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Tertychnyy AS, Pachuashvili NV, Protsenko DD, Avraamova ST, Nagornaya DP, Pavlov PV, Kiryukhin AP, Fedorenko AA. [Pyloric gland adenoma - a rare tumor of the upper gastrointestinal tract with a high risk of malignancy]. Arkh Patol 2024; 86:30-36. [PMID: 38591904 DOI: 10.17116/patol20248602130] [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] [Indexed: 04/10/2024]
Abstract
BACKGROUND Pyloric gland adenomas (PGA) are rare neoplasms of the gastrointestinal tract. According to the literature, these lesions may be underdiagnosed, and their true frequency of occurrence is underestimated. OBJECTIVE Clinical and morphological analysis of eight PGA cases of the upper gastrointestinal tract. MATERIAL AND METHODS The study included 8 cases of detection of PGA. In 7 out of 8 cases, the tumor was diagnosed by examining endoscopic biopsies, in 1 case, PGA was an accidental finding in the surgical material after proximal gastric resection. RESULTS 6 out of 8 patients were female, the median age was 65 years (minimum 36 years and maximum 78 years). In 6 cases, PDA was localized in the stomach, in 1 - in the esophagus and in 1 - in the duodenum The size of the tumors ranged from 0.6 cm to 7.5 cm. 4 out of 6 stomach tumors appeared on the background of confirmed autoimmune gastritis, 1 - on the background of lymphocytic gastritis. 4 tumors were found in the body of the stomach, 1 - in the cardia, 1 - in the bottom of the stomach. In 2 out of 8 cases, there were signs of malignancy of the tumor with the transition to a highly differentiated adenocarcinoma. According to the results of the IHC study, the absence of a p53 mutation was noted in these cases. CONCLUSION PGA should be considered as neoplasms with a high risk of transformation into invasive adenocarcinoma. Increasing the recognition of PGA among pathologists and further understanding of the molecular mechanisms involved in their neoplastic transformation will improve the diagnosis and treatment of this pathology.
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Affiliation(s)
- A S Tertychnyy
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - N V Pachuashvili
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - D D Protsenko
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - S T Avraamova
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - D P Nagornaya
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - P V Pavlov
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - A P Kiryukhin
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - A A Fedorenko
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
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Fukuda M, Ishigaki H, Ban H, Sugimoto M, Tanaka E, Yonemaru J, Kuroe S, Namura T, Matsubara A, Moritani S, Murakami K, Andoh A, Kushima R. No transformation of a fundic gland polyp with dysplasia into invasive carcinoma after 14 years of follow-up in a proton pump inhibitor-treated patient: A case report. Pathol Int 2018; 68:706-711. [PMID: 30511782 DOI: 10.1111/pin.12739] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 10/13/2018] [Indexed: 12/11/2022]
Abstract
A fundic gland polyp (FGP) is a common gastric polyp. Intraepithelial neoplasia in FGPs, referred to as FGP with dysplasia, is often seen in patients with familial adenomatous polyposis (FAP). In sporadic FGPs, low-grade dysplasia (LGD) is rare, and high-grade dysplasia (HGD) or carcinoma arising from sporadic FGPs is extremely rare. Because of this rarity, the prognosis and appropriate management of these lesions have not been clarified. In the present case, a sporadic FGP with LGD did not develop into invasive carcinoma, but contained foci of HGD 14 years after diagnosis. The biopsy specimen of the polyp taken at the first esophagogastroduodenoscopy 15 years earlier was diagnosed as FGP without dysplasia. At the second histological examination, LGD was found. Because the polyp increased in size during proton pump inhibitor therapy for 14 years, endoscopic mucosal resection was performed. The pathological diagnosis of the resected specimen was FGP with HGD mixed in LGD, with no invasive carcinoma. Dysplasia in FGPs might have less malignant potential regardless of dysplasia or size.
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Affiliation(s)
- Masahide Fukuda
- Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan.,Department of Gastroenterology, Oita University, Faculty of Medicine, Yufu, Oita, Japan
| | - Hirohito Ishigaki
- Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Hiromitsu Ban
- Division of Gastrointestinal Endoscopy, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Mitsushige Sugimoto
- Division of Gastrointestinal Endoscopy, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Eri Tanaka
- Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Junpei Yonemaru
- Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Shinobu Kuroe
- Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Tomo Namura
- Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Akiko Matsubara
- Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Suzuko Moritani
- Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Oita University, Faculty of Medicine, Yufu, Oita, Japan
| | - Akira Andoh
- Division of Gastrointestinal Endoscopy, Shiga University of Medical Science Hospital, Otsu, Japan.,Department of Medicine, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Ryoji Kushima
- Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan
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Microsatellite Alterations and Protein Expression of 5 Major Tumor Suppressor Genes in Gastric Adenocarcinomas. Transl Oncol 2017; 11:43-55. [PMID: 29172180 PMCID: PMC5702876 DOI: 10.1016/j.tranon.2017.10.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 10/23/2017] [Accepted: 10/23/2017] [Indexed: 01/01/2023] Open
Abstract
PURPOSE: In gastric adenocarcinoma (GC), the major tumor suppressor genes (TSGs) such as p16, PTEN, Rb, E-cadherin, and p53, may play important roles in various regulatory pathways and in tumor suppression. This study evaluated the loss of heterozygosity (LOH) of microsatellite and protein expression of 5 TSGs and the results were examined for their correlation with clinicopathological factors. METHODS: LOH analysis was carried out using polymerase chain reactions with 15 polymorphic microsatellite markers of 5 chromosomes containing TSGs in 100 surgically resected tumors. Protein expression was evaluated by immunohistochemistry (IHC). RESULTS: LOH was detected in 83% of GCs. LOH of 9p21, 10q23, 13q14, 16q22, and 17p13 were detected in 26%, 31%, 24%, 22%, and 35% of cases, respectively. Protein expression of p16, PTEN, Rb, E-cadherin, and p53 were found to be 31%, 39%, 28%, 32%, and 46% of cases. Advanced GCs showed significantly higher rates of 17p13 LOH and p53 expression. 9p21 LOH and E-cadherin IHC were correlated with higher tumor grade. Lymph node metastasis was correlated with the LOH of 9p21, 16q22, and 17p13 and IHC of the Rb and p53. A higher stage was correlated with 10q23 and 17p13 in LOH and p53 for IHC. CONCLUSION: These results suggest that LOH and protein expression of various TSGs are important in carcinogenesis and tumor invasion. Additionally, LOH and IHC may be useful clinical indicators for determining the prognosis of patients with GCs. In particular, the 17p13 LOH and p53 for IHC can be applied as simple evaluations in the clinic.
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Kwon MJ, Kim KC, Nam ES, Cho SJ, Park HR, Min SK, Seo J, Choe JY, Lee HK, Kang HS, Min KW. Programmed death ligand-1 and MET co-expression is a poor prognostic factor in gastric cancers after resection. Oncotarget 2017; 8:82399-82414. [PMID: 29137273 PMCID: PMC5669899 DOI: 10.18632/oncotarget.19390] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 06/29/2017] [Indexed: 12/29/2022] Open
Abstract
Programmed death-ligand 1 (PD-L1) plays an essential protein for immune evasion, contributing to tumor development and progression. Recent studies have reported MET as an upregulator for PD-L1 overexpression through an oncogenic pathway. However, an association between PD-L1 expression with MET has not been reported in gastric cancer.The prognostic significance of PD-L1 and its association with Epstein-Barr virus (EBV), microsatellite instability (MSI), and mucin phenotype remain controversial. We performed in situ hybridization for EBV-encoded RNA and immunohistochemistry in tissue microarrays for 394 gastric cancers. A multiplex polymerase chain reaction with five quasimonomorphic markers was performed for MSI. PD-L1 expression was observed in 123 cases (31.2%), and clinicopathological features such as MET overexpression, high pT stage, and a lack of lymphatic invasion represent significant risk factors associated with PD-L1 overexpression in gastric cancers. No associations of EBV, MSI, or mucin phenotype with PD-L1 expression were statistically significant. PD-L1 expression was a strong indicator for worse overall survival (OS) but borderline significant in disease-free survival (DFS). A combined analysis of PD-L1 and MET expression indicated that the PD-L1+/MET+ subgroup showed the worst prognosis when compared to the PD-L1-/MET- subgroup, which had the best clinical outcome. Furthermore, PD-L1 overexpression exhibited poor prognosis in terms of both OS and DFS in EBV-negative, microsatellite stable, and intestinal mucin phenotype tumors. In conclusion, this is the first study to evaluate the overexpression of MET as a risk factor for PD-L1 positivity in gastric cancer tissue as well as the reliability and prognostic relevance of PD-L1/MET co-expression after surgery.
