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Gürel İ, Aşıcıoğlu F, Ersoy G, Bülbül Ö, Öztürk T, Filoğlu G. InDEL instability in two different tumoral tissues and its forensic significance. Forensic Sci Med Pathol 2024; 20:1241-1250. [PMID: 38568352 PMCID: PMC11790770 DOI: 10.1007/s12024-024-00808-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2024] [Indexed: 02/04/2025]
Abstract
There may be cases where malignant tumor samples can be used for forensic DNA profiling studies. STRs are the first systems preferred in forensic science laboratories for identification purposes. However, genetic instability in tumoral tissues causes STR polymorphism to change, leading to erroneous results. On the other hand, insertion/deletion polymorphism (InDels) are used as genetic markers in forensic science, as they have features that make both STR and SNPs preferable. Although previous studies approved that STR instability is observed in many different tumors, there are only a few studies that have displayed the instability of InDels in tumoral tissues before. In this study, it was aimed to determine whether instability is observed in formalin-fixed paraffin-embedded breast and thyroid tumoral tissues at 36plex InDel Panel. A total of 47 cases, 26 of which were diagnosed as breast cancer and 21 as thyroid cancer, were included in the study. In 21 of 26 (80.76%) breast cancers mutational changes were observed, however only 6 of 21 (28.57%) thyroid carcinoma cases displayed instability.Moreover, in these six cases, mutations were detected at only 1 or 2 loci. The most common change in both tissues was loss of heterozygosity. These findings suggest that paraffin embedded tissues of thyroid tumor can be used in cases of forensic genetic identification, however paraffin embedded breast cancer tissues should be examined with care. In conclusion, low InDel mutation rates compared to STR instability, make InDel analysis from paraffin blocks suitable for forensic genetic identification. However, researchers should keep in mind that there may be differences between the profiles of the tumoral tissues taken as reference and the actual case. In addition, by incorporating additional markers such as SNPs and microhaplotypes with low mutation rates into the study alongside Indels, researchers can significantly enhance the discrimination power in identification processes.
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Affiliation(s)
- İpek Gürel
- Department of Science, Institute of Forensic Sciences and Legal Medicine, İstanbul University- Cerrahpaşa, İstanbul, Türkiye
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Haliç University, İstanbul, Türkiye
| | - Faruk Aşıcıoğlu
- Department of Medical Sciences, Institute of Forensic Sciences and Legal Medicine, İstanbul University-Cerrahpaşa, İstanbul, Türkiye.
| | - Gökhan Ersoy
- Department of Medical Sciences, Institute of Forensic Sciences and Legal Medicine, İstanbul University-Cerrahpaşa, İstanbul, Türkiye
| | - Özlem Bülbül
- Department of Science, Institute of Forensic Sciences and Legal Medicine, İstanbul University- Cerrahpaşa, İstanbul, Türkiye
| | - Tülin Öztürk
- Department of Medical Pathology, Cerrahpaşa Faculty of Medicine, İstanbul University- Cerrahpaşa, İstanbul, Türkiye
| | - Gönül Filoğlu
- Department of Science, Institute of Forensic Sciences and Legal Medicine, İstanbul University- Cerrahpaşa, İstanbul, Türkiye
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Mejia Perez LK, O'Malley M, Chatterjee A, Lyu R, Yang Q, Cruise MW, LaGuardia L, Liska D, Macaron C, Walsh RM, Burke CA. Endoscopic screening for identification of signet ring cell gastric cancer foci in carriers of germline pathogenic variants in CDH1. Fam Cancer 2024; 23:617-626. [PMID: 39261344 PMCID: PMC11512870 DOI: 10.1007/s10689-024-00421-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 09/03/2024] [Indexed: 09/13/2024]
Abstract
To determine the preoperative detection of signet ring cancer cells (SRC) on upper endoscopy (EGD) in patients with CDH1 pathogenic variant (PV) undergoing gastrectomy. To evaluate the development of advanced diffuse gastric cancer (DGC) in patients choosing surveillance. Guidelines recommend prophylactic total gastrectomy (pTG) in CDH1 PV carriers with family history of DGC between 18 and 40 years. Annual EGD with biopsies according to established protocols is recommended in carriers with no SRC and no family history of DGC, with consideration of pTG. Retrospective analysis of asymptomatic patients with CDH1 PVs with ≥ 1 surveillance EGD. Outcomes included pre-operative EGD detection of SRC, surgical stage, and progression to advanced DGC in those electing surveillance with EGD. 48 patients with CDH1 PVs who had ≥ 1 EGD were included. 24/ 48 (50%) underwent gastrectomy, including pTG in 7 patients. SRCC were detected on gastrectomy specimen in 21/24 (87.5%). SRCs were identified by EGD in 17/21 patients who had SRCC on gastrectomy specimens (sensitivity 81%, 17/21). All cancers were stage pT1a. The remaining 17 patients (50% with a family history of gastric cancer) continue in annual EGD surveillance with a median follow-up of 34.6 months. No SRCC or advanced DGC have been diagnosed. No CDH1 PV carriers without SRCC on random biopsies followed in an endoscopic program developed advanced DGC over a median follow up of 3 years. In the short term, EGD surveillance might be a safe alternative to immediate pTG in experienced hands in referral centers.
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Affiliation(s)
- Lady Katherine Mejia Perez
- Department of Gastroenterology, Hepatology and Nutrition Digestive Disease and Surgical Institute, Cleveland Clinic, Desk A30, 9500 Euclid Avenue, Cleveland, OH, 44195, USA
| | - Margaret O'Malley
- Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA
- Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, USA
| | - Arjun Chatterjee
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Ruishen Lyu
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA
| | - Qijun Yang
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA
| | - Michael W Cruise
- Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, USA
- Department of Pathology and Lab Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Lisa LaGuardia
- Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA
- Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, USA
| | - David Liska
- Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA
- Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, USA
| | - Carole Macaron
- Department of Gastroenterology, Hepatology and Nutrition Digestive Disease and Surgical Institute, Cleveland Clinic, Desk A30, 9500 Euclid Avenue, Cleveland, OH, 44195, USA
- Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, USA
| | - R Matthew Walsh
- Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, USA
- Department of General Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Carol A Burke
- Department of Gastroenterology, Hepatology and Nutrition Digestive Disease and Surgical Institute, Cleveland Clinic, Desk A30, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
- Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA.
- Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, USA.
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Kővári B, Carneiro F, Lauwers GY. Epithelial tumours of the stomach. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2024:227-286. [DOI: 10.1002/9781119423195.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Zeng Z, Zhu Q. Progress and prospects of biomarker-based targeted therapy and immune checkpoint inhibitors in advanced gastric cancer. Front Oncol 2024; 14:1382183. [PMID: 38947886 PMCID: PMC11211377 DOI: 10.3389/fonc.2024.1382183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 05/24/2024] [Indexed: 07/02/2024] Open
Abstract
Gastric cancer and gastroesophageal junction cancer represent the leading cause of tumor-related death worldwide. Although advances in immunotherapy and molecular targeted therapy have expanded treatment options, they have not significantly altered the prognosis for patients with unresectable or metastatic gastric cancer. A minority of patients, particularly those with PD-L1-positive, HER-2-positive, or MSI-high tumors, may benefit more from immune checkpoint inhibitors and/or HER-2-directed therapies in advanced stages. However, for those lacking specific targets and unique molecular features, conventional chemotherapy remains the only recommended effective and durable regimen. In this review, we summarize the roles of various signaling pathways and further investigate the available targets. Then, the current results of phase II/III clinical trials in advanced gastric cancer, along with the superiorities and limitations of the existing biomarkers, are specifically discussed. Finally, we will offer our insights in precision treatment pattern when encountering the substantial challenges.
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Affiliation(s)
| | - Qing Zhu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
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Corso G, Marino E, Zanzottera C, Oliveira C, Bernard L, Macis D, Figueiredo J, Pereira J, Carneiro P, Massari G, Barberis M, De Scalzi AM, Taormina SV, Sajjadi E, Sangalli C, Gandini S, D’Ecclesiis O, Trovato CM, Rotili A, Pesapane F, Nicosia L, La Vecchia C, Galimberti V, Guerini-Rocco E, Bonanni B, Veronesi P. CDH1 Genotype Exploration in Women With Hereditary Lobular Breast Cancer Phenotype. JAMA Netw Open 2024; 7:e247862. [PMID: 38652475 PMCID: PMC11040411 DOI: 10.1001/jamanetworkopen.2024.7862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 02/21/2024] [Indexed: 04/25/2024] Open
Abstract
Importance Pathogenic or likely pathogenic (P/LP) germline CDH1 variants are associated with risk for diffuse gastric cancer and lobular breast cancer (LBC) in the so-called hereditary diffuse gastric cancer (HDGC) syndrome. However, in some circumstances, LBC can be the first manifestation of this syndrome in the absence of diffuse gastric cancer manifestation. Objectives To evaluate the frequency of germline CDH1 variants in women with the hereditary LBC (HLBC) phenotype, somatic CDH1 gene inactivation in germline CDH1 variant carriers' tumor samples, and the association of genetic profiles with clinical-pathological data and survival. Design, Setting, and Participants This single-center, longitudinal, prospective cohort study was conducted from January 1, 1997, to December 31, 2021, with follow-up until January 31, 2023. Women with LBC seen at the European Institute of Oncology were included. Testing for germline CDH1, BRCA1, and BRCA2 genes was performed. Somatic profiling was assessed for germline CDH1 carriers. Main Outcomes and Measures Accurate estimates of prevalence of germline CDH1 variants among patients with HLBC and the association of somatic sequence alteration with HLBC syndrome. The Kaplan-Meier method and a multivariable Cox proportional hazards regression model were applied for overall and disease-free survival analysis. Results Of 5429 cases of primary LBC, familial LBC phenotype accounted for 1867 (34.4%). A total of 394 women with LBC were tested, among whom 15 germline CDH1 variants in 15 unrelated families were identified. Among these variants, 6 (40.0%) were P/LP, with an overall frequency of 1.5% (6 of 394). Of the 6 probands with P/LP CDH1 LBC, 5 (83.3%) had a positive family history of BC and only 1 (16.7%) had sporadic juvenile early-onset LBC. No germline BRCA1 and BRCA2 variants were identified in CDH1 carriers. An inactivating CDH1 mechanism (second hit) was identified in 4 of 6 explored matched tumor samples (66.7%) in P/LP germline carriers. The P/LP CDH1 LBC variant carriers had a significantly lower age at diagnosis compared with the group carrying CDH1 variants of unknown significance or likely benign (42.5 [IQR, 38.3-43.0] vs 51.0 [IQR, 45.0-53.0] years; P = .03). Conclusions and Relevance In this cohort study, P/LP germline CDH1 variants were identified in individuals not fulfilling the classic clinical criteria for HDGC screening, suggesting that identification of these variants may provide a novel method to test women with LBC with early age at diagnosis and/or positive family history of BC.
