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Ishibashi F, Okusa K, Tokai Y, Hirasawa T, Kawakami T, Mochida K, Yanai Y, Yokoi C, Hayashi Y, Ozawa SI, Uraushihara K, Minato Y, Nakanishi H, Ueyama H, Kataoka M, Toyama Y, Mizokami Y, Suzuki S. A mathematical simulation model to determine the optimal endoscopic screening strategy for detection of H. pylori-naïve gastric neoplasms. Gastric Cancer 2024; 27:1078-1087. [PMID: 38937306 DOI: 10.1007/s10120-024-01525-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 06/16/2024] [Indexed: 06/29/2024]
Abstract
BACKGROUND The effectiveness of esophagogastroduodenoscopy (EGD) screening in cohorts with low Helicobacter pylori prevalence is unknown. This study aimed to develop an optimally efficient EGD screening strategy for detecting H. pylori-naïve gastric neoplasms (HpNGNs). METHODS EGD data of 12 institutions from 2016 to 2022 were retrospectively analyzed. Age-related HpNGN prevalence, tumor growth rate, missing rate, and detection threshold size were calculated from the databases. Subsequently, using clinical data, a novel mathematical model that simultaneously simulated demographic changes and HpNGN detection was developed. Screening strategies using different starting ages (40/45/50 years) and intervals (2/5/10 years) were also compared. The detection rates of all tumors occurring within the virtual cohort and number-needed-to-test (NNT) were measured as outcomes. RESULTS Data of 519,368 EGDs and 97 HpNGNs (34 pure signet ring cell carcinomas, 26 gastric adenocarcinomas of the fundic gland type, 30 foveolar gastric adenoma-Raspberry type, and seven undifferentiated-type cancer cases) were analyzed. A virtual cohort with a 70-year time horizon was used to simulate the occurrence, growth, and detection of 346,5836 people. Among the strategies with detection rate > 50%, the screening strategy with a 5-year interval starting at 45 years of age had the lowest NNT. Adopting this strategy, most HpNGNs were detected at < 20 mm in size, and the deep submucosal invasion rate was less than 30%. CONCLUSIONS A mathematical simulation model revealed that screening every 5 years starting at 45 years of age could efficiently assist in identifying HpNGNs at an early stage.
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Affiliation(s)
- Fumiaki Ishibashi
- Department of Gastroenterology, International University of Health and Welfare Ichikawa Hospital, 6-1-14, Konodai, Ichikawa-shi, Chiba, 272-0827, Japan.
| | - Kosuke Okusa
- Faculty of Science and Engineering, Department of Data Science for Business Innovation, Chuo University, Tokyo, 112-8551, Japan
| | - Yoshitaka Tokai
- Department of Gastroenterology, Cancer Institute Hospital, Tokyo, 135-8550, Japan
| | - Toshiaki Hirasawa
- Department of Gastroenterology, Cancer Institute Hospital, Tokyo, 135-8550, Japan
| | | | - Kentaro Mochida
- Department of Gastroenterology, International University of Health and Welfare Ichikawa Hospital, 6-1-14, Konodai, Ichikawa-shi, Chiba, 272-0827, Japan
- Koganei Tsurukame Clinic, Endoscopy Center, Tokyo, 184-0004, Japan
| | - Yuka Yanai
- National Center for Global Health and Medicine, Department of Gastroenterology, Tokyo, 162-8655, Japan
| | - Chizu Yokoi
- National Center for Global Health and Medicine, Department of Gastroenterology, Tokyo, 162-8655, Japan
| | - Yuko Hayashi
- National Center for Global Health and Medicine, Department of Medical Examination Center, Tokyo, 162-8655, Japan
| | - Shun-Ichiro Ozawa
- Department of Gastroenterology and Hepatology, Japan Community Health Care Organization Yamanashi Hospital, Yamanashi, 400-0025, Japan
| | - Koji Uraushihara
- Department of Gastroenterology, Showa General Hospital, Tokyo, 187-8510, Japan
| | - Yohei Minato
- Department of Gastrointestinal Endoscopy, NTT Medical Center Tokyo, Tokyo, 141-8625, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, 180-8610, Japan
| | - Hiroya Ueyama
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, 113-8431, Japan
| | - Mikinori Kataoka
- Department of Gastroenterology, International University of Health and Welfare Mita Hospital, Tokyo, 108-8239, Japan
| | - Yuzo Toyama
- Department of Gastroenterology, New Tokyo Hospital, Chiba, 270-2232, Japan
| | - Yuji Mizokami
- Department of Medical Examination Center, New Tokyo Hospital, Chiba, 270-2232, Japan
| | - Sho Suzuki
- Department of Gastroenterology, International University of Health and Welfare Ichikawa Hospital, 6-1-14, Konodai, Ichikawa-shi, Chiba, 272-0827, Japan
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Inaba Y, Goda K, Kondo M, Abe K, Kanamori A, Suzuki T, Tominaga K, Nakagawa M, Morita S, Kojima K, Ishida K, Irisawa A. Hereditary Diffuse Gastric Cancer Treated by Prophylactic Total Gastrectomy. Intern Med 2024; 63:235-239. [PMID: 37225495 PMCID: PMC10864090 DOI: 10.2169/internalmedicine.1257-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 04/02/2023] [Indexed: 05/26/2023] Open
Abstract
We herein report a rare case of hereditary diffuse gastric cancer in a Japanese man. A 41-year-old man underwent esophagogastroduodenoscopy which revealed a small gastric erosion. Biopsy specimens showed signet ring cell carcinoma, and endoscopic submucosal dissection was performed. The patient's elder sister had died of gastric cancer at 38 years old. Considering the family history, a genetic test was conducted and revealed a CDH1 germline mutation. Although no carcinomatous lesion was detected endoscopically, prophylactic total gastrectomy was performed. The resection specimen showed seven microlesions of signet ring cell carcinoma confined to the lamina propria mucosae.