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Affiliation(s)
- Mi Jung Kwon
- Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Gyeonggi-do 431-796, Republic of Korea
| | - Kab-Choong Kim
- Department of Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Gyeonggi-do 431-796, Republic of Korea
| | - Eun Sook Nam
- Department of Pathology, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul 134-701, Republic of Korea
| | - Seong Jin Cho
- Department of Pathology, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul 134-701, Republic of Korea
| | - Hye-Rim Park
- Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Gyeonggi-do 431-796, Republic of Korea
| | - Soo Kee Min
- Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Gyeonggi-do 431-796, Republic of Korea
| | - Jinwon Seo
- Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Gyeonggi-do 431-796, Republic of Korea
| | - Ji-Young Choe
- Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Gyeonggi-do 431-796, Republic of Korea
| | - Hye Kyung Lee
- Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Gyeonggi-do 431-796, Republic of Korea
| | - Ho Suk Kang
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Gyeonggi-do 431-796, Republic of Korea
| | - Kyueng-Whan Min
- Department of Pathology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Gyeonggi-do 11923, Republic of Korea
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Abstract
Pyloric gland adenomas are rare neoplasms of the gastrointestinal tract. Gastric pyloric gland adenomas have been shown to arise in chronically damaged mucosa. The neoplastic glands have gastric pyloric gland differentiation and have a tightly packed organization with occasional cystic dilatation. The individual cells are cuboidal to columnar, with eosinophilic to amphophilic cytoplasm and either no apical mucin cap or a poorly formed apical mucin cap. The nuclei are round to oval, with occasional prominent nucleoli. Immunohistochemically, the neoplastic cells label with markers of gastric pyloric gland differentiation, including MUC6 and MUC5AC. There is limited information regarding the natural history of pyloric gland adenomas, but clinical series have described adenocarcinomas in association with gastric pyloric gland adenomas. The ideal clinical management is adequate sampling of the lesion to investigate for high-grade dysplasia and/or invasive cancer and recommendation to clinical colleagues to investigate the background mucosa for the etiology of chronic gastritis as well as potential additional neoplastic lesions. This review will focus on gastric pyloric gland adenomas.
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Affiliation(s)
- Maryam Kherad Pezhouh
- From the Department of Pathology (Drs Pezhouh and Park) and the Eugene McDermott Center for Human Growth and Development (Dr Park), University of Texas Southwestern Medical Center, Dallas; and the Department of Pathology, Children's Medical Center Dallas, Dallas, Texas (Dr Park)
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Matsubara A, Sekine S, Kushima R, Ogawa R, Taniguchi H, Tsuda H, Kanai Y. Frequent GNAS and KRAS mutations in pyloric gland adenoma of the stomach and duodenum. J Pathol 2013. [PMID: 23208952 DOI: 10.1002/path.4153] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Gastric and duodenal adenomas exhibit a significant morphological and phenotypical diversity and are classified into intestinal-type, foveolar-type and pyloric gland adenomas. We analysed the mutations in GNAS, KRAS, BRAF and CTNNB1 and the expressions of mismatch repair (MMR) proteins in 80 gastric and 32 duodenal adenomas with histologically distinct subtypes, as well as in 71 gastric adenocarcinomas. Activating GNAS mutations were found in 22 of the 35 pyloric gland adenomas (PGAs; 63%) but in none of the foveolar-type or intestinal-type adenomas or the adenocarcinomas. Fourteen PGAs (41%), two foveolar-type adenomas (9%), five intestinal-type adenomas (9%) and one adenocarcinoma (1%) had KRAS mutations. BRAF mutations were absent in all the adenomas and adenocarcinomas that were examined. CTNNB1 mutations were only found in two intestinal-type adenomas (4%). Notably, 13 of the 14 KRAS-mutated gastric and duodenal PGAs had concurrent GNAS mutations. The loss of the MMR proteins, which is indicative of microsatellite instability, was observed in one PGA (3%), 12 foveolar-type adenomas (52%), one intestinal-type adenoma (2%) and five adenocarcinomas (7%). These observations indicate that each histological subtype of gastric and duodenal adenomas has a distinct genetic background. In particular, the present study identified the frequent presence of activating GNAS mutations, which are often associated with KRAS mutations, as a characteristic genetic feature of PGAs of the stomach and duodenum.
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Affiliation(s)
- Akiko Matsubara
- Pathology and Clinical Laboratories, National Cancer Centre Hospital, Tokyo, Japan
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Takeda Y, Yashima K, Hayashi A, Sasaki S, Kawaguchi K, Harada K, Murawaki Y, Ito H. Expression of AID, P53, and Mlh1 proteins in endoscopically resected differentiated-type early gastric cancer. World J Gastrointest Oncol 2012; 4:131-7. [PMID: 22737274 PMCID: PMC3382659 DOI: 10.4251/wjgo.v4.i6.131] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Revised: 03/14/2012] [Accepted: 03/20/2012] [Indexed: 02/05/2023] Open
Abstract
AIM To analyze the expression of the tumor-related proteins in differentiated-type early gastric carcinoma (DEGC) samples. METHODS Tumor specimens were obtained from 102 patients (75 males and 27 females) who had received an endoscopic tumor resection at Tottori University Hospital between 2007 and 2009. Ninety-one cancer samples corresponded to noninvasive or intramucosal carcinoma according to the Vienna classification system, and 11 samples were submucosal invasive carcinomas. All of the EGCs were histologically differentiated carcinomas. All patients were classified as having Helicobacter pylori (H. pylori) infections by endoscopic atrophic changes or by testing seropositive for H. pylori IgG. All of the samples were histopathologically classified as either tubular or papillary adenocarcinoma according to their structure. The immunohistochemical staining was performed in a blinded manner with respect to the clinical information. Two independent observers evaluated protein expression. All data were statistically analyzed then. RESULTS The rates of aberrant activation-induced cytidine deaminase (AID) expression and P53 overexpression were both 34.3% in DEGCs. The expression of Mlh1 was lost in 18.6% of DEGCs. Aberrant AID expression was not significantly associated with P53 overexpression in DEGCs. However, AID expression was associated with the severity of mononuclear cell activity in the non-cancerous mucosa adjacent to the tumor (P = 0.064). The rate of P53 expression was significantly greater in flat or depressed tumors than in elevated tumors. The frequency of Mlh1 loss was significantly increased in distal tumors, elevated gross-type tumors, papillary histological-type tumors, and tumors with a severe degree of endoscopic atrophic gastritis (P < 0.05). CONCLUSION Aberrant AID expression, P53 overexpression, and the loss of Mlh1 were all associated with clinicopathological features and gastric mucosal alterations in DEGCs. The aberrant expression of AID protein may partly contribute to the induction of nuclear P53 expression.