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Affiliation(s)
- Giovanni Corso
- Division of Breast Surgery, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Elena Marino
- Clinic Unit of Oncogenomics, IEO, IRCCS, Milan, Italy
| | | | - Carla Oliveira
- Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Loris Bernard
- Clinic Unit of Oncogenomics, IEO, IRCCS, Milan, Italy
| | - Debora Macis
- Division of Cancer Prevention and Genetics, IEO, IRCCS, Milan, Italy
| | - Joana Figueiredo
- Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Joana Pereira
- Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Patrícia Carneiro
- Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Giulia Massari
- Division of Breast Surgery, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
| | | | - Alessandra Margherita De Scalzi
- Division of Breast Surgery, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
| | | | | | | | - Sara Gandini
- Department of Experimental Oncology, IEO, IRCCS, Milan, Italy
| | | | | | - Anna Rotili
- Division of Breast Imaging, IEO, IRCCS, Milan, Italy
| | | | - Luca Nicosia
- Division of Breast Imaging, IEO, IRCCS, Milan, Italy
| | - Carlo La Vecchia
- Department of Clinical Sciences and Community Health, Branch of Medical Statistics, Biometry and Epidemiology “G.A. Maccacaro,” University of Milan, Milan, Italy
| | - Viviana Galimberti
- Division of Breast Surgery, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
| | | | - Bernardo Bonanni
- Division of Cancer Prevention and Genetics, IEO, IRCCS, Milan, Italy
| | - Paolo Veronesi
- Division of Breast Surgery, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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6
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Lee M, Eng G, Handte-Reinecker A, Deshpande VS, Yilmaz OH, Gala MK. Germline Determinants of Esophageal Adenocarcinoma. Gastroenterology 2023; 165:1276-1279.e7. [PMID: 37507074 PMCID: PMC10592248 DOI: 10.1053/j.gastro.2023.07.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/14/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023]
Affiliation(s)
- Minyi Lee
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; MD-PhD Program, Boston University School of Medicine, Boston, Massachusetts
| | - George Eng
- Division of Gastroenterology and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Anna Handte-Reinecker
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Vikram S Deshpande
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Omer H Yilmaz
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Manish K Gala
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Lim HJ, Zhuang L, Fitzgerald RC. Current advances in understanding the molecular profile of hereditary diffuse gastric cancer and its clinical implications. J Exp Clin Cancer Res 2023; 42:57. [PMID: 36869400 PMCID: PMC9985294 DOI: 10.1186/s13046-023-02622-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/13/2023] [Indexed: 03/05/2023] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome attributed to germline CDH1 mutations that carries a high risk for early onset DGC. HDGC raises a significant health issue due to its high penetrance and mortality unless diagnosed early. The definitive treatment is to undergo prophylactic total gastrectomy which is associated with significant morbidity., highlighting the urgent need for alternative treatment methods. However, there is limited literature examining potential therapeutic strategies building on emerging insights into the molecular basis of progressive lesions in the context of HDGC. The aim of this review is to summarise the current understanding of HDGC in the context of CDH1 pathogenic variants followed by a review of the proposed mechanisms for progression. In addition, we discuss the development of novel therapeutic approaches and highlight pertinent areas for further research. A literature search was therefore performed for relevant studies examining CDH1 germline variants, second-hit mechanisms of CDH1, pathogenesis of HDGC and potential therapeutic strategies in databases, including PubMed, ScienceDirect and Scopus. Germline mutations are mostly truncating CDH1 variants affecting extracellular domains of E-cadherin, generally due to frameshift, single nucleotide variants or splice site mutations. A second somatic hit of CDH1 most commonly occurs via promoter methylation as shown in 3 studies, but studies are limited with a small sample size. The multi-focal development of indolent lesions in HDGC provide a unique opportunity to understand genetic events that drive the transition to the invasive phenotype. To date, a few signalling pathways have been shown to facilitate the progression of HDGC, including Notch and Wnt. In in-vitro studies, the ability to inhibit Notch signalling was lost in cells transfected with mutant forms of E-cadherin, and increased Notch-1 activity correlated with apoptosis resistance. Furthermore, in patient samples, overexpression of Wnt-2 was associated with cytoplasmic and nuclear β-catenin accumulation and increased metastatic potential. As loss-of-function mutations are challenging to target therapeutically, these findings pave the way towards a synthetic lethal approach in CDH1-deficient cells with some promising results in-vitro. In future, if we could better understand the molecular vulnerabilities in HDGC, there may be opportunities to offer alternative treatment pathways to avoid gastrectomy.
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Affiliation(s)
- Hui Jun Lim
- Department of Oncology, Early Cancer Institute, University of Cambridge, Box 197, Cambridge Biomedical Campus, CB2 0XZ, Cambridge, UK.
- Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
| | - Lizhe Zhuang
- Department of Oncology, Early Cancer Institute, University of Cambridge, Box 197, Cambridge Biomedical Campus, CB2 0XZ, Cambridge, UK
| | - Rebecca C Fitzgerald
- Department of Oncology, Early Cancer Institute, University of Cambridge, Box 197, Cambridge Biomedical Campus, CB2 0XZ, Cambridge, UK
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Passi M, Gamble LA, Samaranayake SG, Schueler SA, Curtin BF, Fasaye GA, Bowden C, Gurram S, Quezado M, Miettinen M, Koh C, Heller T, Davis JL. Association of CDH1 Germline Variants and Colon Polyp Phenotypes in Patients with Hereditary Diffuse Gastric Cancer. GASTRO HEP ADVANCES 2023; 2:244-251. [PMID: 36776716 PMCID: PMC9913407 DOI: 10.1016/j.gastha.2022.10.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Background and Aims Germline CDH1 variants resulting in E-cadherin loss of function result in an increased risk of diffuse type gastric cancer and lobular type breast cancer. However, the risk of developing other epithelial neoplasms, specifically colorectal cancer, is unknown. Methods Patients enrolled in a prospective natural history study of hereditary gastric cancer who underwent at least one colonoscopy were evaluated. Results Out of 300 patients with CDH1 pathogenic or likely pathogenic variants, 85 underwent colonoscopy. More than half of patients (56%, 48/85) had at least one colorectal polyp. Most of those patients (83%, 40/48) had at least one precancerous polyp (adenoma or sessile serrated lesion). More than half (56%) of patients younger than age 45 had a colorectal polyp. Of those with polyps, the most frequent CDH1 variant type was canonical splice site (27%, 13/48) followed by nonsense (21%, 10/48). There was no association between CDH1 variant type and increased likelihood of colorectal polyps. Conclusions In summary, a majority of CDH1 variant carriers who underwent colonoscopy had colorectal polyps detected, and most subjects were less than 45 years old. This study of colorectal cancer risk based on the prevalence of colorectal polyps in the CDH1 population requires further investigation to appropriately counsel patients on colorectal cancer screening. Clinical trial registry website: https://clinicaltrials.gov/. Clinical trial number: NCT03030404.
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Affiliation(s)
- Monica Passi
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
| | - Lauren A. Gamble
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Sarah G. Samaranayake
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Samuel A. Schueler
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
| | - Bryan F. Curtin
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
| | - Grace-Ann Fasaye
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Cassidy Bowden
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Sandeep Gurram
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Martha Quezado
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health
| | - Markku Miettinen
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health
| | - Christopher Koh
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
| | - Theo Heller
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
| | - Jeremy L. Davis
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health
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Hereditary Diffuse Gastric Cancer: A 2022 Update. J Pers Med 2022; 12:jpm12122032. [PMID: 36556253 PMCID: PMC9783673 DOI: 10.3390/jpm12122032] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/21/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer is ranked fifth among the most commonly diagnosed cancers, and is the fourth leading cause of cancer-related deaths worldwide. The majority of gastric cancers are sporadic, while only a small percentage, less than 1%, are hereditary. Hereditary diffuse gastric cancer (HDGC) is a rare malignancy, characterized by early-onset, highly-penetrant autosomal dominant inheritance mainly of the germline alterations in the E-cadherin gene (CDH1) and β-catenin (CTNNA1). In the present study, we provide an overview on the molecular basis of HDGC and outline the essential elements of genetic counseling and surveillance. We further provide a practical summary of current guidelines on clinical management and treatment of individuals at risk and patients with early disease.
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Malpeli G, Barbi S, Innamorati G, Alloggio M, Filippini F, Decimo I, Castelli C, Perris R, Bencivenga M. Landscape of Druggable Molecular Pathways Downstream of Genomic CDH1/Cadherin-1 Alterations in Gastric Cancer. J Pers Med 2022; 12:jpm12122006. [PMID: 36556227 PMCID: PMC9784514 DOI: 10.3390/jpm12122006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/03/2022] [Accepted: 11/24/2022] [Indexed: 12/09/2022] Open
Abstract
Loss of CDH1/Cadherin-1 is a common step towards the acquisition of an abnormal epithelial phenotype. In gastric cancer (GC), mutation and/or downregulation of CDH1/Cadherin-1 is recurrent in sporadic and hereditary diffuse GC type. To approach the molecular events downstream of CDH1/Cadherin-1 alterations and their relevance in gastric carcinogenesis, we queried public databases for genetic and DNA methylation data in search of molecular signatures with a still-uncertain role in the pathological mechanism of GC. In all GC subtypes, modulated genes correlating with CDH1/Cadherin-1 aberrations are associated with stem cell and epithelial-to-mesenchymal transition pathways. A higher level of genes upregulated in CDH1-mutated GC cases is associated with reduced overall survival. In the diffuse GC (DGC) subtype, genes downregulated in CDH1-mutated compared to cases with wild type CDH1/Cadherin-1 resulted in being strongly intertwined with the DREAM complex. The inverse correlation between hypermethylated CpGs and CDH1/Cadherin-1 transcription in diverse subtypes implies a common epigenetic program. We identified nonredundant protein-encoding isoforms of 22 genes among those differentially expressed in GC compared to normal stomach. These unique proteins represent potential agents involved in cell transformation and candidate therapeutic targets. Meanwhile, drug-induced and CDH1/Cadherin-1 mutation-related gene expression comparison predicts FIT, GR-127935 hydrochloride, amiodarone hydrochloride in GC and BRD-K55722623, BRD-K13169950, and AY 9944 in DGC as the most effective treatments, providing cues for the design of combined pharmacological treatments. By integrating genetic and epigenetic aspects with their expected functional outcome, we unveiled promising targets for combinatorial pharmacological treatments of GC.