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Affiliation(s)
- Yasunori Inaba
- Department of Gastroenterology, Dokkyo Medical University, Japan
| | - Kenichi Goda
- Department of Gastroenterology, Dokkyo Medical University, Japan
| | - Masayuki Kondo
- Department of Gastroenterology, Dokkyo Medical University, Japan
| | - Keiichiro Abe
- Department of Gastroenterology, Dokkyo Medical University, Japan
| | - Akira Kanamori
- Department of Gastroenterology, Dokkyo Medical University, Japan
| | - Tsunehiro Suzuki
- Department of Gastroenterology, Dokkyo Medical University, Japan
| | - Keiichi Tominaga
- Department of Gastroenterology, Dokkyo Medical University, Japan
| | - Masatoshi Nakagawa
- Department of Upper Gastrointestinal Surgery, Dokkyo Medical University, Japan
| | - Shinji Morita
- Department of Upper Gastrointestinal Surgery, Dokkyo Medical University, Japan
| | - Kazuyuki Kojima
- Department of Upper Gastrointestinal Surgery, Dokkyo Medical University, Japan
| | - Kazuyuki Ishida
- Department of Diagnostic Pathology, Dokkyo Medical University, Japan
| | - Atsushi Irisawa
- Department of Gastroenterology, Dokkyo Medical University, Japan
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Decourtye-Espiard L, Guilford P. Hereditary Diffuse Gastric Cancer. Gastroenterology 2023; 164:719-735. [PMID: 36740198 DOI: 10.1053/j.gastro.2023.01.038] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 02/07/2023]
Abstract
Hereditary diffuse gastric cancer (HDGC) is a dominantly inherited cancer syndrome characterized by a high incidence of diffuse gastric cancer (DGC) and lobular breast cancer (LBC). HDGC is caused by germline mutations in 2 genes involved in the epithelial adherens junction complex, CDH1 and CTNNA1. We discuss the genetics of HDGC and the variability of its clinical phenotype, in particular the variable penetrance of advanced DGC and LBC, both within and between families. We review the pathology of the disease, the mechanism of tumor initiation, and its natural history. Finally, we describe current best practice for the clinical management of HDGC, including emerging genetic testing criteria for the identification of new families, methods for endoscopic surveillance, the complications associated with prophylactic surgery, postoperative quality of life, and the emerging field of HDGC chemoprevention.
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Affiliation(s)
- Lyvianne Decourtye-Espiard
- Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Parry Guilford
- Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin, New Zealand.
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Muranaka F, Kise E, Tokumaru S, Kitazawa M, Miyagawa Y, Suga T, Uehara T, Iwaya M, Kobayashi S, Sato M, Gomi D, Yamada H, Sugimura H, Kosho T, Soejima Y, Koizumi T. Hereditary diffuse gastric cancer in a Japanese family with CDH1 mutation three case reports. Discov Oncol 2023; 14:14. [PMID: 36719602 PMCID: PMC9889585 DOI: 10.1007/s12672-023-00623-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/25/2023] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1-3% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan. METHOD In this study we report the clinical courses of three cases with HDGC from a single Japanese family. RESULTS The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in these relatives revealing abnormal small pale mucosal patches, small ulcerative lesion and no abnormal findings. Moreover, random and targeted biopsies were compatible with pathological diagnosis of HDGC in the three cases, all of which underwent total prophylactic gastrectomy. CONCLUSION It is critical for the assessment and management of HDGC patients to be actively offered a multidisciplinary and familial-oriented approach. Notably, genetic screening in suspected individuals and familial members is a determining piece for a higher detection rate and the identification of clinical relevant mutations in both low and high-incidence gastric cancer countries.
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Affiliation(s)
- Futoshi Muranaka
- Department of Surgery, Division of Gastroenterological, Transplantation and Pediatric Surgery, Hepato-Biliary-Pancreatic, Shinshu University School of Medicine, Matsumoto, Japan
| | - Emiko Kise
- Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan
| | - Shigeo Tokumaru
- Department of Surgery, Division of Gastroenterological, Transplantation and Pediatric Surgery, Hepato-Biliary-Pancreatic, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masato Kitazawa
- Department of Surgery, Division of Gastroenterological, Transplantation and Pediatric Surgery, Hepato-Biliary-Pancreatic, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yusuke Miyagawa
- Department of Surgery, Division of Gastroenterological, Transplantation and Pediatric Surgery, Hepato-Biliary-Pancreatic, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomoaki Suga
- Endoscopic Examination Center, Shinshu University Hospital, Matsumoto, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Mai Iwaya
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shota Kobayashi
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Midori Sato
- Department of Pathology, Kurashiki Central Hospital, Kurashiki City, Japan
| | - Daisuke Gomi
- Department of Hematology and Medical Oncology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Hidetaka Yamada
- The First Department of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Haruhiko Sugimura
- The First Department of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tomoki Kosho
- Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan
- Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan
- Research Center for Supports to Advanced Science, Shinshu University, Matsumoto, Japan
- Division of Clinical Sequencing, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yuji Soejima
- Department of Surgery, Division of Gastroenterological, Transplantation and Pediatric Surgery, Hepato-Biliary-Pancreatic, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomonobu Koizumi
- Department of Hematology and Medical Oncology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan.