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Affiliation(s)
- Yohei Takeda
- Yohei Takeda, Kazuo Yashima, Akihiro Hayashi, Shuji Sasaki, Koichiro Kawaguchi, Kenichi Harada, Yoshikazu Murawaki, Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago 683-8504, Japan
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Watari J, Moriichi K, Tanabe H, Kashima S, Nomura Y, Fujiya M, Tomita T, Oshima T, Fukui H, Miwa H, Das KM, Kohgo Y. Biomarkers predicting development of metachronous gastric cancer after endoscopic resection: an analysis of molecular pathology of Helicobacter pylori eradication. Int J Cancer 2012; 130:2349-58. [PMID: 21732341 PMCID: PMC3288848 DOI: 10.1002/ijc.26275] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2011] [Accepted: 06/06/2011] [Indexed: 12/30/2022]
Abstract
Metachronous gastric cancer (MGC) after endoscopic resection (ER) of gastric cancer still occurs to some degree even after Helicobacter pylori (H. pylori) treatment. We evaluated whether two biomarkers related to carcinogenesis expressed in intestinal metaplasia (IM) become predictors for MGC development after eradication. We performed a hospital-based, case-control study of 75 patients, including 50 mucosal cancer patients who had undergone ER (Group DYS), and 25 age- and sex-matched chronic gastritis patients for whom H. pylori had been successfully eradicated (control). Additionally, Group DYS patients were divided into two groups: 25 successfully H. pylori-eradicated (eradicated group) and 25 un-eradicated patients (persistent group). All patients were followed for 1 year. We analyzed microsatellite instability (MSI) and immunoperoxidase assays using a monoclonal antibody for the colonic phenotype (Das-1). Both MSI and Das-1 reactivity in IM were significantly higher in Group DYS than in the control (p < 0.05 and p < 0.01, respectively). MSI and Das-1 reactivity were strong and independent predictors for gastric cancer (OR = 7.09, 95% CI 1.27-39.6, p = 0.03 for MSI and OR = 4.96, 95% CI 1.64-15.0, p = 0.005 for Das-1 reactivity). The incidence of MSI tended to decrease in the eradicated group (p = 0.07), but not in the persistent group. The Das-1 immunoreactivity in IM also declined in both the eradicated group and the control. Interestingly, all MGCs after ER were positive for MSI or Das-1 reactivity. MSI or Das-1 reactivity in IM strongly predicts the development of MGC. Patients in whom these biomarkers persist after eradication may therefore have a high risk of developing MGC.
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Affiliation(s)
- Jiro Watari
- Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
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Shin N, Kim HY, Kim WK, Park MG, Kim KB, Shin DH, Choi KU, Kim JY, Lee CH, Huh GY, Sol MY, Park DY. Molecular Biological Characteristics of Differentiated Early Gastric Cancer on the Basis of Mucin Expression. KOREAN JOURNAL OF PATHOLOGY 2011. [DOI: 10.4132/koreanjpathol.2011.45.1.69] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Nari Shin
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Hye-Yeon Kim
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Woo-Kyung Kim
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Min-Gyung Park
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Kyung-Bin Kim
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Dong Hoon Shin
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Kyung-Un Choi
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Jee-Yeon Kim
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Chang Hun Lee
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Gi Young Huh
- Department of Forensic Medicine, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Mee Young Sol
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Do Youn Park
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
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Adenomatous and foveolar gastric dysplasia: distinct patterns of mucin expression and background intestinal metaplasia. Am J Surg Pathol 2008; 32:524-33. [PMID: 18300795 DOI: 10.1097/pas.0b013e31815b890e] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Gastric epithelial dysplasia (GED) can be morphologically categorized into adenomatous (or intestinal) and foveolar (or gastric) types. Although limited genetic differences have been demonstrated between these subtypes, the expression of various mucins has not been systematically evaluated in this context. Endoscopic mucosal resections from 69 cases of GEDs were evaluated for the expression of MUC2, MUC5AC, MUC6, and CD10. The results were correlated with morphologic categorization and clinicopathologic parameters. GED was classified as adenomatous, foveolar, or hybrid (showing features of both types), on the basis of histologic evaluation. The neighboring intestinal metaplasia (IM) was also evaluated. An adenomatous morphology was seen in 45%, hybrid type in 33.3%, and a "pure" foveolar type was seen in 21.7% of the cases. Foveolar GED was often depressed/flat on endoscopy and showed a statistically significant association with high-grade morphology (P = 0.046). Immunohistochemistry confirmed the histologic stratification. The foveolar and hybrid types were more often positive for MUC5AC (P = 0.0001 for both) and negative for CD10 (P = 0.019 and 0.016, respectively) as compared with adenomatous GED. High-grade morphology was associated with MUC5AC expression regardless of the morphologic phenotype (P = 0.026). Foveolar (73.3%) and hybrid (86.9%) GEDs were associated more often with IM showing a retained expression of gastric type mucin than adenomatous GED (29%) (P < 0.01 for both). In contrast, adenomatous type (58.1%) of GED was significantly associated with IM showing a complete intestinal phenotype (CD10+) compared with the foveolar (13.3%) and hybrid types (17.4%) of GED (P = 0.005 for both comparisons). In conclusion, our study indicates that foveolar and adenomatous types of GED have distinct clinicopathologic features, mucin profiles, and association with different types of IM.
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Kamalidehghan B, Houshmand M, Ismail P, Panahi MSS, Akbari MHH. Delta mtDNA4977 is more common in non-tumoral cells from gastric cancer sample. Arch Med Res 2006; 37:730-5. [PMID: 16824932 DOI: 10.1016/j.arcmed.2006.02.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2005] [Accepted: 02/03/2006] [Indexed: 02/07/2023]
Abstract
BACKGROUND The aim of this study was to determine the frequency of delta mtDNA4977 in tumoral cells as compared with adjacent normal cells in gastric cancer. METHODS In order to investigate whether a high incidence of mutation exists in mitochondrial DNA of gastric cancer tissues, we screened one of common region of the mitochondrial genome by PCR amplification and Southern blot followed by DNA sequence analysis. DNA isolated from these cells was used to amplify hypervariable regions ATPase8/6, COXIII, ND3, ND4 and ND5 of delta mtDNA4977. RESULTS In 107 cancer patients, delta mtDNA4977 was detected in 6 cases (5.60%) of the tumoral tissues and 18 cases (16.82%) of the non-tumoral tissues that were adjacent to the tumors. Levels of delta mtDNA4977 deletions were found to be more in non-tumoral tissues than in adjacent tumoral tissues. There was no correlation of patients with certain clinical parameters like age, sex, tumor location and tumor size; however, there was an obvious relationship with intestinal-type of gastric cancer. CONCLUSIONS Unknown genetic aspects, ambiguous environmental factors and reactive oxygen species (ROS) can cause the delta mtDNA4977 mutation rate to be increased in gastric cancer. The results suggest that percentage level of delta mtDNA4977 is less common and intolerable in tumoral tissue, probably because of high metabolism and ROS generation. We supposed that the cells initially had delta mtDNA4977 transform to tumoral cells and the existed deletion conferred metabolic disadvantage; thus, cells containing such a mtDNA deletion would be overgrown by other cancer cells without this mtDNA deletion. As a result, the presence of delta mtDNA4977 will be low in tumoral cells.
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Affiliation(s)
- Behnam Kamalidehghan
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
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Kamalidehghan B, Houshmand M, Panahi MSS, Abbaszadegan MR, Ismail P, Shiroudi MB. Tumoral Cell mtDNA ∼8.9 kb Deletion Is More Common than Other Deletions in Gastric Cancer. Arch Med Res 2006; 37:848-53. [PMID: 16971224 DOI: 10.1016/j.arcmed.2006.03.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2005] [Accepted: 03/03/2006] [Indexed: 12/19/2022]
Abstract
BACKGROUND The aim of the study was to clarify the role of deletion of mitochondrial DNA (mtDNA) in gastric carcinogenesis and to determine prevalence of mitochondrial deletions in different regions of tumoral tissue in comparison with adjacent non-tumoral tissue in gastric cancer. METHODS In order to investigate whether a high incidence of mutations exists in mtDNA of gastric cancer tissues, we screened five regions of the mitochondrial genome by PCR amplification, Southern blot and DNA sequence analysis. RESULTS Of 71 cancer patients, the approximately 8.9 kb deletion was detected among different deletions in 9 cases (12.67%) of the tumoral tissues and 1 case (1.40%) in non-tumoral tissues that were adjacent to the tumors. Level of the 8.9 kb deletion has been found to be more than other deletions in tumoral tissues. CONCLUSIONS The approximately 8.9 kb deletion has an obvious correlation with age and histological type. These data suggest that the approximately 8.9 kb deletion in mtDNA may play an important role in gastric carcinogenesis.