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Affiliation(s)
- Giorgio Malpeli
- Department of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
- Correspondence:
| | - Stefano Barbi
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Giulio Innamorati
- Department of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
| | - Mariella Alloggio
- General and Upper GI Surgery Division, Department and of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
| | - Federica Filippini
- General and Upper GI Surgery Division, Department and of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
| | - Ilaria Decimo
- Section of Pharmacology, Department of Diagnostic and Public Health, University of Verona, 37134 Verona, Italy
| | - Claudia Castelli
- Pathology Unit, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Roberto Perris
- Department of Biosciences, COMT-Centre for Molecular and Translational Oncology, University of Parma, 43124 Parma, Italy
| | - Maria Bencivenga
- General and Upper GI Surgery Division, Department and of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
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Lei ZN, Teng QX, Tian Q, Chen W, Xie Y, Wu K, Zeng Q, Zeng L, Pan Y, Chen ZS, He Y. Signaling pathways and therapeutic interventions in gastric cancer. Signal Transduct Target Ther 2022; 7:358. [PMID: 36209270 PMCID: PMC9547882 DOI: 10.1038/s41392-022-01190-w] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/14/2022] [Accepted: 09/07/2022] [Indexed: 11/23/2022] Open
Abstract
Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.
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Affiliation(s)
- Zi-Ning Lei
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qiu-Xu Teng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qin Tian
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Wei Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Yuhao Xie
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA
| | - Kaiming Wu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Qianlin Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Leli Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Yihang Pan
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA.
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
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12
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Hereditary Diffuse Gastric Cancer: Molecular Genetics, Biological Mechanisms and Current Therapeutic Approaches. Int J Mol Sci 2022; 23:ijms23147821. [PMID: 35887173 PMCID: PMC9319245 DOI: 10.3390/ijms23147821] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 07/01/2022] [Accepted: 07/06/2022] [Indexed: 12/14/2022] Open
Abstract
Hereditary diffuse gastric cancer is an autosomal dominant syndrome characterized by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is caused by inactivating mutations in the tumor suppressor gene CDH1. Genetic testing technologies have become more efficient over the years, also enabling the discovery of other susceptibility genes for gastric cancer, such as CTNNA1 among the most important genes. The diagnosis of pathogenic variant carriers with an increased risk of developing gastric cancer is a selection process involving a multidisciplinary team. To achieve optimal long-term results, it requires shared decision-making in risk management. In this review, we present a synopsis of the molecular changes and current therapeutic approaches in HDGC based on the current literature.
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13
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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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14
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Kheirollahi M, Seyed Tabaei S, Vishteh M, Zeinalian M, Mamaghani A, Zolfaghari M, Mirzapour A, Barati M. Methylation and polymorphism in CDH1 gene promoter among patients with diffuse gastric cancer. Int J Prev Med 2022; 13:44. [PMID: 35529508 PMCID: PMC9069152 DOI: 10.4103/ijpvm.ijpvm_288_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 08/07/2020] [Indexed: 12/24/2022] Open
Abstract
Background: The promoter methylation and single nucleotide polymorphisms (SNPs) affect the transcription activity of cancer-related genes in several cancers including diffuse gastric cancer (DGC). Here we aimed to evaluate the promoter methylation status and the rs16260 at the promoter region of the CDH1 gene in DGC. Methods: This case-control study was performed of 48 formalin-fixed paraffin-embedded (FFPE) blocks of DGC patients and 41 fresh frozen tissue samples of healthy individuals. Methylation status was evaluated using methylation-specific polymerase chain reaction (PCR) and the rs16260 at the promoter region of the CDH1 gene was assessed using PCR and sequencing method. Results: The occurrence of methylation at the promoter region of the CDH1 gene in DGC patients was significantly higher than control samples (P < 0.0001). The methylated status was significantly associated with the poor differentiated histological type of DGC (P = 0.0428). The frequency of AC genotype and the A allele in DGC patients was significantly higher than the control subjects (P = 0.006 and 0.003, respectively). Conclusions: Here we showed that methylation at the CDH1 promoter may contribute to the DGC development, and also the AC genotype was associated with the risk of DGC.
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15
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Kheirollahi M, Saneipour M, Moridnia A. Germline likely pathogenic variants in ataxia-telangiectasia-mutated gene in an Iranian family with hereditary diffuse gastric cancer without CDH1 mutation. J Cancer Res Ther 2021; 17:1434-1437. [PMID: 34916374 DOI: 10.4103/jcrt.jcrt_344_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Background Gastric cancer (GC) is the fourth common cancer in the world and the second cause of cancer-related mortality. Germline mutations in the E-cadherin gene (CDH1) are the most common cause of hereditary diffuse GC (HDGC) and explain 25%-30% of cases. In HDGC families without the pathogenic CDH1 variant, there is poor management and therapeutic strategies, and detect other genetic defects in HDGC, except CDH1 gene will be useful for further clarification of the disease mechanisms and risk-reducing strategies. Here, we reported an Iranian pedigree with familial HDGC to assess the fundamental genetic causes by whole-exome sequencing (WES). Materials and Methods WES performed in an Iranian with a history of familial GC in whom no pathogenic variants or indels has been found in CDH1 and CTNNA1 genes with Sanger sequencing and multiplex ligation-dependent probe amplification methods. Results Prioritizing genes associate with HDGC recognized several variants include c.2572T>C, and c.3161C>G in ataxia-telangiectasia mutated (ATM), c.1114A>C in BRCA2, and finally c.1173A>G in PIK3CA. Protein function prediction software tools reveal that c.3161C>G in ATM is likely pathogen. Conclusion The results of this study suggested a role for the known cancer predisposition gene ATM in families with HDGC with no pathogenic variant in CDH1. Our results suggested that mutations in ATM and other genes, particularly the mutations found in this study, should be considered even in one case of positive familial status of HDGC disease. The presence of these mutations in patients with familial history raises important issues regarding genetic counseling.
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Affiliation(s)
- Majid Kheirollahi
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Saneipour
- Department of Genetics and Molecular Biology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
| | - Abbas Moridnia
- Department of Genetics and Molecular Biology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
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16
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Garcia-Pelaez J, Barbosa-Matos R, São José C, Sousa S, Gullo I, Hoogerbrugge N, Carneiro F, Oliveira C. Gastric cancer genetic predisposition and clinical presentations: Established heritable causes and potential candidate genes. Eur J Med Genet 2021; 65:104401. [PMID: 34871783 DOI: 10.1016/j.ejmg.2021.104401] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 11/10/2021] [Accepted: 11/28/2021] [Indexed: 12/12/2022]
Abstract
Tumour risk syndromes (TRS) are characterized by an increased risk of early-onset cancers in a familial context. High cancer risk is mostly driven by loss-of-function variants in a single cancer-associated gene. Presently, predisposition to diffuse gastric cancer (DGC) is explained by CDH1 and CTNNA1 pathogenic and likely pathogenic variants (P/LP), causing Hereditary Diffuse Gastric Cancer (HDGC); while APC promoter 1B single nucleotide variants predispose to Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS). Familial Intestinal Gastric Cancer (FIGC), recognized as a GC-predisposing disease, remains understudied and genetically unsolved. GC can also occur in the spectrum of other TRS. Identification of heritable causes allows defining diagnostic testing criteria, helps to clinically classify GC families into the appropriate TRS, and allows performing pre-symptomatic testing identifying at-risk individuals for downstream surveillance, risk reduction and/or treatment. However, most of HDGC, some GAPPS, and most FIGC patients/families remain unsolved, expecting a heritable factor to be discovered. The missing heritability in GC-associated tumour risk syndromes (GC-TRS) is likely explained not by a single major gene, but by a diversity of genes, some, predisposing to other TRS. This would gain support if GC-enriched small families or apparently isolated early-onset GC cases were hiding a family history compatible with another TRS. Herein, we revisited current knowledge on GC-TRS, and searched in the literature for individuals/families bearing P/LP variants predisposing for other TRS, but whose probands display a clinical presentation and/or family history also fitting GC-TRS criteria. We found 27 families with family history compatible with HDGC or FIGC, harbouring 28 P/LP variants in 16 TRS-associated genes, mainly associated with DNA repair. PALB2 or BRCA2 were the most frequently mutated candidate genes in individuals with family history compatible with HDGC and FIGC, respectively. Consolidation of PALB2 and BRCA2 as HDGC- or FIGC-associated genes, respectively, holds promise and worth additional research. This analysis further highlighted the influence, that proband's choice and small or unreported family history have, for a correct TRS diagnosis, genetic screening, and disease management. In this review, we provide a rational for identification of particularly relevant candidate genes in GC-TRS.
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Affiliation(s)
- José Garcia-Pelaez
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Rita Barbosa-Matos
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; International Doctoral Programme in Molecular and Cellular Biotechnology Applied to Health Sciences from Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Celina São José
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Sónia Sousa
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
| | - Irene Gullo
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal; Centro Hospitalar e Universitário S. João, Porto, Portugal
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
| | - Fátima Carneiro
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal; Centro Hospitalar e Universitário S. João, Porto, Portugal
| | - Carla Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal.
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17
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Businello G, Angerilli V, Parente P, Realdon S, Savarino E, Farinati F, Grillo F, Vanoli A, Galuppini F, Paccagnella S, Pennelli G, Mastracci L, Saragoni L, Fassan M. Molecular Landscapes of Gastric Pre-Neoplastic and Pre-Invasive Lesions. Int J Mol Sci 2021; 22:9950. [PMID: 34576114 PMCID: PMC8468646 DOI: 10.3390/ijms22189950] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/03/2021] [Accepted: 09/11/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric carcinoma (GC) represents one of the most common and most lethal malignancies worldwide. The histopathological characterization of GC precursor lesions has provided great knowledge about gastric carcinogenesis, with the consequent introduction of effective strategies of primary and secondary prevention. In recent years, a large amount of data about the molecular events in GC development is emerging, flanking the histomorphological descriptions. In this review, we describe the landscape of molecular alterations in gastric pre-invasive lesions with a glance at their potential use in the diagnostic and therapeutic decision-making process.
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Affiliation(s)
- Gianluca Businello
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Valentina Angerilli
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
| | - Stefano Realdon
- Veneto Institute of Oncology (IOV-IRCCS), 35128 Padua, Italy;
| | - Edoardo Savarino
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35121 Padua, Italy; (E.S.); (F.F.)
| | - Fabio Farinati
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35121 Padua, Italy; (E.S.); (F.F.)
| | - Federica Grillo
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, 16132 Genova, Italy; (F.G.); (L.M.)
- Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, 16132 Genova, Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, 27100 Pavia, Italy;
| | - Francesca Galuppini
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Silvia Paccagnella
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Gianmaria Pennelli
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Luca Mastracci
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, 16132 Genova, Italy; (F.G.); (L.M.)
- Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, 16132 Genova, Italy
| | - Luca Saragoni
- UO Anatomia Patologica, Ospedale G.B. Morgagni-L. Pierantoni, 47121 Forlì, Italy;
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
- Veneto Institute of Oncology (IOV-IRCCS), 35128 Padua, Italy;
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18
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CDH1 Gene Mutation Hereditary Diffuse Gastric Cancer Outcomes: Analysis of a Large Cohort, Systematic Review of Endoscopic Surveillance, and Secondary Cancer Risk Postulation. Cancers (Basel) 2021; 13:cancers13112622. [PMID: 34073553 PMCID: PMC8199234 DOI: 10.3390/cancers13112622] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/13/2021] [Accepted: 05/22/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Some patients carry a mutated copy of the CDH1 gene that can lead to a very rare form of hereditary gastric cancer called signet-ring cell adenocarcinoma (SRCC). SRCCs rarely form visible tumors prior to spreading. Hence, patients are recommended to have prophylactic gastrectomies at a young age. Many patients wish to avoid surgery and thus have regular checks with upper endoscopy with biopsies to rule out cancer. Further, these patients may also be at risk of other cancers beyond the already known breast cancer risks, but this is not known. In this study, we show that despite systematic biopsy protocols, many early cancers might be missed on endoscopy. Therefore, patients should not rely on endoscopy to delay surgery. These patients may also be at increased risk of colorectal SRCC, which has very poor survival outcomes. To confirm this, we need a central database that captures outcomes for this patient population. Abstract Hereditary diffuse gastric cancer (HDGC) is a rare signet-ring cell adenocarcinoma (SRCC) linked to CDH1 (E-cadherin) inactivating germline mutations, and increasingly other gene mutations. Female CDH1 mutation carriers have additional risk of lobular breast cancer. Risk management includes prophylactic total gastrectomy (PTG). The utility of endoscopic surveillance is unclear, as early disease lacks macroscopic lesions. The current systematic biopsy protocols have unknown efficacy, and other secondary cancer risks are postulated. We conducted a retrospective study of consecutive asymptomatic HDGC patients undergoing PTG, detailing endoscopic, pathologic, and outcome results. A systematic review compared endoscopic biopsy foci detection via random sampling versus Cambridge Protocol against PTG findings. A population-level secondary-cancer-risk postulation among sporadic gastric SRCC patients was completed using the Surveillance, Epidemiology, and End Results database. Of 97 patients, 67 underwent PTG, with 25% having foci detection on random endoscopic biopsy despite 75% having foci on final pathology. There was no improvement in the endoscopic detection rate by Cambridge Protocol. The postulated hazard ratio among sporadic gastric SRCC patients for a secondary colorectal SRCC was three-fold higher, relative to conventional adenocarcinoma patients. Overall, HDGC patients should not rely on endoscopic surveillance to delay PTG, and may have secondary SRCC risks. A definitive determination of actual risk requires collaborative patient outcome data banking.
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19
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Gamble LA, Heller T, Davis JL. Hereditary Diffuse Gastric Cancer Syndrome and the Role of CDH1: A Review. JAMA Surg 2021; 156:387-392. [PMID: 33404644 DOI: 10.1001/jamasurg.2020.6155] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Importance Inherited variants in the tumor suppressor gene CDH1 are associated with an increased risk of gastric and breast cancers. This review aims to address the most current topics in management of the hereditary diffuse gastric cancer syndrome attributed to CDH1. Observations Consensus management guidelines have broadened genetic testing criteria for CDH1. Prophylactic total gastrectomy is recommended for any pathogenic or likely pathogenic CDH1 variant carrier starting at the age of 20 years. Annual surveillance endoscopy is recommended to those who defer prophylactic total gastrectomy. Women with a CDH1 variant should initiate magnetic resonance imaging breast surveillance starting at age 30 years. Further research is needed to understand the pathogenesis of early-stage gastric cancers (T1a), which are pathognomonic of hereditary diffuse gastric cancer syndrome, that lead to advanced gastric cancer to develop both treatment and prevention strategies for this patient population. Conclusions and Relevance The heritable CDH1 gene mutation is of importance to today's surgeons because it is associated with a substantial increased risk of developing both gastric and breast cancers. Management of this cancer syndrome currently uses prophylactic surgery and enhanced cancer surveillance strategies.
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Affiliation(s)
- Lauren A Gamble
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Theo Heller
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Jeremy L Davis
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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20
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Marwitz T, Hüneburg R, Spier I, Lau JF, Kristiansen G, Lingohr P, Kalff JC, Aretz S, Nattermann J, Strassburg CP. Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status. Cancers (Basel) 2020; 12:E3726. [PMID: 33322525 PMCID: PMC7763201 DOI: 10.3390/cancers12123726] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/05/2020] [Accepted: 12/09/2020] [Indexed: 12/14/2022] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is an inherited cancer susceptibility syndrome characterized by an elevated risk for diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Some patients fulfilling the clinical testing criteria harbor a pathogenic CDH1 or CTNNA1 germline variant. However, the underlying mechanism for around 80% of the patients with a family or personal history of DGC and LBC has so far not been elucidated. In this cohort study, patients meeting the 2015 HDGC clinical testing criteria were included, and subsequently, CDH1 sequencing was performed. Of the 207 patients (161 families) in this study, we detected 21 pathogenic or likely pathogenic CDH1 variants (PV) in 60 patients (28 families) and one CTNNA1 PV in two patients from one family. Sixty-eight percent (n = 141) of patients were female. The overall PV detection rate was 18% (29/161 families). Criterion 1 and 3 of the 2015 HDGC testing criteria yielded the highest detection rate of CDH1/CTNNA1 PVs (21% and 28%). PV carriers and patients without proven PV were compared. Risk of gastric cancer (GC) (38/62 61% vs. 102/140 73%) and age at diagnosis (40 ± 13 years vs. 44 ± 12 years) were similar between the two groups. However, GC was more advanced in gastrectomy specimens of patients without PV (81% vs. 26%). LBC prevalence in female carriers of a PV was 20% (n = 8/40). Clinical phenotypes differed strongly between families with the same PV. Emphasis should be on detecting more causative genes predisposing for HDGC and improve the management of patients without a proven pathogenic germline variant.
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Affiliation(s)
- Tim Marwitz
- Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany; (T.M.); (J.N.); (C.P.S.)
- National Center for Hereditary Tumor Syndromes, University Hospital Bonn, 53127 Bonn, Germany; (I.S.); (J.-F.L.); (G.K.); (P.L.); (J.C.K.); (S.A.)
| | - Robert Hüneburg
- Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany; (T.M.); (J.N.); (C.P.S.)
- National Center for Hereditary Tumor Syndromes, University Hospital Bonn, 53127 Bonn, Germany; (I.S.); (J.-F.L.); (G.K.); (P.L.); (J.C.K.); (S.A.)
| | - Isabel Spier
- National Center for Hereditary Tumor Syndromes, University Hospital Bonn, 53127 Bonn, Germany; (I.S.); (J.-F.L.); (G.K.); (P.L.); (J.C.K.); (S.A.)
- Institute of Human Genetics, University Hospital Bonn, 53127 Bonn, Germany
| | - Jan-Frederic Lau
- National Center for Hereditary Tumor Syndromes, University Hospital Bonn, 53127 Bonn, Germany; (I.S.); (J.-F.L.); (G.K.); (P.L.); (J.C.K.); (S.A.)
- Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany
| | - Glen Kristiansen
- National Center for Hereditary Tumor Syndromes, University Hospital Bonn, 53127 Bonn, Germany; (I.S.); (J.-F.L.); (G.K.); (P.L.); (J.C.K.); (S.A.)
- Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany
| | - Philipp Lingohr
- National Center for Hereditary Tumor Syndromes, University Hospital Bonn, 53127 Bonn, Germany; (I.S.); (J.-F.L.); (G.K.); (P.L.); (J.C.K.); (S.A.)
- Department of Surgery, University Hospital Bonn, 53127 Bonn, Germany
| | - Jörg C. Kalff
- National Center for Hereditary Tumor Syndromes, University Hospital Bonn, 53127 Bonn, Germany; (I.S.); (J.-F.L.); (G.K.); (P.L.); (J.C.K.); (S.A.)
- Department of Surgery, University Hospital Bonn, 53127 Bonn, Germany
| | - Stefan Aretz
- National Center for Hereditary Tumor Syndromes, University Hospital Bonn, 53127 Bonn, Germany; (I.S.); (J.-F.L.); (G.K.); (P.L.); (J.C.K.); (S.A.)
- Institute of Human Genetics, University Hospital Bonn, 53127 Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany; (T.M.); (J.N.); (C.P.S.)
- National Center for Hereditary Tumor Syndromes, University Hospital Bonn, 53127 Bonn, Germany; (I.S.); (J.-F.L.); (G.K.); (P.L.); (J.C.K.); (S.A.)
| | - Christian P. Strassburg
- Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany; (T.M.); (J.N.); (C.P.S.)
- National Center for Hereditary Tumor Syndromes, University Hospital Bonn, 53127 Bonn, Germany; (I.S.); (J.-F.L.); (G.K.); (P.L.); (J.C.K.); (S.A.)
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21
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Hu MN, Hu SH, Zhang XW, Xiong SM, Deng H. Overview on new progress of hereditary diffuse gastric cancer with CDH1 variants. TUMORI JOURNAL 2020; 106:346-355. [PMID: 32811340 DOI: 10.1177/0300891620949668] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hereditary diffuse gastric cancer (HDGC), comprising 1%-3% of gastric malignances, has been associated with CDH1 variants. Accumulating evidence has demonstrated more than 100 germline CDH1 variant types. E-cadherin encoded by the CDH1 gene serves as a tumor suppressor protein. CDH1 promoter hypermethylation and other molecular mechanisms resulting in E-cadherin dysfunction are involved in the tumorigenesis of HDGC. Histopathology exhibits characteristic signet ring cells, and immunohistochemical staining may show negativity for E-cadherin and other signaling proteins. Early HDGC is difficult to detect by endoscopy due to the development of lesions beneath the mucosa. Prophylactic gastrectomy is the most recommended treatment for pathogenic CDH1 variant carriers. Recent studies have promoted the progression of promising molecular-targeted therapies and management strategies. This review summarizes recent advances in CDH1 variant types, tumorigenesis mechanisms, diagnosis, and therapy, as well as clinical implications for future gene therapies.