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Akazawa Y, Ueyama H, Hayashi T, Utsunomiya H, Uchida R, Abe D, Oki S, Suzuki N, Ikeda A, Yatagai N, Komori H, Takeda T, Matsumoto K, Ueda K, Matsumoto K, Asaoka D, Hojo M, Saito T, Yao T, Nagahara A. Clinicopathological and molecular characterization of early gastric adenocarcinoma in Helicobacter pylori-uninfected patients: emphasis on differentiated gastric adenocarcinoma. J Gastroenterol 2022; 57:725-734. [PMID: 35939123 DOI: 10.1007/s00535-022-01906-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 07/19/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recently, Helicobacter pylori (HP)-uninfected gastric mucosal cancer has been reported; however, the clinicopathological and molecular features of HP-uninfected gastric cancer have not been elucidated. METHODS We evaluated the clinicopathological, immunohistochemical, and genetic alterations in HP-uninfected early gastric adenocarcinoma using next-generation sequencing (NGS). RESULTS Among 968 primary early gastric carcinomas, 64 (6.6%) were HP-uninfected gastric adenocarcinoma and were pathologically classified as gastric adenocarcinoma of fundic-gland type (GA-FG, n = 39), differentiated gastric adenocarcinoma (DGA, n = 16), and signet-ring cell carcinoma (SRCC, n = 9). Based on the expression profile of the mucin core protein, DGAs were classified into a gastrointestinal phenotype showing either MUC5AC or MUC6 expression and MUC2 or CD10 expression simultaneously (n = 5), and a gastric phenotype (n = 11) showing either MUC5AC or MUC6 expression. All DGAs with a gastrointestinal phenotype shared similar endoscopic characteristics, such as reddish depressed lesions in the antrum. In contrast, DGAs with a gastric phenotype exhibited several distinct endoscopic features, including a raspberry-shaped appearance and whitish flat-elevated appearance; the former expressed only MUC5AC and the latter exhibited co-expression of MUC5AC and MUC6. Among 16 HP-uninfected DGAs, seven were subjected to NGS. APC was recurrently mutated in DGA (42.9%) and was enriched in DGAs with a gastrointestinal phenotype (75%). CONCLUSIONS Overall, HP-uninfected gastric adenocarcinomas showed distinct clinicopathologic and endoscopic characteristics. Furthermore, HP-uninfected DGAs, especially those with a gastrointestinal phenotype, may be characterized by recurrent APC mutations.
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Affiliation(s)
- Yoichi Akazawa
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hiroya Ueyama
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takuo Hayashi
- Department of Human Pathology, Juntendo University School of Medicine, 1-1-19 Hongo, Bunkyo-Ku, Tokyo, Japan.
| | - Hisanori Utsunomiya
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Ryota Uchida
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Daiki Abe
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Shotaro Oki
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Nobuyuki Suzuki
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Atsushi Ikeda
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Noboru Yatagai
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hiroyuki Komori
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tsutomu Takeda
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kohei Matsumoto
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kumiko Ueda
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kenshi Matsumoto
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Daisuke Asaoka
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Mariko Hojo
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Juntendo University School of Medicine, 1-1-19 Hongo, Bunkyo-Ku, Tokyo, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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Malfertheiner P, Megraud F, Rokkas T, Gisbert JP, Liou JM, Schulz C, Gasbarrini A, Hunt RH, Leja M, O'Morain C, Rugge M, Suerbaum S, Tilg H, Sugano K, El-Omar EM. Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report. Gut 2022; 71:gutjnl-2022-327745. [PMID: 35944925 DOI: 10.1136/gutjnl-2022-327745] [Citation(s) in RCA: 583] [Impact Index Per Article: 194.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/21/2022] [Indexed: 01/06/2023]
Abstract
Helicobacter pyloriInfection is formally recognised as an infectious disease, an entity that is now included in the International Classification of Diseases 11th Revision. This in principle leads to the recommendation that all infected patients should receive treatment. In the context of the wide clinical spectrum associated with Helicobacter pylori gastritis, specific issues persist and require regular updates for optimised management.The identification of distinct clinical scenarios, proper testing and adoption of effective strategies for prevention of gastric cancer and other complications are addressed. H. pylori treatment is challenged by the continuously rising antibiotic resistance and demands for susceptibility testing with consideration of novel molecular technologies and careful selection of first line and rescue therapies. The role of H. pylori and antibiotic therapies and their impact on the gut microbiota are also considered.Progress made in the management of H. pylori infection is covered in the present sixth edition of the Maastricht/Florence 2021 Consensus Report, key aspects related to the clinical role of H. pylori infection were re-evaluated and updated. Forty-one experts from 29 countries representing a global community, examined the new data related to H. pylori infection in five working groups: (1) indications/associations, (2) diagnosis, (3) treatment, (4) prevention/gastric cancer and (5) H. pylori and the gut microbiota. The results of the individual working groups were presented for a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in various clinical fields.