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Affiliation(s)
- Behnam Kamalidehghan
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
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Tamura G. Alterations of tumor suppressor and tumor-related genes in the development and progression of gastric cancer. World J Gastroenterol 2006; 12:192-8. [PMID: 16482617 PMCID: PMC4066026 DOI: 10.3748/wjg.v12.i2.192] [Citation(s) in RCA: 160] [Impact Index Per Article: 8.4] [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
The development and progression of gastric cancer involves a number of genetic and epigenetic alterations of tumor suppressor and tumor-related genes. The majority of differentiated carcinomas arise from intestinal metaplastic mucosa and exhibit structurally altered tumor suppressor genes, typified by p53, which is inactivated via the classic two-hit mechanism, i.e. loss of heterozygosity (LOH) and mutation of the remaining allele. LOH at certain chromosomal loci accumulates during tumor progression. Approximately 20% of differentiated carcinomas show evidence of mutator pathway tumorigenesis due to hMLH1 inactivation via hypermethylation of promoter CpG islands, and exhibit high-frequency microsatellite instability. In contrast, undifferentiated carcinomas rarely exhibit structurally altered tumor suppressor genes. For instance, while methylation of E-cadherin is often observed in undifferentiated carcinomas, mutation of this gene is generally associated with the progression from differentiated to undifferentiated carcinomas. Hypermethylation of tumor suppressor and tumor-related genes, including APC, CHFR, DAP-kinase, DCC, E-cadherin, GSTP1, hMLH1, p16, PTEN, RASSF1A, RUNX3, and TSLC1, can be detected in both differentiated and undifferentiated carcinomas at varying frequencies. However, the significance of the hypermethylation varies according to the analyzed genomic region, and hypermethylation of these genes can also be present in non-neoplastic gastric epithelia. Promoter demethylation of specific genes, such as MAGE and synuclein γ, can occur during the progressive stages of both histological types, and is associated with patient prognosis. Thus, while the molecular pathways of gastric carcinogenesis are dependent on histological background, specific genetic alterations can still be used for risk assessment, diagnosis, and prognosis.
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Affiliation(s)
- Gen Tamura
- Department of Pathology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
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Goldstein NS, Bosler DS. Immunohistochemistry of the Gastrointestinal Tract, Pancreas, Bile Ducts, Gallbladder and Liver. DIAGNOSTIC IMMUNOHISTOCHEMISTRY 2006:442-508. [DOI: 10.1016/b978-0-443-06652-8.50019-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Nakamura T, Yao T, Kabashima A, Nishiyama K, Maehara Y, Tsuneyoshi M. Loss of phenotypic expression is related to tumour progression in early gastric differentiated adenocarcinoma. Histopathology 2005; 47:357-67. [PMID: 16178890 DOI: 10.1111/j.1365-2559.2005.02242.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
AIMS To evaluate the relationship between phenotypic expression and tumour progression as represented by macroscopic features, submucosal invasion and lymph node metastasis in early differentiated gastric adenocarcinoma. METHODS One hundred and fifty-five cases of early gastric differentiated adenocarcinoma without any poorly differentiated components were studied. The mucosal and submucosal components of carcinomas and lymph node metastatic lesions were classified into four categories, gastric type (G-type), incomplete intestinal type (I-type), complete intestinal type (C-type) and unclassified type (U-type), based on the combination of the phenotypic expression of HGM (gastric foveolar epithelium), MUC 6 (gastric pyloric glands), MUC 2 (intestinal goblet cells) and CD 10 (small intestinal brush border). In addition, a new classification representing a phenotypic shift from mucosa to submucosa or from primary lesion to lymph node metastasis was established with the categories of preserved group (P-group), loss group (L-group) and acquired group (A-group). RESULTS (1) In submucosal carcinoma, U-type was more common in the submucosa (39%) than in the mucosa (9%). (2) U-type was more common in the metastatic lesions (42%) than in the primary lesions (5%). (3) The submucosal component and lymph node metastatic lesions were classified as P-group in 48% and 43% of cases, respectively, and as L-group in 50% and 52% of cases, respectively. (4) Lymph node metastatic lesions comprising undifferentiated carcinoma were classified as L-group in 100% of cases. CONCLUSION During the course of tumour progression, early differentiated adenocarcinoma at first tends to lose its phenotypic expression despite preserving its morphology, but subsequently morphological dedifferentiation occurs.
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Affiliation(s)
- T Nakamura
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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16
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Rugge M, Bersani G, Bertorelle R, Pennelli G, Russo VM, Farinati F, Bartolini D, Cassaro M, Alvisi V. Microsatellite instability and gastric non-invasive neoplasia in a high risk population in Cesena, Italy. J Clin Pathol 2005; 58:805-10. [PMID: 16049280 PMCID: PMC1770888 DOI: 10.1136/jcp.2004.025676] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS In the natural history of gastric cancer, non-invasive neoplasia (NiN) precedes invasive carcinoma. A histological classification of gastric NiN has recently been proposed by a World Health Organisation international panel of experts. Genetic instability is known to be among the molecular pathways involved in gastric oncogenesis. In this retrospective cross sectional study, microsatellite instability (MSI) was analysed in a consecutive series of NiN and NiN related histological alterations from a northern Italian region at high risk for gastric cancer. PATIENTS/METHODS Fifty five consecutive cases (indefinite for NiN, 29 cases; low grade NiN, 17 cases; high grade NiN, nine cases) were analysed by radioactive polymerase chain reaction and electrophoresis for microsatellite alterations at six loci (BAT25, BAT26, D2S123, D5S346, D17S250, and D3S1317). MSI was defined according to the Bethesda criteria distinguishing: (1) no instability in the analysed loci; (2) low frequency MSI (MSI-L); and (3) high frequency MSI (MSI-H). Immunohistochemical expression of MLH1 and MSH2 proteins was also analysed in all cases. RESULTS Overall, MSI was found in 11 of 55 cases (indefinite for NiN, five of 29 (MSI-L, four; MSI-H, one); low grade NiN, three of 17 (MSI-L, one; MSI-H, two); high grade NiN, three of nine (MSI-L, one; MSI-H, two). CONCLUSIONS In an Italian high risk area for gastric cancer, MSI is part of the spectrum of genetic alterations in gastric non-invasive neoplasia. In European populations at high risk of gastric cancer, DNA repair system alterations are thought to be among the early molecular events in gastric carcinogenesis.
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Affiliation(s)
- M Rugge
- Department of Oncology and Surgical Sciences, University of Padova, I-35121 Padova, Italy.
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Kim HC, Kim JC, Roh SA, Yu CS, Yook JH, Oh ST, Kim BS, Park KC, Chang R. Aberrant CpG island methylation in early-onset sporadic gastric carcinoma. J Cancer Res Clin Oncol 2005; 131:733-40. [PMID: 16075282 DOI: 10.1007/s00432-005-0017-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2004] [Accepted: 06/24/2005] [Indexed: 12/20/2022]
Abstract
PURPOSE Gastric carcinoma more commonly affects older patients, and it is thought that cases of early-onset gastric carcinoma may develop with a different molecular profile different from that of carcinoma occurring at a later age. We assayed the methylation status and genetic changes in genes associated with the APC-beta-catenin axis and the mismatch repair system in relatively early-onset gastric carcinoma samples to determine their association with gastric carcinogenesis. METHODS Tumor and normal tissue DNA samples were obtained from 40 patients with early-onset (< 50 y) gastric carcinomas and assayed for APC and CTNNB1 mutations, microsatellite instability, and methylation of the promoters of the hMLH1, TIMP3, THBS1, DAP- K, GSTP1 , APC, and MINT2. RESULTS Promoter methylation at these seven loci ranged from 12.5 to 62%, with 38/40 tumors (95%) showing promoter methylation at more than one locus. The CpG island methylation phenotype (CIMP) was classified as high in 16 tumors (40%), low in 22 tumors (55%), and negative in 2 tumors (5%). Two concurrent missense mutations (E1685G, R1763L) in the APC mutation cluster region were detected in two tumors, nine tumors showed loss of APC heterozygosity (LOH), and two showed both LOH and promoter methylation. CONCLUSIONS Our results indicate that, unlike in colorectal carcinoma, APC and CTNNB1 mutations do not appear to be highly implicated in early-onset gastric carcinogenesis. In contrast, our data show that promoter methylation is a prevalent phenomenon in early-onset gastric carcinoma and may be related to gastric carcinogenesis.