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Affiliation(s)
- Mu-Ni Hu
- Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Shu-Hui Hu
- Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Xing-Wei Zhang
- Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Shu-Min Xiong
- Department of Ophthalmology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Huan Deng
- Molecular Medicine and Genetics Center, the Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China.,Renmin Institute of Forensic Medicine in Jiangxi, Nanchang, Jiangxi Province, China
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22
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Caggiari L, Fornasarig M, De Zorzi M, Cannizzaro R, Steffan A, De Re V. Family's History Based on the CDH1 Germline Variant (c.360delG) and a Suspected Hereditary Gastric Cancer Form. Int J Mol Sci 2020; 21:ijms21144904. [PMID: 32664545 PMCID: PMC7402300 DOI: 10.3390/ijms21144904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/07/2020] [Accepted: 07/09/2020] [Indexed: 11/16/2022] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome caused by germline pathogenic variant in CDH1, the gene encoding E-cadherin. The germline loss-of-function variants are the only proven cause of the cancer syndrome HDGC, occurring in approximately 10-18% of cases and representing a helpful tool in genetic counseling. The current case reports the family history based on a CDH1 gene variant, c.360delG, p.His121Thr in a suspected family for hereditary gastric cancer form. This frameshift deletion generates a premature stop codon at the amino acid 214, which leads to a truncated E-cadherin protein detecting it as a deleterious variant. The present study expands the mutational spectra of the family with the CDH1 variant. Our results highlight the clinical impact of the reported CDH1 variant running in gastric cancer families.
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Affiliation(s)
- Laura Caggiari
- Immunopathology and Cancer Biomarkers, Bioproteomic facility, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (L.C.); (M.D.Z.); (A.S.)
| | - Mara Fornasarig
- Gastroenterology, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.F.); (R.C.)
| | - Mariangela De Zorzi
- Immunopathology and Cancer Biomarkers, Bioproteomic facility, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (L.C.); (M.D.Z.); (A.S.)
| | - Renato Cannizzaro
- Gastroenterology, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.F.); (R.C.)
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers, Bioproteomic facility, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (L.C.); (M.D.Z.); (A.S.)
| | - Valli De Re
- Immunopathology and Cancer Biomarkers, Bioproteomic facility, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (L.C.); (M.D.Z.); (A.S.)
- Correspondence: ; Tel.: +39-0434-659672
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23
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Wang SC, Yeu Y, Hammer STG, Xiao S, Zhu M, Hong C, Clemenceau JR, Yoon LY, Nassour I, Shen J, Agarwal D, Reznik SI, Mansour JC, Yopp AC, Zhu H, Hwang TH, Porembka MR. Hispanic/Latino Patients with Gastric Adenocarcinoma Have Distinct Molecular Profiles Including a High Rate of Germline CDH1 Variants. Cancer Res 2020; 80:2114-2124. [PMID: 32269045 PMCID: PMC7489496 DOI: 10.1158/0008-5472.can-19-2918] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 02/05/2020] [Accepted: 03/30/2020] [Indexed: 01/04/2023]
Abstract
Hispanic/Latino patients have a higher incidence of gastric cancer and worse cancer-related outcomes compared with patients of other backgrounds. Whether there is a molecular basis for these disparities is unknown, as very few Hispanic/Latino patients have been included in previous studies. To determine the genomic landscape of gastric cancer in Hispanic/Latino patients, we performed whole-exome sequencing (WES) and RNA sequencing on tumor samples from 57 patients; germline analysis was conducted on 83 patients. The results were compared with data from Asian and White patients published by The Cancer Genome Atlas. Hispanic/Latino patients had a significantly larger proportion of genomically stable subtype tumors compared with Asian and White patients (65% vs. 21% vs. 20%, P < 0.001). Transcriptomic analysis identified molecular signatures that were prognostic. Of the 43 Hispanic/Latino patients with diffuse-type cancer, 7 (16%) had germline variants in CDH1. Variant carriers were significantly younger than noncarriers (41 vs. 50 years, P < 0.05). In silico algorithms predicted five variants to be deleterious. For two variants that were predicted to be benign, in vitro modeling demonstrated that these mutations conferred increased migratory capability, suggesting pathogenicity. Hispanic/Latino patients with gastric cancer possess unique genomic landscapes, including a high rate of CDH1 germline variants that may partially explain their aggressive clinical phenotypes. Individualized screening, genetic counseling, and treatment protocols based on patient ethnicity and race may be necessary. SIGNIFICANCE: Gastric cancer in Hispanic/Latino patients has unique genomic profiles that may contribute to the aggressive clinical phenotypes seen in these patients.
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Affiliation(s)
- Sam C Wang
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
| | - Yunku Yeu
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Suntrea T G Hammer
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Shu Xiao
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Min Zhu
- Departments of Pediatrics and Internal Medicine, Children's Research Institute, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Changjin Hong
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Jean R Clemenceau
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Lynn Y Yoon
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ibrahim Nassour
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jeanne Shen
- Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - Deepak Agarwal
- Department of Internal Medicine, University of Texas at Austin, Austin, Texas
| | - Scott I Reznik
- Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - John C Mansour
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Adam C Yopp
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Hao Zhu
- Departments of Pediatrics and Internal Medicine, Children's Research Institute, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Tae Hyun Hwang
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
| | - Matthew R Porembka
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
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24
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CDH1 Mutation Distribution and Type Suggests Genetic Differences between the Etiology of Orofacial Clefting and Gastric Cancer. Genes (Basel) 2020; 11:genes11040391. [PMID: 32260281 PMCID: PMC7231129 DOI: 10.3390/genes11040391] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 03/26/2020] [Accepted: 03/31/2020] [Indexed: 01/16/2023] Open
Abstract
Pathogenic variants in CDH1, encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least ‘likely pathogenic’, and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants.
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25
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Renaud F, Svrcek M. [Hereditary gastric cancer: Challenges for the pathologist in 2020]. Ann Pathol 2020; 40:95-104. [PMID: 32147190 DOI: 10.1016/j.annpat.2020.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 01/26/2020] [Accepted: 02/05/2020] [Indexed: 12/24/2022]
Abstract
Gastric cancer is the third most common cancer worldwide. The majority of gastric cancers are sporadic but familial clustering is seen in more than 10% of cases. This manuscript is divided into two parts. The first part is dedicated to the non-syndromic hereditary gastric cancer, particularly the hereditary diffuse gastric cancer (HDGC) and other gastric polyposes including the recently described GAPPS (Gastric adenocarcinoma and proximal polyposis of the stomach). The second part concerns the syndromic gastric cancer, namely the HNPCC syndrome (Hereditary Non Polyposis Colorectal Cancer) occurring as part of a genetic predisposition syndrome to cancer. Recent advances in oncogenetics and next generation sequencing technology have enabled the identification of new entities. This enhancement in knowledge regarding inherited syndromes predisposing to gastric cancer has consequently improved the management of patients and their families. In this context, pathologists play a major role in identifying particular morphologic entities prompting genetic investigation. The aim of this manuscript is to provide an update on the current knowledge about hereditary gastric cancer.
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Affiliation(s)
- Florence Renaud
- Sorbonne université, Inserm, unité Mixte de Recherche Scientifique 938, SIRIC CURAMUS, centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, 75012 Paris, France; Service d'anatomie et cytologie pathologiques, hôpital Saint-Antoine, AP-HP, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France.
| | - Magali Svrcek
- Sorbonne université, Inserm, unité Mixte de Recherche Scientifique 938, SIRIC CURAMUS, centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, 75012 Paris, France; Service d'anatomie et cytologie pathologiques, hôpital Saint-Antoine, AP-HP, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France
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26
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Moridnia A, Tabatabaiefar MA, Zeinalian M, Minakari M, Kheirollahi M, Moghaddam NA. Novel Variants and Copy Number Variation in CDH1 Gene in Iranian Patients with Sporadic Diffuse Gastric Cancer. J Gastrointest Cancer 2020; 50:420-427. [PMID: 29577179 DOI: 10.1007/s12029-018-0082-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION The aim of this study was to survey the nucleotide changes and copy number variations (CNV) in the CDH1 gene in Iranian patients with sporadic diffuse gastric cancer (SDGC). MATERIALS AND METHODS In this study, 28 patients were examined who upon gastrectomy had been diagnosed with SDGC according to the familial history and histopathological criteria which was confirmed by the pathologist. DNA extraction was performed from formalin-fixed paraffin-embedded tissues using a phenol-chloroform method following xylene deparaffinization. Determination of DNA sequence by Sanger was performed using PCR amplification of 16 exons and boundaries of intron/exon of CDH1 gene. Multiplex ligation-dependent probe amplification (MLPA) was performed on patients with pathogenic disorders in the sequence. RESULTS In total, patients included 20 males and 8 females. Of all patients, 12 patients were under 45 years old (early onset gastric cancer, EODC) and 16 patients were older. The tumor was diagnosed in the early TNM stage (I, II) in six patients and in late stages (III, IV) in 19 cases. Altogether, 16 variants (three exonic with one new variant and 13 intronic with nine new variants) were found in DNA sequencing of the CDH1 gene in five samples. Also, using MLPA, a new duplication in exon 9 and one deletion in exon 2 were detected in two other patients. Altogether, CDH1 variants were identified in seven out of 28 patients (25%). CONCLUSION Our study revealed several novel somatic variants in the CDH1 gene in Iranian patients with sporadic diffuse GC. Our data supports the hypothesis that mutations in CDH1 gene, and particularly the mutations we describe, should be considered, even in sporadic cases of gastric cancer. The presence of these mutations in patients raises important issues regarding genetic counseling and diagnostic test in DGC patients.