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Affiliation(s)
- Peter Malfertheiner
- Medical Department 2, LMU, Munchen, Germany
- Department of Radiology, LMU, Munchen, Germany
| | - Francis Megraud
- INSERM U853 UMR BaRITOn, University of Bordeaux, Bordeaux, France
| | - Theodore Rokkas
- Gastroenterology, Henry Dunant Hospital Center, Athens, Greece
- Medical School, European University, Nicosia, Cyprus
| | - Javier P Gisbert
- Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Jyh-Ming Liou
- Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Christian Schulz
- Medical Department 2, LMU, Munchen, Germany
- Partner Site Munich, DZIF, Braunschweig, Germany
| | - Antonio Gasbarrini
- Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Roma, Italy
| | - Richard H Hunt
- Medicine, McMaster University, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada
| | - Marcis Leja
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
| | - Colm O'Morain
- Faculty of Health Sciences, Trinity College Dublin, Dublin, Ireland
| | - Massimo Rugge
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padova, Padova, Italy
- Veneto Tumor Registry (RTV), Padova, Italy
| | - Sebastian Suerbaum
- Partner Site Munich, DZIF, Braunschweig, Germany
- Max von Pettenkofer Institute, LMU, Munchen, Germany
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medizinische Universitat Innsbruck, Innsbruck, Austria
| | - Kentaro Sugano
- Department of Medicine, Jichi Medical School, Tochigi, Japan
| | - Emad M El-Omar
- Department of Medicine, University of New South Wales, Sydney, New South Wales, Australia
- School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK
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Carneiro F. Familial and hereditary gastric cancer, an overview. Best Pract Res Clin Gastroenterol 2022; 58-59:101800. [PMID: 35988963 DOI: 10.1016/j.bpg.2022.101800] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 04/11/2022] [Accepted: 04/24/2022] [Indexed: 02/08/2023]
Abstract
There are three major hereditable syndromes that affect primarily the stomach: hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) and familial intestinal gastric cancer (FIGC). HDGC is caused by germline mutations in CDH1 gene that occur in 10-40% of HDGC families and, in a minority of cases, by mutations in CTNNA1 gene. GAPPS is caused by germline mutations in the promoter 1B of APC gene, and the genetic cause of FIGC is not fully elucidated. Gastric cancer can also be observed as part of other inherited cancer disorders, namely in familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, and hereditary breast and ovarian cancer syndrome. In this article, the state of the art of familial gastric cancer regarding the clinical, molecular and pathology features is reviewed, as well as the practical aspects for a correct diagnosis and clinical management.
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Affiliation(s)
- Fátima Carneiro
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-135, Porto, Portugal; Department of Pathology, Faculty of Medicine of the University of Porto, Alameda Prof. Hernâni Monteiro, 4100-319, Porto, Portugal; Centro Hospitalar Universitário São João, Alameda Prof. Hernani Monteiro, 4100-319, Porto, Portugal.
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8
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Nikaido M, Miyamoto S, Minato Y, Muto M. Intramucosal signet-ring cell carcinoma with reduced expression of E-cadherin in a Helicobacter pylori-uninfected stomach remained unchanged for 8 years. Clin J Gastroenterol 2021; 15:268-269. [PMID: 34755318 DOI: 10.1007/s12328-021-01545-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 10/22/2021] [Indexed: 11/29/2022]
Affiliation(s)
- Mitsuhiro Nikaido
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-Cho, Sakyo, Kyoto, 606-8507, Japan
| | - Shin'ichi Miyamoto
- Department of Gastroenterology, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa-Mukaihata-Cho, Fushimi, Kyoto, 612-8555, Japan.
| | - Yumiko Minato
- Department of Gastroenterology, The Japan Baptist Hospital, 47 Yamanomoto-cho, Kitashirakawa, Sakyo, Kyoto, 606-8273, Japan
| | - Manabu Muto
- Department of Clinical Oncology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-Cho, Sakyo, Kyoto, 606-8507, Japan
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9
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Garcia‐Pelaez J, Barbosa‐Matos R, Gullo I, Carneiro F, Oliveira C. Histological and mutational profile of diffuse gastric cancer: current knowledge and future challenges. Mol Oncol 2021; 15:2841-2867. [PMID: 33724653 PMCID: PMC8564639 DOI: 10.1002/1878-0261.12948] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 02/23/2021] [Accepted: 03/12/2021] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer (GC) pathogenesis is complex and heterogeneous, reflecting morphological, molecular and genetic diversity. Diffuse gastric cancer (DGC) and intestinal gastric cancer (IGC) are the major histological types. GC may be sporadic or hereditary; sporadic GC is related to environmental and genetic low-risk factors and hereditary GC is caused by inherited high-risk mutations, so far identified only for the diffuse histotype. DGC phenotypic heterogeneity challenges the current understanding of molecular mechanisms underlying carcinogenesis. The definition of a DGC-specific mutational profile remains controversial, possibly reflecting the heterogeneity of DGC-related histological subtypes [signet-ring cell carcinoma (SRCC) and poorly cohesive carcinoma not otherwise specified (PCC-NOS)]. Indeed, DGC and DGC-related subtypes may present specific mutational profiles underlying the particularly aggressive behaviour and dismal prognosis of DGC vs IGC and PCC-NOS vs SRCC. In this systematic review, we revised the histological presentations, molecular classifications and approved therapies for gastric cancer, with a focus on DGC. We then analysed results from the most relevant studies, reporting mutational analysis data specifying mutational frequencies, and their relationship with DGC and IGC histological types, and with specific DGC subtypes (SRCC and PCC-NOS). We aimed at identifying histology-associated mutational profiles with an emphasis in DGC and its subtypes (DGC vs IGC; sporadic vs hereditary DGC; and SRCC vs PCC-NOS). We further used these mutational profiles to identify the most commonly affected molecular pathways and biological functions, and explored the clinical trials directed specifically to patients with DGC. This systematic analysis is expected to expose a DGC-specific molecular profile and shed light into potential targets for therapeutic intervention, which are currently missing.