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Affiliation(s)
- Hee Cheol Kim
- Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Asan Medical Center 388-1, Pungnap-dong, Songpa-gu, Seoul, Korea.
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18
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Lee WA. Gastric extremely well differentiated adenocarcinoma of gastric phenotype: as a gastric counterpart of adenoma malignum of the uterine cervix. World J Surg Oncol 2005; 3:28. [PMID: 15907218 PMCID: PMC1180859 DOI: 10.1186/1477-7819-3-28] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2005] [Accepted: 05/23/2005] [Indexed: 11/29/2022] Open
Abstract
Background Most of gastric adenocarcinoma can be simply diagnosed by microscopic examination of biopsy specimen. Rarely the structural and cellular atypia of tumor cells is too insignificant to discriminate from benign foveolar epithelium. Case presentation A 67-year-old male presented with a gastric mass incidentally found on the abdominal computed tomography (CT) for routine medical examination. Gastric endoscopic examination revealed a huge fungating mass at the cardia and mucosal biopsy was performed. Microscopically the biopsy specimen showed proliferation of bland looking foveolar epithelia in the inflammatory background and diagnosed as foveolar epithelial hyperplasia. Because the clinical and endoscopic features of this patient were strongly suggestive of malignancy, the patient underwent radical total gastrectomy. The resected stomach revealed a huge fungating tumor at the cardia. The cut surface of the tumor was whitish gelatinous. Microscopically the tumor was sharply demarcated from surrounding mucosa and composed of very well formed glandular structures without significant cellular atypia, which invaded into the whole layer of the gastric wall. Tumor glands were occasionally complicated or dilated, and glandular lumina were filled with abundant mucin. Immunohistochemically the tumor cells revealed no overexpression of p53 protein but high Ki-67 labeling index. The tumor cells and intraluminal mucin were diffusely expressed MUC1 and MUC5AC and only focally expressed MUC2. On abdominal CT taken after 12 months demonstrated peritoneal carcinomatosis and multiple metastatic foci in the lung. Conclusion The clinicopathologic profiles of gastric extremely well differentiated adenocarcinoma of gastric phenotype include cardiac location, fungating gross type, very similar histology to foveolar epithelial hyperplasia, foveolar mucin phenotype, lack of p53 overexpressoin and high proliferative index.
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Affiliation(s)
- Won Ae Lee
- Department of Pathology, College of Medicine, Dankook University, Cheonan, Republic of Korea.
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19
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Huang MF, Zhu YQ, Chen ZF, Xiao J, Huang X, Xiong YY, Yang GF. Syndecan-1 and E-cadherin expression in differentiated type of early gastric cancer. World J Gastroenterol 2005; 11:2975-80. [PMID: 15902740 PMCID: PMC4305671 DOI: 10.3748/wjg.v11.i19.2975] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [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 elucidate the role and alterations of syndecan-1 and E-cadherin expression in different cellular phenotypes of differentiated-type gastric cancers (DGCs).
METHODS: A total of 120 DGCs at an early stage, and their adjacent mucosa, were studied both by immunohis-tochemistry. Syndecan-1 and E-cadherin were assessed by immunohistochemical staining with anti-syndecan-1 and anti-E-cadherin antibodies, respectively. Based on immunohistochemistry, DGCs and their surrounding mucosa were divided into four types: gastric type (G-type), ordinary type (O-type), complete-intestinal type (CI-type), and null type (N-type).
RESULTS: Syndecan-1 expression was significantly lower in G-type cancers (29.4%) than in O-type (79.6%) and CI-type cancers (90%) (P<0.05, respectively), but E-cadherin did not show this result. In addition, syndecan-1 expression was significantly reduced in DGCs comprised partly of poorly differentiated adenocarcinoma or signet-ring cell carcinoma, compared to DGCs demonstrating papillary and/or tubular adenocarcinoma (P<0.05). G-type intestinal metaplasia (IM) surrounding the tumors was observed in 23.8% of G-type, 4.9% of O-type, and 6.7% of CI-type cancers (P<0.05; G-type vs O-type). Reduction of syndecan-1 expression was significant in G-type IM (25%) compared to non-G-type IM (75%; P<0.05).
CONCLUSION: Loss of syndecan-1 plays a role in the growth of G-type cancers of DGCs at an early stage, and the reduction of syndecan-1 expression in IM surrounding the tumors may influence the growth of G-type cancer.
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Affiliation(s)
- Mei-Fang Huang
- Department of Digestive Disease, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
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20
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Tsuchiya T, Osanai T, Ogose A, Tamura G, Chano T, Kaneko Y, Ishikawa A, Orui H, Wada T, Ikeda T, Namba M, Takigawa M, Kawashima H, Hotta T, Tsuchiya A, Ogino T, Motoyama T. Methylation status of EXT1 and EXT2 promoters and two mutations of EXT2 in chondrosarcoma. ACTA ACUST UNITED AC 2005; 158:148-55. [PMID: 15796962 DOI: 10.1016/j.cancergencyto.2004.08.031] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2004] [Revised: 08/09/2004] [Accepted: 08/19/2004] [Indexed: 10/25/2022]
Abstract
Germline mutation and functional loss of EXT1 or EXT2 are commonly found in multiple osteochondromas and predispose to the development of chondrosarcoma. Mutations of EXT1 and EXT2 have rarely been detected in sporadic secondary chondrosarcomas from osteochondroma; these frequently display loss of heterozygosity at the EXT1 and EXT2 loci, but primary chondrosarcomas typically do not. To evaluate promoter methylation (which is an epigenetic gene silencing mechanism) of EXT1 and EXT2, we performed methylation-specific polymerase chain reaction (PCR) for 20 chondrosarcoma cases (12 primary, 3 secondary to osteochondroma, 2 secondary to enchondromatosis, 2 extraskeletal ordinary, and 1 clear cell) and in five cell lines. In addition, mutation analysis of the EXT1 and EXT2 coding regions was performed using PCR-single-strand conformation polymorphism and sequencing analysis for 12 of the 20 chondrosarcoma cases (8 primary, 1 secondary to enchondromatosis, 1 secondary to osteochondroma, and 2 extraskeletal ordinary) and five cell lines. Promoter methylation of EXT1 and EXT2 was not detected in any of the cases, and both EXT1 and EXT2 were expressed in all cell lines. Two missense mutations in EXT2 (D227E and R299H) were detected among the chondrosarcoma cases. When considering tumor development in primary chondrosarcoma, we should include mutations in EXT2, along with the status of other members of the EXT gene family.
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Affiliation(s)
- Takashi Tsuchiya
- Department of Orthopaedic Surgery, Yamagata University School of Medicine, Yamagata, Japan.
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21
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French AJ, Petroni G, Thibideau SN, Smolkin M, Bissonette E, Roviello F, Harper JC, Koch BR, Anderson SA, Hebbring SJ, Powell SM. Allelic imbalance of 8p indicates poor survival in gastric cancer. J Mol Diagn 2005; 6:243-52. [PMID: 15269302 PMCID: PMC1867637 DOI: 10.1016/s1525-1578(10)60517-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Gastric cancer is a common tumor worldwide and a tremendous health burden. However, the underlying mechanisms of tumorigenesis in this cancer's development are primarily undefined. Allelic imbalance (AI) of 8p has been reported in many cancers, yet, the target(s) of alteration and the importance of allelic imbalance on this chromosomal arm in gastric carcinoma development remained to be characterized. Our findings confirmed a high rate of AI on 8p in gastric cancers. Moreover, we demonstrated that AI on 8p, either overall or at marker D8S560, was associated with poorer survival in patients with gastric cancer. Finally, gastric cancers with a high rate of microsatellite instability were significantly associated with noncardia tumors and with female gender.