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Affiliation(s)
- Abbas Moridnia
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable disease and Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, P.O.Box: 81746-73461, Isfahan, Iran
| | - Mohammad Amin Tabatabaiefar
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable disease and Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, P.O.Box: 81746-73461, Isfahan, Iran
| | - Mehrdad Zeinalian
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable disease and Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, P.O.Box: 81746-73461, Isfahan, Iran
| | - Mohammad Minakari
- Internal medicine department, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Majid Kheirollahi
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable disease and Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, P.O.Box: 81746-73461, Isfahan, Iran.
| | - Noushin Afshar Moghaddam
- Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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27
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Shenoy S. CDH1 (E-Cadherin) Mutation and Gastric Cancer: Genetics, Molecular Mechanisms and Guidelines for Management. Cancer Manag Res 2019; 11:10477-10486. [PMID: 31853199 PMCID: PMC6916690 DOI: 10.2147/cmar.s208818] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Accepted: 12/03/2019] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Germline mutation in CDH1 (E-cadherin) tumor suppressor gene is associated with hereditary diffuse gastric cancer (HDGC) and lobular breast cancers (LBC). E-Cadherin protein is necessary for physiological signaling pathways, such as cell proliferation, maintenance of cell adhesion, cell polarity and epithelial-mesenchymal transition. Dysregulation leads to tumor proliferation, invasion, migration and metastases. We review current perspectives in CDH1 genetics with molecular mechanisms and also discuss management strategies for this aggressive form of gastric cancer. METHODS Relevant articles from PubMed/Medline and Embase (1994-2019) were searched and collected using the phrases "Hereditary diffuse gastric cancer, Familial gastric cancer, CDH1 mutation, E-Cadherin, Lobular breast cancer, Prophylactic total gastrectomy". RESULTS Current guidelines suggest maintaining a high degree of suspicion of hereditary etiology and recommend testing for CDH1 mutations in patients with familial clustering of HDGC and LBC, especially onset at an early age (before 40 years). In families lacking CDH1 mutations but with high suspicion for hereditary predisposition, testing of CTNNA1 and other closely related HDGC susceptibility genes could be considered. Prophylactic total gastrectomy is recommended for individuals with identified pathogenic germline variants. Endoscopic surveillance with biopsies is recommended for those choosing to delay prophylactic gastrectomy. CONCLUSION Mutation or transcriptional silencing of the CDH1 gene is associated with familial diffuse gastric cancer. Further studies on the expression and the alteration in the proteins in the E-cadherin pathways may serve as biomarkers for early detection; stratify risk and selection of appropriate therapy in these families. Until then prophylactic total gastrectomy is recommended for individuals with CDH1 mutations and family history of diffuse gastric cancer. Endoscopic surveillance and biopsies by experienced gastroenterologists is recommended for those choosing not to have prophylactic gastrectomy and in individuals with CDH1 variants.
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Affiliation(s)
- Santosh Shenoy
- Clinical Associate Professor of Surgery, Department of Surgery, Kansas City VA Medical Center, University of Missouri Kansas City, Kansas City, MO 64128, USA and Cancer Biology and Therapeutics, HMS High-Impact Cancer Research (HI-CR) Program, Harvard Medical School 2018–2019, Boston, MA02115, USA
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28
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van der Post RS, Oliveira C, Guilford P, Carneiro F. Hereditary gastric cancer: what's new? Update 2013-2018. Fam Cancer 2019; 18:363-367. [PMID: 30989426 DOI: 10.1007/s10689-019-00127-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Around 10-20% of gastric cancer patients have relatives with a diagnosis of GC and in 1-3% of patients a genetic cause can be confirmed. Histopathologically, GC is classified into intestinal-type, with glandular growth, and diffuse-type with poorly cohesive growth pattern often with signet ring cells. Familial or hereditary GC is classified into hereditary diffuse GC (HDGC), familial intestinal GC (FIGC) and polyposis forms. This review focuses on recent research findings and new concepts of hereditary GC.
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Affiliation(s)
- Rachel S van der Post
- Department of Pathology, Radboud university medical centre, Nijmegen, The Netherlands
| | - Carla Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Júlio Amaral de Carvalho, 45, 4200-135, Porto, Portugal.,Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Faculty of Medicine, University of Porto, Porto, Portugal
| | - Parry Guilford
- Cancer Genetics Laboratory, Department of Biochemistry, Centre for Translational Cancer Research, Te Aho Matatū, University of Otago, Dunedin, Aotearoa, New Zealand
| | - Fátima Carneiro
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Júlio Amaral de Carvalho, 45, 4200-135, Porto, Portugal. .,Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal. .,Faculty of Medicine, University of Porto, Porto, Portugal.
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29
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Lo W, Zhu B, Sabesan A, Wu HH, Powers A, Sorber RA, Ravichandran S, Chen I, McDuffie LA, Quadri HS, Beane JD, Calzone K, Miettinen MM, Hewitt SM, Koh C, Heller T, Wacholder S, Rudloff U. Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC). J Med Genet 2019; 56:370-379. [PMID: 30745422 PMCID: PMC6716162 DOI: 10.1136/jmedgenet-2018-105361] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 12/11/2018] [Accepted: 01/03/2019] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC. METHODS One hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at <40 or breast cancer <50 years of age). RESULTS Frequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and β-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants. CONCLUSION Type and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies.
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Affiliation(s)
- Winifred Lo
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - Bin Zhu
- Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA
| | - Arvind Sabesan
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - Ho-Hsiang Wu
- Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA
| | - Astin Powers
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Rebecca A Sorber
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
- Department of Surgery, indiana University School of Medicine, indianapolis, indiana, USA
| | - Sarangan Ravichandran
- Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Ina Chen
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Lucas A McDuffie
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
- Department of Surgery, indiana University School of Medicine, indianapolis, indiana, USA
| | - Humair S Quadri
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
- Department of Surgery, MedStar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Joal D Beane
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
- Department of Surgery, indiana University School of Medicine, indianapolis, indiana, USA
| | - Kathleen Calzone
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Markku M Miettinen
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Stephen M Hewitt
- Experimental Pathology Laboratory, National Cancer Institute, Bethesda, Maryland, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | - Sholom Wacholder
- Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA
| | - Udo Rudloff
- Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
- Rare Tumor initiative, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
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30
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Figueiredo J, Melo S, Carneiro P, Moreira AM, Fernandes MS, Ribeiro AS, Guilford P, Paredes J, Seruca R. Clinical spectrum and pleiotropic nature of CDH1 germline mutations. J Med Genet 2019; 56:199-208. [PMID: 30661051 PMCID: PMC6581119 DOI: 10.1136/jmedgenet-2018-105807] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 12/05/2018] [Accepted: 12/10/2018] [Indexed: 12/12/2022]
Abstract
CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.
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Affiliation(s)
- Joana Figueiredo
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Soraia Melo
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.,Medical Faculty of the University of Porto, Porto, Portugal
| | - Patrícia Carneiro
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Ana Margarida Moreira
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Medical Faculty of the University of Porto, Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Maria Sofia Fernandes
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.,Institute for Systems and Robotics (ISR/IST), LARSyS, Bioengineering Department, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Ana Sofia Ribeiro
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Parry Guilford
- Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Joana Paredes
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Medical Faculty of the University of Porto, Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Raquel Seruca
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Medical Faculty of the University of Porto, Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
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Bustos-Carpinteyro AR, Oliveira C, Sousa A, Oliveira P, Pinheiro H, Carvalho J, Magaña-Torres MT, Flores-Miramontes MG, Aguilar-Lemarroy A, Jave-Suárez LF, Peregrina-Sandoval J, Cruz-Ramos JA, Sánchez-López JY. CDH1 somatic alterations in Mexican patients with diffuse and mixed sporadic gastric cancer. BMC Cancer 2019; 19:69. [PMID: 30642281 PMCID: PMC6332846 DOI: 10.1186/s12885-019-5294-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 01/07/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Diffuse gastric cancer (DGC) is associated with the reduction or absence of the expression of the cell adhesion protein E-cadherin (encoded by the CDH1 gene). Molecular characteristics are less well described for mixed gastric cancer (MGC). The main somatic alterations that have been described in the CDH1 gene are mutations, loss of heterozygosity (LOH) and promoter methylation. The aim was to analyze CDH1 somatic alterations in Mexican patients with diffuse and mixed gastric cancer. METHODS We searched for mutations in the CDH1 gene in tumor DNA from DGC (n = 13) and MGC (n = 7) patients by next generation sequencing (NGS). Validation of findings was performed using Sanger sequencing. LOH was analyzed using dinucleotide repeat markers surrounding the CDH1 gene, and methylation was investigated by DNA bisulfite conversion and sequencing. E-cadherin protein deficiency was analyzed by immunohistochemistry. RESULTS Seventeen point variants were identified by NGS, 13 of them were validated by Sanger sequencing. Only 1/13 had not been previously reported (c.-137C > A), and 12/13 were already reported as polymorphisms. Two DGC cases presented LOH at the locus 16q22.1 (13.3%). CDH1 promoter methylation was positive in (7/11) 63.6% and (4/6) 66.6% of the cases with DGC and MGC, respectively. E-cadherin protein deficiency was observed in 58.3% of DGC cases while 100% in MGC cases. CONCLUSIONS While no pathogenic somatic mutations were found that could explain the diffuse histology of gastric cancer in DGC and MGC, methylation was the most common somatic inactivation event of the CDH1 gene, and LOH was rare. The previously unreported c.-137C > A variant modify the CDH1 gene expression since it alters the binding sites for transcription factors.
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Affiliation(s)
- Andrea Rebeca Bustos-Carpinteyro
- División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Sierra Mojada N. 800, Col. Independencia, C. P. 44340, Guadalajara, Jalisco, México.,Doctorado en Genética Humana, Universidad de Guadalajara, Guadalajara, Jalisco, México
| | - Carla Oliveira
- Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S; University of Porto, Porto, Portugal.,Faculty of Medicine, University of Porto, Porto, Portugal
| | - Abel Sousa
- Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S; University of Porto, Porto, Portugal
| | - Patricia Oliveira
- Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S; University of Porto, Porto, Portugal
| | - Hugo Pinheiro
- Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S; University of Porto, Porto, Portugal.,Department of Internal Medicine, Centro Hospitalar Tâmega e Sousa Avenida do Hospital Padre Américo, N° 210 4564-007, Guilhufe - Penafiel, Portugal
| | - Joana Carvalho
- Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S; University of Porto, Porto, Portugal
| | - María Teresa Magaña-Torres
- División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Sierra Mojada N. 800, Col. Independencia, C. P. 44340, Guadalajara, Jalisco, México
| | - María Guadalupe Flores-Miramontes
- División de Inmunología, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, México
| | - Adriana Aguilar-Lemarroy
- División de Inmunología, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, México
| | - Luis Felipe Jave-Suárez
- División de Inmunología, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, México
| | - Jorge Peregrina-Sandoval
- Laboratorio de Inmunobiología, Departamento de Biología Celular y Molecular. Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, CP 45510, Nextipac, Jalisco, México
| | | | - Josefina Yoaly Sánchez-López
- División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Sierra Mojada N. 800, Col. Independencia, C. P. 44340, Guadalajara, Jalisco, México.