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Affiliation(s)
- José Garcia‐Pelaez
- i3S – Instituto de Investigação e Inovação em Saúde da Universidade do PortoPortugal
- IPATIMUP – Institute of Molecular Pathology and ImmunologyUniversity of PortoPortugal
- Doctoral Programme on BiomedicineFaculty of MedicineUniversity of PortoPortugal
| | - Rita Barbosa‐Matos
- i3S – Instituto de Investigação e Inovação em Saúde da Universidade do PortoPortugal
- IPATIMUP – Institute of Molecular Pathology and ImmunologyUniversity of PortoPortugal
- Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences (BiotechHealth)ICBAS – Institute of Biomedical Sciences Abel SalazarUniversity of PortoPortugal
| | - Irene Gullo
- i3S – Instituto de Investigação e Inovação em Saúde da Universidade do PortoPortugal
- IPATIMUP – Institute of Molecular Pathology and ImmunologyUniversity of PortoPortugal
- Department of PathologyFMUP ‐ Faculty of Medicine of the University of PortoPortugal
- Department of PathologyCHUSJ – Centro Hospitalar Universitário São JoãoPortoPortugal
| | - Fátima Carneiro
- i3S – Instituto de Investigação e Inovação em Saúde da Universidade do PortoPortugal
- IPATIMUP – Institute of Molecular Pathology and ImmunologyUniversity of PortoPortugal
- Department of PathologyFMUP ‐ Faculty of Medicine of the University of PortoPortugal
- Department of PathologyCHUSJ – Centro Hospitalar Universitário São JoãoPortoPortugal
| | - Carla Oliveira
- i3S – Instituto de Investigação e Inovação em Saúde da Universidade do PortoPortugal
- IPATIMUP – Institute of Molecular Pathology and ImmunologyUniversity of PortoPortugal
- Department of PathologyFMUP ‐ Faculty of Medicine of the University of PortoPortugal
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10
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Wang Y, Yin H, Chen X. Circ-LDLRAD3 Enhances Cell Growth, Migration, and Invasion and Inhibits Apoptosis by Regulating MiR-224-5p/NRP2 Axis in Gastric Cancer. Dig Dis Sci 2021; 66:3862-3871. [PMID: 33389349 DOI: 10.1007/s10620-020-06733-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 11/18/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND Emerging as a newly discovered type of noncoding RNAs, circular RNAs have been manifested as a crucial regulator in tumorigenesis of human malignancies, including gastric cancer (GC). Although circ-LDLRAD3 has been revealed as an oncogene in pancreatic cancer, the underlying role of circ-LDLRAD3 in GC remains poorly understood. AIMS Exploring the underlying function of circ-LDLRAD3 on GC progression. METHODS Circ-LDLRAD3 expression was detected through RT-qPCR. EdU, colony formation, TUNEL, and transwell assays were performed to analyze the function of circ-LDLRAD3 on GC progression. Luciferase reporter and RIP assays were applied to testify the interaction between circ-LDLRAD, miR-224-5p, and NRP2 in GC. RESULTS We detected preliminarily the expression of circ-LDLRAD3 and observed a markedly high expression of circ-LDLRAD3 in GC cells. Besides, circ-LDLRAD3 was featured with loop structure. Biological function assays testified that silenced circ-LDLRAD3 inhibited cell proliferation, migration, and invasion capacity but facilitated apoptosis of GC cells. Molecular mechanism assays uncovered that circ-LDLRAD3 combined with miR-224-5p in GC. Moreover, rescue assays delineated that inhibited expression of miR-224-5p could restore the inhibitive influence of circ-LDLRAD3 knockdown on the progression of GC. Moreover, neuropilin 2 (NRP2) was a downstream target of miR-224-5p. Additionally, circ-LDLRAD3 regulated NRP2 expression by sponging miR-224-5p in GC. Furthermore, circ-LDLRAD3 depletion-mediated effect on GC progression could be reversed by overexpressing NRP2. CONCLUSIONS Circ-LDLRAD3 facilitates GC progression by regulating miR-224-5p/NRP2 axis, providing new insights for the researches of GC treatment.
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Affiliation(s)
- Yan Wang
- The Department of Geriatric Oncology, The Fourth People's Hospital of Shenyang, Shenyang, 110031, Liaoning, China
| | - Hailin Yin
- Department of Medical Oncology, People's Hospital of Lianshui County, No. 6 East Hongri Avenue, Lianshui County, Huaian, 223400, Jangsu, China.
| | - Xin Chen
- The Department of Geriatric Oncology, The Fourth People's Hospital of Shenyang, Shenyang, 110031, Liaoning, China
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11
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Lifestyles, genetics, and future perspectives on gastric cancer in east Asian populations. J Hum Genet 2021; 66:887-899. [PMID: 34267306 PMCID: PMC8384627 DOI: 10.1038/s10038-021-00960-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/08/2021] [Accepted: 07/05/2021] [Indexed: 12/17/2022]
Abstract
The prevalence of gastric cancer (GC) differs among regions worldwide, with the highest occurrence in east Asia. Thus, its etiology, with respect to ethnic background, environmental factors, and lifestyles, is also thought to differ essentially. In addition, etiology of GC is speculated to be changing due to the recent decrease in the Helicobacter pylori (H. pylori) infection in Japan. State-of-the-art somatic/germline cancer genomics has clarified the etiologies of gastric carcinogenesis. In this review article, we summarize past and present milestones in our understanding of GC achieved through genomic approaches, including a recent report that revealed higher-than-expected frequencies of GCs attributed to east Asian-specific germline variants in ALDH2 or CDH1 in combination with lifestyles. Based on this updated knowledge, we also discuss the possible impact of and high-risk approaches for GCs in the upcoming "H. pylori-negative era."