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Affiliation(s)
- Amy J French
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
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22
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Homma N, Tamura G, Honda T, Jin Z, Ohmura K, Kawata S, Motoyama T. Hypermethylation of Chfr and hMLH1 in gastric noninvasive and early invasive neoplasias. Virchows Arch 2004; 446:120-6. [PMID: 15735977 DOI: 10.1007/s00428-004-1146-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2004] [Accepted: 09/19/2004] [Indexed: 12/18/2022]
Abstract
Human tumors are genetically unstable, and the instability exists at two distinct levels-the chromosomal level and the nucleotide level. Chfr and hMLH1 hypermethylation, which may lead to chromosomal instability (CIN) and microsatellite instability (MSI), respectively, was analyzed in gastric noninvasive neoplasias (NIN, Padova international classification) and submucosal invasive adenocarcinomas and in their corresponding non-neoplastic gastric epithelia. Results were compared with microsatellite status, p53 immunoreactivity, and cellular phenotype. Hypermethylation of Chfr and hMLH1 was observed in: 10% (1/10) and 0% (0/10) of low-grade NIN (L-NIN); 63% (5/8) and 63% (5/8) of high-grade NIN, including suspicion for carcinoma without invasion (H-NIN); 36% (5/14) and 57% (8/14) of high-grade NIN, including carcinoma without invasion; and 35% (7/20) and 25% (5/20) of submucosal invasive adenocarcinomas, respectively. Hypermethylation was less frequent in L-NIN than H-NIN (P<0.05) for Chfr and was also less frequent in L-NIN than the others (P<0.05) for hMLH1. We failed to find a significant correlation between Chfr hypermethylation and chromosomal loss of heterozygosity, although hypermethylation of hMLH1 was significantly associated with high-frequency MSI (P<0.01). Expression of p53 was not associated with Chfr or hMLH1 methylation. As for cellular phenotype, hypermethylation of Chfr and hMLH1 was frequent in tumors exhibiting the foveolar epithelial phenotype (50%, 2/4 and 75%, 3/4, respectively) and the ordinary phenotype (40%, 16/40 and 38%, 15/40, respectively), but never in those with the complete-type intestinal metaplastic phenotype (0%, 0/8 for both). In addition, hypermethylation of Chfr and hMLH1 occurred concurrently (P<0.01); methylation was more frequent in patients over 70 years of age (P<0.01), and it was also present in some samples of non-neoplastic gastric epithelia from elderly patients. Thus, some gastric tumors with the foveolar or ordinary phenotype may develop as a result of age-related methylation of Chfr and hMLH1, although Chfr methylation was not associated with CIN.
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Affiliation(s)
- Naoyuki Homma
- Department of Pathology, Yamagata University School of Medicine, 990-9585, Yamagata, 2-2-2 Iida-nishi, Japan
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23
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Sugai T, Habano W, Uesugi N, Jao YF, Nakamura SI, Abe K, Takagane A, Terashima M. Three independent genetic profiles based on mucin expression in early differentiated-type gastric cancers--a new concept of genetic carcinogenesis of early differentiated-type adenocarcinomas. Mod Pathol 2004; 17:1223-34. [PMID: 15154009 DOI: 10.1038/modpathol.3800170] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Recent molecular studies have shown that the genetic profiles of differentiated-type adenocarcinomas of the stomach are associated with distinct cellular mucin phenotypes (gastric- intestinal- and mixed-phenotypes). Therefore, we examined whether these cellular mucin phenotypes reflect specific molecular genetic alterations, and whether the phenotypes can be used to help categorize the intramucosal neoplasias of gastric tumors. We subclassified tumors into four cellular phenotypes using immunohistochemical mucin analysis. In all, 62 early gastric carcinomas (gastric-phenotype, 13; intestinal-phenotype, 17; mixed-phenotype, 31; unclassified-phenotype, 1) were examined using a combination of polymerase chain reaction microsatellite assays and immunohistochemical analysis in order to detect chromosomal allelic losses of multiple cancer-related chromosomal loci (1p, 3p. 4p, 5q, 8p, 9p, 13p, 17p, 18q and 22q), microsatellite instability (MSI), and overexpression of the p53 protein. In addition, we analyzed the relationship between MSI status and hMLH1 promoter hypermethylation, which is thought to be a cause of high MSI status. For gastric phenotype cancers, the frequency of 3p allelic loss was higher than that of other microsatellite markers, whereas 5q allelic loss was frequently found in intestinal phenotype cancers. The genetic profile of mixed phenotype cancers is comprised of two distinct genetic types: LOH and MSI types. In the former, 5q, 3p and 18q allelic losses are seen frequently in intramucosal carcinomas. On the other hand, 17p, 1p and 9p allelic losses are associated with the development of submucosal carcinomas. MSI was observed only in mixed phenotype cancers (six of 31 mixed phenotype cancers). Overexpression of the p53 protein is common in differentiated-type gastric cancers. In addition, the MSI status of the tumor cells was correlated with the extent of hypermethylation of the hMLH1 promoter. We suggest that the cellular mucin phenotypes of the differentiated-type adenocarcinomas result from distinct genetic alterations.
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Affiliation(s)
- Tamotsu Sugai
- Division of Pathology, Central Clinical Laboratory, Iwate Medical University, Morioka, Japan.
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Ling XL, Fang DC, Wang RQ, Yang SM, Fang L. Mitochondrial microsatellite instability in gastric cancer and its precancerous lesions. World J Gastroenterol 2004; 10:800-3. [PMID: 15040020 PMCID: PMC4727000 DOI: 10.3748/wjg.v10.i6.800] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To evaluate the role of mitochondrial microsatellite instability (mtMSI) in gastric carcinogenesis.
METHODS: MtMSI was measured with PCR-single strand conformation polymophism (PCR-SSCP) in 68 cases of advanced gastric cancer, 40 cases of chronic gastritis, 30 cases of intestinal metaplasia and 20 cases of dysplasia.
RESULTS: MtMSI was observed in 12.5% (5 of 40) of chronic gastritis, 20.0% (6 of 30) of intestinal metaplasia, 25.0% (5 of 20) of dysplasia and 38.2% (26 of 68) of gastric cancer. These findings showed a sequential accumulation of mtMSI in the histological progression from chonic gastritis to gastric cancer. An association of mtMSI with intestinal histological type and distal location was found (P = 0.001 and P = 0.002), whereas no significant correlation was found between mtMSI and age at diagnosis, sex, tumor size, depth of invasion, lymph node spread and clinical stages (P > 0.05).
CONCLUSION: MtMSI may play an early and important role in the gastric carcinogenesis pathway, especially in the intestinal type and distal gastric cancer.
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Affiliation(s)
- Xian-Long Ling
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
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25
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Garay J, Bravo JC, Correa P, Schneider BG. Infrequency of microsatellite instability in complete and incomplete gastric intestinal metaplasia. Hum Pathol 2004; 35:102-6. [PMID: 14745731 DOI: 10.1016/j.humpath.2003.08.023] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Chronic inflammation may be associated with microsatellite instability (MSI). To test the hypothesis that MSI frequently occurs in gastric intestinal metaplasia, we examined gastric biopsies from 58 subjects from an area of high risk for gastric cancer. These were selected to have 2 types of intestinal metaplasia: complete (31 subjects) and incomplete or mixed-type (27 subjects). None of the subjects had gastric cancer, but 95% had chronic inflammation with Helicobacter pylori. We used laser capture microdissection to retrieve metaplastic glands to compare with lymphocytes microdissected from the adjacent gastric mucosae in the same subjects. We performed microsatellite analysis using 6 microsatellite loci, including BAT26. None of the cases were found to have reproducible MSI, and only 1 case showed loss of heterozygosity at 1 marker, D3S1067. To test the sensitivity of our assay, we mixed templates to produce bands of different mobility and found that we could detect an aberrant microsatellite pattern if only 2% of the DNA showed that pattern. Our results indicate that MSI is a rare event in intestinal metaplasia in subjects who do not have gastric cancer.