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Luo W, Fedda F, Lynch P, Tan D. CDH1 Gene and Hereditary Diffuse Gastric Cancer Syndrome: Molecular and Histological Alterations and Implications for Diagnosis And Treatment. Front Pharmacol 2018; 9:1421. [PMID: 30568591 PMCID: PMC6290068 DOI: 10.3389/fphar.2018.01421] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer, a group of common malignancies, results in the most cancer mortality worldwide after only lung and colorectal cancer. Although familial gastric cancers have long been recognized, it was not until recently that they were discovered to be associated with mutations of specific genes. Mutations of CDH1, the gene encoding E-cadherin, are the most common germline mutations detected in gastric cancer and underlie hereditary diffuse gastric cancer (HDGC) syndrome. All reported HDGCs are the pure diffuse type by Lauren classification and are associated with dismal prognosis once the tumor invades the submucosa. Because CDH1 germline mutations are inherited in an autosomal-dominant fashion and have high penetrance, the International Gastric Cancer Linkage Consortium (IGCLC) developed criteria to facilitate the screening of CDH1 mutation carriers; these criteria have been proven to have excellent sensitivity and specificity. Recent histologic studies suggest that HDGC progresses through several stages. Even when the tumor becomes "invasive" in lamina propria, it may stay indolent for a long time. However, the molecular mechanisms that induce the transitions between stages and determine the length of the indolent phase remain to be determined. Although the standard management for CDH1 mutation carriers is prophylactic total gastrectomy, many questions must be answered before the surgery can be done. These include the optimal surveillance strategy, the best strategy to choose surgical candidates, and the ideal time to perform surgery. In addition to increasing the risk of gastric cancer, CDH1 germline mutations also increase the risk of invasive lobular carcinoma of the breast, and possibly colorectal adenocarcinoma, and are associated with blepharocheilodontic syndrome (a congenital development disorder). However, the optimal management of these conditions is less established owing to insufficient data regarding the risk of cancer development. This review focuses on molecular and histological findings in HDGC, as opposed to sporadic diffuse gastric cancer, and their implications for the management of CDH1 mutation carriers and the diagnosis and treatment of HDGC. Other conditions associated with CDH1 germline mutations and future research directions are also discussed.
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Affiliation(s)
- Wenyi Luo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Faysal Fedda
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Patrick Lynch
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Dongfeng Tan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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Glycosylation in cancer: Selected roles in tumour progression, immune modulation and metastasis. Cell Immunol 2018; 333:46-57. [DOI: 10.1016/j.cellimm.2018.03.007] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 03/13/2018] [Accepted: 03/16/2018] [Indexed: 01/20/2023]
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Emerging Concepts in Gastric Neoplasia: Heritable Gastric Cancers and Polyposis Disorders. Surg Pathol Clin 2018; 10:931-945. [PMID: 29103540 DOI: 10.1016/j.path.2017.07.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hereditary gastric cancer is a relatively rare disease with specific clinical and histopathologic characteristics. Hereditary gastric cancer of the diffuse type is predominantly caused by germline mutations in CDH1. The inherited cause of familial intestinal gastric cancer is unknown. Gastric adenocarcinoma and proximal polyposis of the stomach is a hereditary cancer syndrome caused by germline mutations in promoter 1B of APC. Other well-defined cancer syndromes, such as Lynch, Li-Fraumeni, and hereditary breast or ovarian cancer syndromes, are associated with increased risk of gastric cancer. This article reviews important histopathologic features and emerging concepts regarding gastric carcinogenesis in these syndromes.
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Spoto CP, Gullo I, Carneiro F, Montgomery EA, Brosens LA. Hereditary gastrointestinal carcinomas and their precursors: An algorithm for genetic testing. Semin Diagn Pathol 2018; 35:170-183. [DOI: 10.1053/j.semdp.2018.01.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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de Freitas Junior JCM, Morgado-Díaz JA. The role of N-glycans in colorectal cancer progression: potential biomarkers and therapeutic applications. Oncotarget 2017; 7:19395-413. [PMID: 26539643 PMCID: PMC4991391 DOI: 10.18632/oncotarget.6283] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 10/22/2015] [Indexed: 12/12/2022] Open
Abstract
Changes in glycosylation, which is one of the most common protein post-translational modifications, are considered to be a hallmark of cancer. N-glycans can modulate cell migration, cell-cell adhesion, cell signaling, growth and metastasis. The colorectal cancer (CRC) is a leading cause of cancer-related mortality and the correlation between CRC progression and changes in the pattern of expression of N-glycans is being considered in the search for new biomarkers. Here, we review the role of N-glycans in CRC cell biology. The perspectives on emerging N-glycan-related anticancer therapies, along with new insights and challenges, are also discussed.
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Affiliation(s)
| | - José Andrés Morgado-Díaz
- Cellular Biology Program, Structural Biology Group, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
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Lowstuter K, Espenschied CR, Sturgeon D, Ricker C, Karam R, LaDuca H, Culver JO, Dolinsky JS, Chao E, Sturgeon J, Speare V, Ma Y, Kingham K, Melas M, Idos GE, McDonnell KJ, Gruber SB. Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges. JCO Precis Oncol 2017; 1:1-12. [DOI: 10.1200/po.16.00021] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose Mutations in the CDH1 gene confer up to an 80% lifetime risk of diffuse gastric cancer and up to a 60% lifetime risk of lobular breast cancer. Testing for CDH1 mutations is recommended for individuals who meet the International Gastric Cancer Linkage Consortium (IGCLC) guidelines. However, the interpretation of unexpected CDH1 mutations identified in patients who do not meet IGCLC criteria or do not have phenotypes suggestive of hereditary diffuse gastric cancer is clinically challenging. This study aims to describe phenotypes of CDH1 mutation carriers identified through multigene panel testing (MGPT) and to offer informed recommendations for medical management. Patients and Methods This cross-sectional prevalence study included all patients who underwent MGPT between March 2012 and September 2014 from a commercial laboratory (n = 26,936) and an academic medical center cancer genetics clinic (n = 318) to estimate CDH1 mutation prevalence and associated clinical phenotypes. CDH1 mutation carriers were classified as IGCLC positive (met criteria), IGCLC partial phenotype, and IGCLC negative. Results In the laboratory cohort, 16 (0.06%) of 26,936 patients were identified as having a pathogenic CDH1 mutation. In the clinic cohort, four (1.26%) of 318 had a pathogenic CDH1 mutation. Overall, 65% of mutation carriers did not meet the revised testing criteria published in 2015. All three CDH1 mutation carriers who had risk-reducing gastrectomy had pathologic evidence of diffuse gastric cancer despite not having met IGCLC criteria. Conclusion The majority of CDH1 mutations identified on MGPT are unexpected and found in individuals who do not fit the accepted diagnostic testing criteria. These test results alter the medical management of CDH1-positive patients and families and provide opportunities for early detection and risk reduction.
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Affiliation(s)
- Katrina Lowstuter
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Carin R. Espenschied
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Duveen Sturgeon
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Charité Ricker
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Rachid Karam
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Holly LaDuca
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Julie O. Culver
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Jill S. Dolinsky
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Elizabeth Chao
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Julia Sturgeon
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Virginia Speare
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Yanling Ma
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Kerry Kingham
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Marilena Melas
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Gregory E. Idos
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Kevin J. McDonnell
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
| | - Stephen B. Gruber
- Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA
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Diagnostic, Predictive, Prognostic, and Therapeutic Molecular Biomarkers in Third Millennium: A Breakthrough in Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7869802. [PMID: 29094049 PMCID: PMC5637861 DOI: 10.1155/2017/7869802] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 07/12/2017] [Indexed: 02/08/2023]
Abstract
Introduction Gastric cancer is the fifth most common cancer and the third cause of cancer death. The clinical outcomes of the patients are still not encouraging with a low rate of 5 years' survival. Often the disease is diagnosed at advanced stages and this obviously negatively affects patients outcomes. A deep understanding of molecular basis of gastric cancer can lead to the identification of diagnostic, predictive, prognostic, and therapeutic biomarkers. Main Body This paper aims to give a global view on the molecular classification and mechanisms involved in the development of the tumour and on the biomarkers for gastric cancer. We discuss the role of E-cadherin, HER2, fibroblast growth factor receptor (FGFR), MET, human epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (HGFR), mammalian target of rapamycin (mTOR), microsatellite instability (MSI), PD-L1, and TP53. We have also considered in this manuscript new emerging biomarkers as matrix metalloproteases (MMPs), microRNAs, and long noncoding RNAs (lncRNAs). Conclusions Identifying and validating diagnostic, prognostic, predictive, and therapeutic biomarkers will have a huge impact on patients outcomes as they will allow early detection of tumours and also guide the choice of a targeted therapy based on specific molecular features of the cancer.
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Cho SY, Park JW, Liu Y, Park YS, Kim JH, Yang H, Um H, Ko WR, Lee BI, Kwon SY, Ryu SW, Kwon CH, Park DY, Lee JH, Lee SI, Song KS, Hur H, Han SU, Chang H, Kim SJ, Kim BS, Yook JH, Yoo MW, Kim BS, Lee IS, Kook MC, Thiessen N, He A, Stewart C, Dunford A, Kim J, Shih J, Saksena G, Cherniack AD, Schumacher S, Weiner AT, Rosenberg M, Getz G, Yang EG, Ryu MH, Bass AJ, Kim HK. Sporadic Early-Onset Diffuse Gastric Cancers Have High Frequency of Somatic CDH1 Alterations, but Low Frequency of Somatic RHOA Mutations Compared With Late-Onset Cancers. Gastroenterology 2017; 153:536-549.e26. [PMID: 28522256 PMCID: PMC6863080 DOI: 10.1053/j.gastro.2017.05.012] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 05/08/2017] [Accepted: 05/08/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Early-onset gastric cancer, which develops in patients younger than most gastric cancers, is usually detected at advanced stages, has diffuse histologic features, and occurs more frequently in women. We investigated somatic genomic alterations associated with the unique characteristics of sporadic diffuse gastric cancers (DGCs) from younger patients. METHODS We conducted whole exome and RNA sequence analyses of 80 resected DGC samples from patients 45 years old or younger in Korea. Patients with pathogenic germline mutations in CDH1, TP53, and ATM were excluded from the onset of this analysis, given our focus on somatic alterations. We used MutSig2CV to evaluate the significance of mutated genes. We recruited 29 additional early-onset Korean DGC samples and performed SNP6.0 array and targeted sequencing analyses of these 109 early-onset DGC samples (54.1% female, median age, 38 years). We compared the SNP6.0 array and targeted sequencing data of the 109 early-onset DGC samples with those from diffuse-type stomach tumor samples collected from 115 patients in Korea who were 46 years or older (late onset) at the time of diagnosis (controls; 29.6% female, median age, 67 years). We compared patient survival times among tumors from different subgroups and with different somatic mutations. We performed gene silencing of RHOA or CDH1 in DGC cells with small interfering RNAs for cell-based assays. RESULTS We identified somatic mutations in the following genes in a significant number of early-onset DGCs: the cadherin 1 gene (CDH1), TP53, ARID1A, KRAS, PIK3CA, ERBB3, TGFBR1, FBXW7, RHOA, and MAP2K1. None of 109 early-onset DGC cases had pathogenic germline CDH1 mutations. A higher proportion of early-onset DGCs had mutations in CDH1 (42.2%) or TGFBR1 (7.3%) compared with control DGCs (17.4% and 0.9%, respectively) (P < .001 and P = .014 for CDH1 and TGFBR1, respectively). In contrast, a smaller proportion of early-onset DGCs contained mutations in RHOA (9.2%) than control DGCs (19.1%) (P = .033). Late-onset DGCs in The Cancer Genome Atlas also contained less frequent mutations in CDH1 and TGFBR1 and more frequent RHOA mutations, compared with early-onset DGCs. Early-onset DGCs from women contained significantly more mutations in CDH1 or TGFBR1 than early-onset DGCs from men. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times in patients with early-onset DGCs (hazard ratio, 3.4; 95% confidence interval, 1.5-7.7). RHOA activity was reduced by an R5W substitution-the RHOA mutation most frequently detected in early-onset DGCs. Silencing of CDH1, but not RHOA, increased migratory activity of DGC cells. CONCLUSIONS In an integrative genomic analysis, we found higher proportions of early-onset DGCs to contain somatic mutations in CDH1 or TGFBR1 compared with late-onset DGCs. However, a smaller proportion of early-onset DGCs contained somatic mutations in RHOA than late-onset DGCs. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times of patients, which might account for the aggressive clinical course of early-onset gastric cancer. Female predominance in early-onset gastric cancer may be related to relatively high rates of somatic CDH1 and TGFBR1 mutations in this population.
