British patients for mutations of the APC gene using a single-strand conformation polymorphism (SSCP) and heteroduplex assay in conjunction with the protein truncation test (PTT). In addition, we performed loss of heterozygosity (LOH) analysis of the APC and MCC genes. We detected an inactivating somatic mutation in one gastric tumour. LOH of APC was observed in one of 12 informative cases (8%) and of MCC in two of 20 cases (10%). We thus find that alteration of the APC and MCC genes are infrequent in gastric cancers from the British population. Tumour-suppressor genes on other chromosomes must play a more significant role in the development of these tumours.
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Affiliation(s)
- R Sud
- Human Genetics Group, Galton Laboratory, University College London, UK
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40
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White S, Bubb VJ, Wyllie AH. Germline APC mutation (Gln1317) in a cancer-prone family that does not result in familial adenomatous polyposis. Genes Chromosomes Cancer 1996; 15:122-8. [PMID: 8834176 DOI: 10.1002/(sici)1098-2264(199602)15:2<122::aid-gcc7>3.0.co;2-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Germline mutations of the adenomatous polyposis coli gene are associated with the dominantly inherited syndrome of familial adenomatous polyposis. Somatic mutations in this gene are an early event in sporadic colorectal tumorigenesis. Here we report a family with genetic characteristics that do not conform exactly to either of these situations. The index case and three siblings presented with colorectal cancer, and another sibling had lung cancer. There was no evidence of colorectal cancer susceptibility in previous generations, although one case of gastric cancer was observed. Using restriction fragment length polymorphism, single-strand conformational polymorphism, and sequencing analysis, we screened each living family member for alterations in the mutation cluster region of exon 15 of the APC gene. A constitutional single base pair substitution at codon 1317 was observed in two of the siblings with colorectal cancer, but neither exhibited any colonic features typical of FAP nor an early onset of cancer. This constitutional change is a missense mutation and therefore does not result in the truncation of the APC protein, the most commonly observed result of mutation in this gene. We present evidence that this change is not a polymorphism and may be capable of conferring a growth advantage. This particular germline APC mutation does not completely cosegregate with cancer in this family; therefore, we conclude that another gene locus may be responsible for the increased cancer risk observed.
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Affiliation(s)
- S White
- Department of Pathology, University Medical School, Edinburgh, United Kingdom
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41
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Solcia E, Fiocca R, Luinetti O, Villani L, Padovan L, Calistri D, Ranzani GN, Chiaravalli A, Capella C. Intestinal and diffuse gastric cancers arise in a different background of Helicobacter pylori gastritis through different gene involvement. Am J Surg Pathol 1996; 20 Suppl 1:S8-22. [PMID: 8694148 DOI: 10.1097/00000478-199600001-00003] [Citation(s) in RCA: 116] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Investigation of extensively sampled nontumor gastric mucosa from 205 early gastric cancers showed Helicobacter pylori colonization in 85% of cases, including 100% of diffuse and 78% (83% in 97 cases with Swiss rolls) of glandular or mixed cancers. Intestinal metaplasia, including its type III variant, was prominent in the mucosa associated with glandular and mixed (but not diffuse) early cancers. Both glandular (usually called "intestinal") and diffuse-type cancers showed admixtures of intestinal and gastric tumor cell phenotypes. Both p53 gene mutations and p53 protein immunostaining were essentially restricted to glandular or mixed cancers and associated dysplastic lesions. Their appearance in the advanced stage of diffuse cancer was partly due to a change of the histologic pattern from glandular to diffuse during progression of some tumors. Loss of laminin, beta I integrin, or zonula adherens junctions was a common finding in both early and advanced diffuse cancer. It is concluded that two main pathways operate in gastric carcinogenesis, both starting from H. pylori gastritis and both leading to phenotypically variable, often mixed gastric/intestinal tumor growth. However, only one of the two pathways involves intestinal metaplasia, its type III variant, p53 gene alteration, and dysplasia to end in glandular cancer. In the other pathway, diffuse cancer apparently arises directly from hyperplastic, sometimes atypical necks of mostly nonmetaplastic gastric glands, through primary involvement of genes affecting cell-cell and cell-matrix junctional proteins.