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12
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Yu L, Gao Y, Ji B, Feng Z, Li T, Luan W. CTCF-induced upregulation of LINC01207 promotes gastric cancer progression via miR-1301-3p/PODXL axis. Dig Liver Dis 2021; 53:486-495. [PMID: 33495099 DOI: 10.1016/j.dld.2020.12.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Long non coding RNAs (lncRNAs) have been validated to be involved in the complicated biological processes during tumor progression. LINC01207 has been identified as an oncogene in several cancer types. However, the function of LINC01207 and its underlying molecular mechanism in gastric cancer (GC) are poorly understood. METHODS The expression level of LINC01207, miR-1301-3p and PODXL mRNA was detected in GC tissues and cells by RT-qPCR. The level of PODXL protein was examined by western blot. Colony formation assay, EdU assay, TUNEL assay, caspase-3 activity test and transwell assays were carried out to analyze the effect of LINC01207 on GC cell proliferation, apoptosis, migration and invasion. The interaction between RNAs was confirmed by luciferase reporter assay, RNA pull-down assay and RIP assay. RESULTS LINC01207 was expressed at high level in GC tissues and cells. Silencing of LINC01207 impaired GC cell proliferation, migration and invasion but promoted cell apoptosis. Mechanistically, LINC01207 acted as a ceRNA by sponging miR-1301-3p to upregulate PODXL. Besides, miR-1301-3p silencing or PODXL overexpression could abolish the inhibitory effect of LINC01207 knockdown on GC cell growth and migration. CCCTC-binding factor (CTCF) could transcriptionally activate LINC01207 in GC cells. CONCLUSIONS CTCF-induced activation of LINC01207 contributes to GC progression through regulating miR-1301-3p/PODXL axis.
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Affiliation(s)
- Lan Yu
- Clinical Medical Research Center, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, 010017, China
| | - Yanwei Gao
- Surgery of Abdominal Tumors, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, 010017, China
| | - Beibei Ji
- Departments of Oncology, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, 010017, China
| | - Zongqi Feng
- Clinical Medical Research Center, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, 010017, China
| | - Tianfang Li
- Clinical Medical Research Center, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, 010017, China
| | - Wei Luan
- Departments of Oncology, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, 010017, China.
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13
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Takita M, Ohata K, Inamoto R, Kurebayashi M, Takayanagi S, Kimoto Y, Suzuki Y, Ishii R, Ono K, Negishi R, Minato Y, Sakai E, Muramoto T, Matsuhashi N, Ichihara S. Endoscopic and histological features of Helicobacter pylori-negative differentiated gastric adenocarcinoma arising in the antrum. JGH Open 2021; 5:470-477. [PMID: 33860098 PMCID: PMC8035464 DOI: 10.1002/jgh3.12518] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 01/20/2021] [Accepted: 02/22/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIM With the increasing prevalence of persons without Helicobacter pylori (HP) infection, cases of HP-negative gastric cancer are increasing. Although rare, cases of differentiated adenocarcinoma of the antrum have been reported in HP-negative patients. We collected cases with such lesions and investigated their endoscopic and histological features. METHODS Of 1965 consecutive patients with early gastric cancer who underwent endoscopic resection between January 2009 and December 2017, we extracted 9 cases of HP-negative differentiated adenocarcinoma located in the antrum (HPN-DAA). The clinical data, endoscopic findings, and histopathological findings were reviewed. RESULTS Of the nine patients with HPN-DAA, seven were male, and the median age was 53.8 years. The tumor arose from the pyloric gland mucosa in all cases. According to the endoscopic findings, the lesions were flat-elevated or depressed, mimicking varioliform gastritis. Magnifying endoscopy with narrow-band imaging showed the absence of a clear demarcation line or an irregular microvessel/surface pattern. As for the histopathological findings, eight of the nine lesions were diagnosed as high-grade dysplasia/intraepithelial neoplasia, while the remaining case was diagnosed as tubular adenocarcinoma with submucosal infiltration. The findings of immunohistochemistry confirmed that three cases were of the intestinal mucin phenotype and six were of the mixed gastric and intestinal mucin phenotype. CONCLUSION HPN-DAA is a very rarely occurring cancer that had never been recognized earlier. They belong to the new category of HP-negative cancers, and there seems to be a certain number of such cases.
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Affiliation(s)
- Maiko Takita
- Department of Gastrointestinal EndoscopyNTT Medical Center TokyoTokyoJapan
| | - Ken Ohata
- Department of Gastrointestinal EndoscopyNTT Medical Center TokyoTokyoJapan
| | - Rin Inamoto
- Department of Gastrointestinal EndoscopyNTT Medical Center TokyoTokyoJapan
| | - Marie Kurebayashi
- Department of Gastrointestinal EndoscopyNTT Medical Center TokyoTokyoJapan
| | - Syunya Takayanagi
- Department of Gastrointestinal EndoscopyNTT Medical Center TokyoTokyoJapan
| | - Yoshiaki Kimoto
- Department of Gastrointestinal EndoscopyNTT Medical Center TokyoTokyoJapan
| | - Yuichiro Suzuki
- Department of Gastrointestinal EndoscopyNTT Medical Center TokyoTokyoJapan
| | - Rindo Ishii
- Department of Gastrointestinal EndoscopyNTT Medical Center TokyoTokyoJapan
| | - Kohei Ono
- Department of Gastrointestinal EndoscopyNTT Medical Center TokyoTokyoJapan
| | - Ryoju Negishi
- Department of Gastrointestinal EndoscopyNTT Medical Center TokyoTokyoJapan
| | - Yohei Minato
- Department of Gastrointestinal EndoscopyNTT Medical Center TokyoTokyoJapan
| | - Eiji Sakai
- Department of Gastrointestinal EndoscopyNTT Medical Center TokyoTokyoJapan
- Department of GastroenterologyYokohama Sakae Kyosai HospitalYokohamaJapan
| | - Takashi Muramoto
- Department of Gastrointestinal EndoscopyNTT Medical Center TokyoTokyoJapan
| | | | - Shin Ichihara
- Department of Surgical PathologySapporo Kosei General HospitalSapporoJapan
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14
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Lee SY. Helicobacter pylori-negative Gastric Cancer. THE KOREAN JOURNAL OF HELICOBACTER AND UPPER GASTROINTESTINAL RESEARCH 2021. [DOI: 10.7704/kjhugr.2020.0036] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