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Affiliation(s)
- Jone Garay
- Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
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26
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Akiyama S, Tamura G, Endoh Y, Fukushima N, Ichihara Y, Aizawa K, Kawata S, Motoyama T. Histogenesis of hepatoid adenocarcinoma of the stomach: molecular evidence of identical origin with coexistent tubular adenocarcinoma. Int J Cancer 2003; 106:510-515. [PMID: 12845645 DOI: 10.1002/ijc.11246] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Hepatoid adenocarcinoma of the stomach is a highly malignant neoplasm. Most gastric hepatoid adenocarcinomas coexist with tubular adenocarcinoma. However, the relationship between hepatoid adenocarcinoma and tubular adenocarcinoma is still unclear. In the present study, the characteristics of the coexistent tubular adenocarcinomas were determined by examining their profiles of mucin production. Subsequently, molecular pathological techniques were applied to determine the clonality of 15 mixed hepatoid and tubular adenocarcinomas of the stomach. Mucin analysis suggested that the coexistent tubular adenocarcinomas with hepatoid adenocarcinoma were of the intestinal type. The patterns of chromosome X inactivation were identical between the hepatoid adenocarcinoma component and tubular adenocarcinoma component in all of 3 informative female cases. Mutations in the p53 gene were found in 5 cases. The sequences were identical within both tumor components in all 5 cases. Microsatellite analysis indicated more than 3 common patterns of loss of heterozygosity in 8 cases. These observations strongly suggested that hepatoid adenocarcinomas were of identical origin to coexistent tubular adenocarcinomas.
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Affiliation(s)
- Sunao Akiyama
- Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan
- Department of Internal Medicine, Yamagata University School of Medicine, Yamagata, Japan
| | - Gen Tamura
- Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan
| | - Yasushi Endoh
- Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan
| | | | - Yukihiro Ichihara
- Department of Surgery, Prefectural Central Hospital, Yamagata, Japan
| | - Kikuo Aizawa
- Department of Surgery, Tsubame Rosai Hospital, Tsubame, Japan
| | - Sumio Kawata
- Department of Internal Medicine, Yamagata University School of Medicine, Yamagata, Japan
| | - Teiichi Motoyama
- Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan
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Shibata N, Watari J, Fujiya M, Tanno S, Saitoh Y, Kohgo Y. Cell kinetics and genetic instabilities in differentiated type early gastric cancers with different mucin phenotype. Hum Pathol 2003; 34:32-40. [PMID: 12605364 DOI: 10.1053/hupa.2003.2] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
To clarify the biological impact and molecular pathogenesis of cellular phenotype in differentiated-type gastric cancers (DGCs), we investigated cell kinetics and genetic instabilities in early stage of DGCs. A total of 43 early gastric cancers (EGCs) were studied. EGCs were divided into 3 phenotypic categories: gastric (G type, n = 11), ordinary (O type, n = 20), and complete intestinal (CI type, n = 12) based on the combination of HGM, ConA, MUC2, and CD10. Proliferative index (PI), apoptotic index (AI), and p53 overexpression were investigated by immunohistochemical staining with anti-Ki-67, the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method, and p53 antibody, respectively. Using a high-resolution fluorescent microsatellite analysis system, microsatellite instability (MSI) and loss of heterozygosity (LOH) were examined. Frameshift mutation analysis of transforming growth factor-beta type II receptor (TGF-betaRII) and bcl-2-associated X (BAX) in cancers with MSI was also performed. The mean AI/PI ratio values were 0.04 for G-type, 0.10 for O-type, and 0.13 for CI-type cancers--significantly lower in G type than in O and CI types (P = 0.02 and P = 0.001, respectively). No difference in the incidence of MSI and LOH was seen among the 3 cellular phenotypes. However, the major pattern of MSI, which showed drastic and widely dispersed changes and is related to an increased risk for cancer, was significantly higher in G and O types than in CI type (P <0.005). No frame shift mutations of TGF-betaRII or BAX were found in CI-type cancers. These results indicate that G-type cancers are likely to show more aggressive behaviors than CI-type cancers, and that O-type cancers show the intermediate characteristics of both types. However, the molecular pathogenesis of each phenotypic cancer is not associated with microsatellite alterations.
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Affiliation(s)
- Naomi Shibata
- Third Department of Internal Medicine, Asahikawa Medical College, Asahikawa, Japan
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28
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Jin Z, Tamura G, Honda T, Motoyama T. Molecular and cellular phenotypic profiles of gastric noninvasive neoplasia. J Transl Med 2002; 82:1637-45. [PMID: 12480914 DOI: 10.1097/01.lab.0000041712.58604.cc] [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: 01/27/2023] Open
Abstract
According to the Padova international classification, 52 gastric noninvasive neoplasias (NIN) were classified as follows: 20 low-grade NIN (L-NIN); 9 high-grade NIN including suspicion for carcinoma without invasion (H-NIN); and 23 high-grade NIN including carcinoma without invasion (Ca-NIN). The molecular and cellular phenotypic profiles were investigated and compared. The APC gene was mutated in seven (35%) L-NIN, two (22%) H-NIN, and two (9%) Ca-NIN tumors; APC mutations were significantly more frequent in L-NIN compared with Ca-NIN tumors (p < 0.05). Mutations of the p53 gene were found in five (22%) Ca-NIN tumors but were not observed in L-NIN or H-NIN tumors (p < 0.05). Loss of heterozygosity involving at least one chromosomal locus was detected in 14 (61%) Ca-NIN tumors but was not detected in L-NIN or H-NIN tumors. High-frequency microsatellite instability (MSI-H) was detected in one (5%) L-NIN tumor and in six (26%) Ca-NIN tumors. The frequencies of loss of heterozygosity and MSI-H were significantly higher in Ca-NIN than in L-NIN or H-NIN tumors (p < 0.05). Nuclear accumulation of p53 protein was detected in no L-NIN tumors, 1 (11%) H-NIN tumor, and 10 (44%) Ca-NIN tumors (p < 0.01). All tumors with loss of hMLH1 expression exhibited MSI-H (p < 0.01). Cellular phenotypic analysis revealed that seven (35%) L-NIN tumors and one (4%) Ca-NIN tumor had complete-type intestinal metaplastic phenotype and that one (5%) L-NIN tumor and one (4%) Ca-NIN tumor had a gastric foveolar epithelial phenotype, whereas the remaining tumors exhibited an ordinary phenotype. Thus, the complete-type intestinal metaplastic phenotype was more characteristic of L-NIN tumors than of H-NIN or Ca-NIN tumors (p < 0.01). In summary, the Padova international classification correlated with both the molecular and cellular phenotypic profiles. In practice, p53 and hMLH1 immunohistochemistry discriminated Ca-NIN from L-NIN and H-NIN tumors.