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Affiliation(s)
- E Solcia
- Department of Human Pathology and Genetics, University of Pavia, Italy
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42
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Hayashi N, Sugai S, Ito I, Nakamori S, Ogawa M, Nakamura Y. Ethnic difference in the pattern of K-ras oncogene mutations in human colorectal cancers. Hum Mutat 1996; 8:258-61. [PMID: 8889585 DOI: 10.1002/(sici)1098-1004(1996)8:3<258::aid-humu9>3.0.co;2-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- N Hayashi
- Department of Biochemistry, Cancer Institute, Tokyo, Japan
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43
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Hayashi N, Ito I, Yanagisawa A, Kato Y, Nakamori S, Imaoka S, Watanabe H, Ogawa M, Nakamura Y. Genetic diagnosis of lymph-node metastasis in colorectal cancer. Lancet 1995; 345:1257-9. [PMID: 7746054 DOI: 10.1016/s0140-6736(95)90922-2] [Citation(s) in RCA: 203] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
If a regional lymph node taken during surgery for colorectal cancer is found to be free of tumour on histological examination this is taken to be a good sign. However, conventional staining may not be sensitive enough. Mutant-allele-specific amplification (MASA) is a technique that can detect, at the level of an individual cell, micrometastases to lymph nodes that are histologically diagnosed as negative. To examine the prognostic significance of such genetically detectable tumour cells we screened 120 colorectal cancers from patients who had no histologically detectable lymph-node metastasis at the time of surgery for mutations in K-ras (codons 12, 13, and 61) or p53 (exons 5-8). Somatic mutations were identified by MASA in 71 tumours. We next examined preserved tissues from corresponding regional lymph nodes, using MASA to look for the specific mutation found in the primary. Of 37 patients with genetically positive lymph nodes 27 had had a tumour recurrence within 5 years of surgery; none of the 34 patients who were MASA negative for lymph node metastasis had had a recurrence. Genetic diagnosis of lymph node metastasis may be a useful prognostic factor in colorectal cancer, and it could also serve as a selective marker for intensive postoperative adjuvant chemotherapy.
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Affiliation(s)
- N Hayashi
- Department of Biochemistry, Cancer Institute, Tokyo, Japan
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44
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Herman-Bonert V, Fagin JA. Molecular pathogenesis of pituitary tumours. BAILLIERE'S CLINICAL ENDOCRINOLOGY AND METABOLISM 1995; 9:203-23. [PMID: 7625983 DOI: 10.1016/s0950-351x(95)80290-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Human pituitary tumours account for 10% of intracranial neoplasms. These tumours are usually sporadic and benign; malignant change and metastasis are extremely rare events. Autosomal dominant inheritance of MEN 1 accounts for a minority of pituitary tumours. Pituitary tumours have been found to be monoclonal in several studies. This would suggest that an intrinsic genetic pituitary defect is pivotal in the pathogenesis of these tumours. However, this concept does not exclude a role for the hypothalamus in the genesis of pituitary tumours; the trophic function of several hypothalamic peptides could promote initiation of the genetic event or facilitate a sequence of events leading to clonal expansion of the transformed cell. There has been modest progress made in the elucidation of the intrinsic genetic pituitary cell abnormalities that underlie pituitary tumorigenesis. A mutant alpha subunit of the Gs gene, designated gsp, which results in constitutive activation of adenylyl cylcase has been described in a subset of GH cell adenomas. Loss of genetic material on chromosome 11q13, the locus of the MEN 1 gene, is found in under 20% of pituitary adenomas, suggesting that inactivation of a tumour suppressor gene at this locus may be significant in the tumorigenic process. H-ras point mutations have been described in distant metastatic pituitary tumour secondaries. The genetic abnormalities described occur in only a small subset of pituitary tumours, indicating that the more significant tumour promoting genes are still to be discovered.
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Affiliation(s)
- V Herman-Bonert
- Division of Endocrinology and Metabolism, Cedars-Sinai Medical Center-UCLA School of Medicine 90048-1865, USA
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