<i>Helicobacter pylori (H. pylori)</i>-negative gastric cancer is diagnosed when gastric malignancies are found in patients in <i>H. pylori</i>-naïve stomachs. There are four types of noncardiac <i>H. pylori</i>-negative gastric cancers. The signet ring cell-type poorly cohesive carcinoma is most common, followed by the chief cell-predominant type gastric adenocarcinoma of the fundic gland. Extremely well-differentiated adenocarcinoma of the corpus and well-differentiated pyloric gland cancers are rare outside Japan because of country-specific differences in diagnostic criteria. In endemic areas of <i>H. pylori</i> infection, strict criteria are required for diagnosing an <i>H. pylori</i>-naïve stomach. Both invasive and noninvasive <i>H. pylori</i> tests should show negative results in a subject without a history of <i>H. pylori</i> infection. Furthermore, the serum pepsinogen (PG) assay and endoscopic findings of the background gastric mucosa are required to discriminate subjects with past infections owing to spontaneous regression or unintended eradication of <i>H. pylori</i>. There should be no gastric corpus atrophy (PG I ≤70 ng/mL and PG I/II ≤3.0). Gastroscopy should reveal a regular arrangement of collecting venules without gastric xanthoma, metaplastic gastritis, or advanced atrophy over the angle. On biopsy, there should be no gastric atrophy, intestinal metaplasia, neutrophils, or <i>H. pylori</i> infiltration, and only a mild degree of mononuclear cell infiltration is permitted. The types and characteristics of noncardiac <i>H. pylori</i>-negative gastric cancers are summarized in this review, along with current diagnostic challenges found in Korea.
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15
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Hirakawa M, Takada K, Sato M, Fujita C, Hayasaka N, Nobuoka T, Sugita S, Ishikawa A, Mizukami M, Ohnuma H, Murase K, Miyanishi K, Kobune M, Takemasa I, Hasegawa T, Sakurai A, Kato J. Case series of three patients with hereditary diffuse gastric cancer in a single family: Three case reports and review of literature. World J Gastroenterol 2020; 26:6689-6697. [PMID: 33268956 PMCID: PMC7673959 DOI: 10.3748/wjg.v26.i42.6689] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/11/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome often associated with germline mutations in the CDH1 gene. However, the frequency of CDH1 mutations is low in patients with HDGC in East Asian countries. Herein, we report three cases of HDGC harboring a missense CDH1 variant, c.1679C>G, from a single Japanese family.
CASE SUMMARY A 26-year-old female (Case 1) and a 51-year-old male (father of Case 1), who had a strong family history of gastric cancer, were diagnosed with advanced diffuse gastric cancer. After genetic counselling, a 25-year-old younger brother of Case 1 underwent surveillance esophagogastroduodenoscopy that detected small signet ring cell carcinoma foci as multiple pale lesions in the gastric mucosa. Genetic analysis revealed a CDH1 c.1679C>G variant in all three patients.
CONCLUSION It is important for individuals suspected of having HDGC to be actively offered genetics evaluation. This report will contribute to an increased awareness of HDGC.
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Affiliation(s)
- Masahiro Hirakawa
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
- Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, Sapporo 003-0804, Hokkaido, Japan
| | - Kohichi Takada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Masanori Sato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Chisa Fujita
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Naotaka Hayasaka
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Takayuki Nobuoka
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Shintaro Sugita
- Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Aki Ishikawa
- Department of Medical Genetics, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Miyako Mizukami
- Department of Medical Genetics, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Hiroyuki Ohnuma
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Kazuyuki Murase
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Masayoshi Kobune
- Department of Hematology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Ichiro Takemasa
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Tadashi Hasegawa
- Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Akihiro Sakurai
- Department of Medical Genetics, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan
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16
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Histopathologic Analysis of Signet-ring Cell Carcinoma In Situ in Patients With Hereditary Diffuse Gastric Cancer. Am J Surg Pathol 2020; 44:1204-1212. [PMID: 32520759 DOI: 10.1097/pas.0000000000001511] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Hereditary diffuse gastric cancer (HDGC) is a rare autosomal dominant syndrome associated with an increased risk of developing Laurén's diffuse-type gastric carcinoma and lobular breast carcinoma. Although signet-ring cell carcinoma (SRCC) in situ (SRCC-pTis) has been reported as a characteristic lesion in HDGC cases with CDH1 germline mutations (CDH1 pathogenic variant), and a precursor of conventional intramucosal SRCC (SRCC-pT1a), its histopathologic features and specificity have not been sufficiently clarified. Here, we examined gastrectomy samples from 6 Japanese HDGC patients with CDH1 germline mutation, belonging to 4 families, and analyzed SRCC lesions histologically and immunohistochemically. Of the 274 foci found in the 6 samples, SRCC-pT1a accounted for 225 lesions (range: 8 to 107, mean 45.7 lesions per patient), while 46 foci were of SRCC-pTis (range: 1 to 15, mean 7.67 foci per patient). All SRCC-pTis foci were observed in the fundic gland area and on the superficial side of the mucosa. Histologically, tumor cells of SRCC-pTis were found between normal foveolar epithelial cells and the basement membrane, following a typical pagetoid spread pattern. Immunohistochemically, E-cadherin expression was lost in SRCC-pTis (27/28, 96.4%) more frequently than in SRCC-pT1a (95/197, 48.2%; P<0.001). To elucidate the specificity of SRCC-pTis for HDGC, 60 samples (range: 0.12 to 1.49 m, total 28.8 m of mucosal length) from gastric cancer cases were analyzed as controls, in which no SRCC-pTis were identified. Our results indicate that SRCC-pTis is a distinct histologic feature with high specificity for HDGC cases with CDH1 germline mutations.