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Affiliation(s)
- Zhe Jin
- Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan
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29
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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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30
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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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31
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Honda T, Tamura G, Waki T, Jin Z, Sato K, Motoyama T, Kawata S, Kimura W, Nishizuka S, Murakami Y. Hypermethylation of the TSLC1 gene promoter in primary gastric cancers and gastric cancer cell lines. Jpn J Cancer Res 2002; 93:857-60. [PMID: 12716461 PMCID: PMC5927103 DOI: 10.1111/j.1349-7006.2002.tb01329.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The TSLC1 (tumor suppressor in lung cancer-1) gene is a novel tumor suppressor gene on chromosomal region 11q23.2, and is frequently inactivated by concordant promoter hypermethylation and loss of heterozygosity (LOH) in non-small cell lung cancer (NSCLC). Because LOH on 11q has also been observed frequently in other human neoplasms including gastric cancer, we investigated the promoter methylation status of TSLC1 in 10 gastric cancer cell lines and 97 primary gastric cancers, as well as the corresponding non-cancerous gastric tissues, by bisulfite-SSCP analysis followed by direct sequencing. Allelic status of the TSLC1 gene was also investigated in these cell lines and primary gastric cancers. The TSLC1 promoter was methylated in two gastric cancer cell lines, KATO-III and ECC10, and in 15 out of 97 (16%) primary gastric cancers. It was not methylated in non-cancerous gastric tissues, suggesting that this hypermethylation is a cancer-specific alteration. KATO-III and ECC10 cells retained two alleles of TSLC1, both of which showed hypermethylation, associated with complete loss of gene expression. Most of the primary gastric cancers with promoter methylation also retained heterozygosity at the TSLC1 locus on 11q23.2. These data indicate that bi-allelic hypermethylation of the TSLC1 promoter and resulting gene silencing occur in a subset of primary gastric cancers.
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Affiliation(s)
- Teiichiro Honda
- Department of Pathology, Yamagata University School of Medicine, Yamagata 990-9585, Japan
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32
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Sakata K, Tamura G, Endoh Y, Ohmura K, Ogata S, Motoyama T. Hypermethylation of the hMLH1 gene promoter in solitary and multiple gastric cancers with microsatellite instability. Br J Cancer 2002; 86:564-7. [PMID: 11870538 PMCID: PMC2375269 DOI: 10.1038/sj.bjc.6600076] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2001] [Accepted: 11/14/2001] [Indexed: 12/17/2022] Open
Abstract
Human cancers with a high frequency microsatellite instability phenotype develop due to defects in DNA mismatch repair genes. Silencing of a DNA mismatch repair gene, hMLH1 gene, by promoter hypermethylation is a frequent cause of the microsatellite instability-H phenotype. Using methylation specific PCR we investigated the methylation status of the hMLH1 gene promoter in 17 solitary gastric cancers (12 microsatellite instability-H and five microsatellite stable tumours from 17 patients), and 13 multiple gastric cancers (eight microsatellite instability-H, one low frequency microsatellite instability-L and four microsatellite stable tumours from five patients) and also examined non-cancerous gastric mucosa both adjacent to and distant from each tumour. Expression of hMLH1 protein was evaluated by immunohistochemistry. All microsatellite instability-H tumours (20 out of 20) had evidence of methylation of hMLH1 promoter, whereas only one out of 10 microsatellite instability-L and microsatellite stable tumours did (P<0.0000005), and the methylation status correlated with hMLH1 protein expression (P<0.000003). Furthermore, methylation of the hMLH1 promoter was detected in 50% (6 out of 12) and 63% (5 out of 8) of non-cancerous gastric mucosa samples adjacent to, and in 33% (4 out of 12) and 40% (2 out of 5) of those obtained from distant portion of, solitary and multiple cancers with microsatellite instability-H. Thus both solitary and multiple gastric cancers with microsatellite instability-H have evidence of similar high levels of hMLH1 promoter hypermethylation in the surrounding non-cancerous tissue. Hypermethylation of the hMLH1 promoter occurs in non-cancerous gastric mucosa of microsatellite instability-H tumours and may increase the risk of subsequent neoplasia.
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Affiliation(s)
- K Sakata
- Department of Pathology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585, Japan
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33
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Endoh Y, Ajioka Y, Watanabe H, Tamura G, Motoyama T. Author's reply. J Pathol 2001. [DOI: 10.1002/path.957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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34
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Zheng YL, Herr AM, Jacobson BA, Ferrin LJ. High-density allelotype of the commonly studied gastric cancer cell lines. Genes Chromosomes Cancer 2001; 32:67-81. [PMID: 11477663 DOI: 10.1002/gcc.1168] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Gastric cancer is one of the leading causes of death from cancer throughout the world, and studies to elucidate the genetic defects found in this type of cancer are growing in number. Increasingly sophisticated techniques and the sequencing of the human genome have had an impact on the scope of such studies. While the use of tumor specimens remains popular, more emphasis is being placed on cell lines as model systems where specific data can be directly combined with results from other studies. This article describes a genetic survey of the most widely used gastric adenocarcinoma cell lines. The allelotype at 351 polymorphic loci in 14 cell lines was obtained, and the results from the 4,900 polymerase chain reactions are displayed. In addition to confirming loss of heterozygosity on chromosome arms 6p, 7q, 17p, and 18, additional deletions on arm 5p and the pericentromeric regions of chromosomes 1 and 10 were detected. Areas that might contain homozygous deletions or amplifications also were mapped. The rate of microsatellite instability was quantified and shown to vary greatly among the different cell lines. Most important, this study serves as a genetic scaffold for the integration of past and future studies on the nature of the genetic defects in gastric cancer.
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Affiliation(s)
- Y L Zheng
- National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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35
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Jin Z, Tamura G, Satoh M, Meguro T, Miura T, Hayashi M, Osakabe M, Ohmura K, Ogata S, Endoh Y, Motoyama T. Absence of BAT-26 instability in gastric intestinal metaplasia. Pathol Int 2001; 51:473-5. [PMID: 11422810 DOI: 10.1046/j.1440-1827.2001.01220.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BAT-26 instability, a sensitive marker for the high-frequency microsatellite instability (MSI-H) phenotype, was analyzed in samples of gastric cancer and in adjacent intestinal metaplastic mucosae. Although all MSI-H gastric cancer samples showed BAT-26 instability, as assessed using 12 dinucleotide microsatellite markers, BAT-26 instability was not found in the adjacent intestinal metaplastic mucosa in any of the samples.
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Affiliation(s)
- Z Jin
- Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan
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36
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Tamura G, Sato K, Akiyama S, Tsuchiya T, Endoh Y, Usuba O, Kimura W, Nishizuka S, Motoyama T. Molecular characterization of undifferentiated-type gastric carcinoma. J Transl Med 2001; 81:593-8. [PMID: 11304579 DOI: 10.1038/labinvest.3780268] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
As the great majority of gastric cancers develop histologically differentiated, and a significant proportion of differentiated-type carcinomas progress to become undifferentiated, both histological types are likely to share several common genetic abnormalities, such as p53 mutations at advanced stages. However, a subset of gastric cancers develop as undifferentiated carcinomas, including signet-ring cell carcinoma and poorly differentiated adenocarcinoma, and the molecular pathogenesis of this tumor type remains largely unknown. To characterize the molecular features of undifferentiated-type gastric carcinomas that developed as undifferentiated-type, we examined for p53, APC, and epithelial (E)-cadherin gene mutations, microsatellite alterations including loss of heterozygosity (LOH) and microsatellite instability (MSI), and hypermethylation of the E-cadherin gene promoter in 26 early undifferentiated gastric carcinomas, consisting of 14 signet-ring cell carcinomas and 12 poorly differentiated adenocarcinomas. E-cadherin expression was evaluated immunohistochemically. p53 mutations were detected in only one poorly differentiated adenocarcinoma sample (3.8%; 1/26), whereas no APC or E-cadherin mutations were found. LOH was present only at D8S261 on the short arm of chromosome 8 in 2 of 14 (14%) informative tumors, both of which were poorly differentiated adenocarcinomas, and MSI was not observed in any of the tumors. No signet-ring cell carcinomas have been found to carry gene mutations or microsatellite alterations. In contrast, hypermethylation of the E-cadherin promoter occurred in 69% (18/26) of the tumors; 57% (8/14) of signet-ring cell carcinomas, and 83% (10/12) of poorly differentiated adenocarcinomas, and was significantly associated with loss or reduced expression of E-cadherin. Thus, whereas tumor suppressor gene mutation, LOH, and MSI were less common in undifferentiated-type early gastric carcinomas, epigenetic inactivation of E-cadherin via promoter hypermethylation may be an early critical event in the development of undifferentiated tumors.
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Affiliation(s)
- G Tamura
- Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan.
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