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17
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Lin M, Gao M, Cavnar MJ, Kim J. Utilizing gastric cancer organoids to assess tumor biology and personalize medicine. World J Gastrointest Oncol 2019; 11:509-517. [PMID: 31367270 PMCID: PMC6657221 DOI: 10.4251/wjgo.v11.i7.509] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/25/2019] [Accepted: 06/13/2019] [Indexed: 02/05/2023] Open
Abstract
While the incidence and mortality of gastric cancer (GC) have declined due to public health programs, it remains the third deadliest cancer worldwide. For patients with early disease, innovative endoscopic and complex surgical techniques have improved survival. However, for patients with advanced disease, there are limited treatment options and survival remains poor. Therefore, there is an urgent need for more effective therapies. Since novel therapies require extensive preclinical testing prior to human trials, it is important to identify methods to expedite this process. Traditional cancer models are restricted by the inability to accurately recapitulate the primary human tumor, exorbitant costs, and the requirement for extended periods of development time. An emerging in vitro model to study human disease is the patient-derived organoid, which is a three-dimensional system created from fresh surgical or biopsy tissues of a patient’s gastric tumor. Organoids are cultured in plastic wells and suspended in a gelatinous matrix, providing a substrate for extension and growth in all dimensions. They are rapid-growing and highly representative of the molecular landscape, histology, and morphology of the various subtypes of GC. Organoids uniquely model tumor initiation and growth, including steps taken by normal stomach cells to transform into invasive, intestinal-type tumor cells. Additionally, they provide ample material for biobanking and screening novel therapies. Lastly, organoids are a promising model for personalized therapy and warrant further investigation in drug sensitivity studies for GC patients.
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Affiliation(s)
- Miranda Lin
- Department of Surgery, University of Kentucky, Lexington, KY 40536, United States
| | - Mei Gao
- Department of Surgery, University of Kentucky, Lexington, KY 40536, United States
| | - Michael J Cavnar
- Department of Surgery, University of Kentucky, Lexington, KY 40536, United States
| | - Joseph Kim
- Department of Surgery, University of Kentucky, Lexington, KY 40536, United States
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18
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Ding L, Zhao Y, Dang S, Wang Y, Li X, Yu X, Li Z, Wei J, Liu M, Li G. Circular RNA circ-DONSON facilitates gastric cancer growth and invasion via NURF complex dependent activation of transcription factor SOX4. Mol Cancer 2019; 18:45. [PMID: 30922402 PMCID: PMC6437893 DOI: 10.1186/s12943-019-1006-2] [Citation(s) in RCA: 185] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 03/15/2019] [Indexed: 12/24/2022] Open
Abstract
Background Circular RNAs (circRNAs) are a novel type of noncoding RNAs and play important roles in tumorigenesis, including gastric cancer (GC). However, the functions of most circRNAs remain poorly understood. In our study, we aimed to investigate the functions of a new circRNA circ-DONSON in GC progression. Methods The expression of circ-DONSON in gastric cancer tissues and adjacent normal tissues was analyzed by bioinformatics method, qRT-PCR, Northern blotting and in situ hybridization (ISH). The effects of circ-DONSON on GC cell proliferation, apoptosis, migration and invasion were measured by using CCK8, colony formation, EdU, immunofluorescence (IF), FACS and Transwell assays. qRT-PCR and Western blotting were utilized to validate how circ-DONSON regulates SOX4 expression. ChIP, DNA fluorescence in situ hybridization (DNA-FISH) and DNA accessibility assays were used to investigate how circ-DONSON regulates SOX4 transcription. The interaction between circ-DONSON and NURF complex was evaluated by mass spectrum, RNA immunoprecipitation (RIP), pulldown and EMSA assays. Xenograft mouse model was used to analyze the effect of circ-DONSON on GC growth in vivo. Results Elevated expression of circ-DONSON was observed in GC tissues and positively associated with advanced TNM stage and unfavorable prognosis. Silencing of circ-DONSON significantly suppressed the proliferation, migration and invasion of GC cells while promoting apoptosis. circ-DONSON was localized in the nucleus, recruited the NURF complex to SOX4 promoter and initiated its transcription. Silencing of the NURF complex subunit SNF2L, BPTF or RBBP4 similarly attenuated GC cell growth and increased apoptosis. circ-DONSON knockdown inhibited GC growth in vivo. Conclusion circ-DONSON promotes GC progression through recruiting the NURF complex to initiate SOX4 expression. Electronic supplementary material The online version of this article (10.1186/s12943-019-1006-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lixian Ding
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001, People's Republic of China.,Bio-Bank of Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Yuying Zhao
- Department of Medical Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Shuwei Dang
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001, People's Republic of China.,Bio-Bank of Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Yue Wang
- Department of Pharmacology and Toxicology, Wright State University, Fairborn, OH, 45435, USA
| | - Xinglong Li
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001, People's Republic of China.,Bio-Bank of Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Xiaotong Yu
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001, People's Republic of China.,Bio-Bank of Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Zhongsheng Li
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001, People's Republic of China.,Bio-Bank of Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Jiufeng Wei
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001, People's Republic of China.,Bio-Bank of Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Ming Liu
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001, People's Republic of China.,Bio-Bank of Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Guodong Li
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001, People's Republic of China. .,Bio-Bank of Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China.
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