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Affiliation(s)
- Soo Young Cho
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Jun Won Park
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Yang Liu
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hee Kim
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Hanna Yang
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Hyejin Um
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Woo Ri Ko
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Byung Il Lee
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Sun Young Kwon
- Department of Pathology, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Seung Wan Ryu
- Department of Surgery, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Chae Hwa Kwon
- Department of Pathology and BioMedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Busan, Republic of Korea
| | - Do Youn Park
- Department of Pathology and BioMedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Busan, Republic of Korea
| | - Jae-Hyuk Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Sang Il Lee
- Department of Surgery, School of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Kyu Sang Song
- Department of Pathology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Hoon Hur
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Sang-Uk Han
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Heekyung Chang
- Department of Pathology, Kosin University College of Medicine, Busan, Republic of Korea
| | - Su-Jin Kim
- Department of Pathology, Dong-A University College of Medicine, Busan, Republic of Korea
| | - Byung-Sik Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeong-Hwan Yook
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Moon-Won Yoo
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Beom-Su Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - In-Seob Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | | | - Nina Thiessen
- British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - An He
- British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Chip Stewart
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Andrew Dunford
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Jaegil Kim
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Juliann Shih
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Gordon Saksena
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Andrew D Cherniack
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Steven Schumacher
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Amaro-Taylor Weiner
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Mara Rosenberg
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Gad Getz
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Eun Gyeong Yang
- Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Adam J Bass
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
| | - Hark Kyun Kim
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea; National Cancer Center Graduate School of Cancer Science and Policy, Goyang, Gyeonggi, Republic of Korea.
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Feroce I, Serrano D, Biffi R, Andreoni B, Galimberti V, Sonzogni A, Bottiglieri L, Botteri E, Trovato C, Marabelli M, Ranzani GN, Bonanni B. Hereditary diffuse gastric cancer in two families: A case report. Oncol Lett 2017; 14:1671-1674. [PMID: 28789394 DOI: 10.3892/ol.2017.6354] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 01/17/2017] [Indexed: 12/23/2022] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is associated with E-cadherin 1 (CDH1) germline mutations. In the present study, two unusual HDGC cases are described. Case 1 was a female with no family history of gastric cancer who developed Hodgkin's lymphoma at 19 years of age, and DGC at 32 years of age. Due to her young age (32 years), the patient was examined for CDH1 abnormalities and a deleterious mutation was identified. Her father and younger sister were identified to be carriers of the mutation. Case 2 was a 36-year-old female diagnosed with lobular breast cancer (LBC); her mother had LBC, and her grandmother had LBC and DGC. The molecular test was wild-type for breast cancer susceptibility genes 1 and 2; however, a large deletion in CDH1 was identified. At prophylactic gastrectomy, early DGC was identified. Early onset of DGC and LBC justifies testing for CDH1. A better knowledge of tumor natural history in carrier subjects is important to aid genetic counseling, in order to assess the surveillance time required prior to carrying out prophylactic surgery.
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Affiliation(s)
- Irene Feroce
- Division of Cancer Prevention and Genetics, European Institute of Oncology, I-20141 Milan, Italy
| | - Davide Serrano
- Division of Cancer Prevention and Genetics, European Institute of Oncology, I-20141 Milan, Italy
| | - Roberto Biffi
- Division of Abdomino-Pelvic Surgery, European Institute of Oncology, I-20141 Milan, Italy
| | - Bruno Andreoni
- Division of Palliative Care, European Institute of Oncology, I-20141 Milan, Italy
| | - Viviana Galimberti
- Unit of Molecular Senology, European Institute of Oncology, I-20141 Milan, Italy
| | - Angelica Sonzogni
- Division of Pathology, European Institute of Oncology, I-20141 Milan, Italy
| | - Luca Bottiglieri
- Division of Pathology, European Institute of Oncology, I-20141 Milan, Italy
| | - Edoardo Botteri
- Division of Epidemiology and Biostatistics, European Institute of Oncology, I-20141 Milan, Italy
| | - Cristina Trovato
- Division of Endoscopy, European Institute of Oncology, I-20141 Milan, Italy
| | - Monica Marabelli
- Department of Biology and Biotechnology, University of Pavia, I-27100 Pavia, Italy
| | | | - Bernardo Bonanni
- Division of Cancer Prevention and Genetics, European Institute of Oncology, I-20141 Milan, Italy
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De Mello RA. Gastric Cancer in Southern Europe: High-Risk Disease. Am Soc Clin Oncol Educ Book 2017; 37:261-266. [PMID: 28561674 DOI: 10.1200/edbk_175227] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Gastric cancer is an aggressive disease. Several risk factors are involved in gastric cancer pathogenesis, likely Helicobacter pylori (H. pylori) infection, genetic factors in hereditary syndromes, lifestyle, and diet. However, well-implemented screening strategies are lacking in most countries, including those in Southern Europe. Nevertheless, gastric cancer outcomes are better in some Southern European countries than in others, likely because of the incidence and distribution of different histologic types. Robotic surgery has been gaining favor as a treatment of early-stage disease, and the need for perioperative chemotherapy or adjuvant chemoradiotherapy (CRT) for locally advanced disease has been debated. In the metastatic setting, trastuzumab in combination with chemotherapy has helped to extend survival compared with chemotherapy alone for HER2-positive disease. This article will describe how gastric cancer is assessed and treated in Southern Europe in an attempt to correlate these approaches from a global perspective.
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Affiliation(s)
- Ramon Andrade De Mello
- From the Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal, and the Department of Medical Oncology, Clatterbridge Cancer Centre, Merseyside, United Kingdom
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Chen I, Mathews-Greiner L, Li D, Abisoye-Ogunniyan A, Ray S, Bian Y, Shukla V, Zhang X, Guha R, Thomas C, Gryder B, Zacharia A, Beane JD, Ravichandran S, Ferrer M, Rudloff U. Transcriptomic profiling and quantitative high-throughput (qHTS) drug screening of CDH1 deficient hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for familial gastric cancer. J Transl Med 2017; 15:92. [PMID: 28460635 PMCID: PMC5412046 DOI: 10.1186/s12967-017-1197-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 04/24/2017] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Patients with hereditary diffuse gastric cancer (HDGC), a cancer predisposition syndrome associated with germline mutations of the CDH1 (E-cadherin) gene, have few effective treatment options. Despite marked differences in natural history, histopathology, and genetic profile to patients afflicted by sporadic gastric cancer, patients with HDGC receive, in large, identical systemic regimens. The lack of a robust preclinical in vitro system suitable for effective drug screening has been one of the obstacles to date which has hampered therapeutic advances in this rare disease. METHODS In order to identify therapeutic leads selective for the HDGC subtype of gastric cancer, we compared gene expression profiles and drug phenotype derived from an oncology library of 1912 compounds between gastric cancer cells established from a patient with metastatic HDGC harboring a c.1380delA CDH1 germline variant and sporadic gastric cancer cells. RESULTS Unsupervised hierarchical cluster analysis shows select gene expression alterations in c.1380delA CDH1 SB.mhdgc-1 cells compared to a panel of sporadic gastric cancer cell lines with enrichment of ERK1-ERK2 (extracellular signal regulated kinase) and IP3 (inositol trisphosphate)/DAG (diacylglycerol) signaling as the top networks in c.1380delA SB.mhdgc-1 cells. Intracellular phosphatidylinositol intermediaries were increased upon direct measure in c.1380delA CDH1 SB.mhdgc-1 cells. Differential high-throughput drug screening of c.1380delA CDH1 SB.mhdgc-1 versus sporadic gastric cancer cells identified several compound classes with enriched activity in c.1380 CDH1 SB.mhdgc-1 cells including mTOR (Mammalian Target Of Rapamycin), MEK (Mitogen-Activated Protein Kinase), c-Src kinase, FAK (Focal Adhesion Kinase), PKC (Protein Kinase C), or TOPO2 (Topoisomerase II) inhibitors. Upon additional drug response testing, dual PI3K (Phosphatidylinositol 3-Kinase)/mTOR and topoisomerase 2A inhibitors displayed up to >100-fold increased activity in hereditary c.1380delA CDH1 gastric cancer cells inducing apoptosis most effectively in cells with deficient CDH1 function. CONCLUSION Integrated pharmacological and transcriptomic profiling of hereditary diffuse gastric cancer cells with a loss-of-function c.1380delA CDH1 mutation implies various pharmacological vulnerabilities selective to CDH1-deficient familial gastric cancer cells and suggests novel treatment leads for future preclinical and clinical treatment studies of familial gastric cancer.
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Affiliation(s)
- Ina Chen
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes for Health, CCR 4 West/4-3740, 10 Center Drive, Bethesda, MD, 20892-0001, USA.,Washington University School of Medicine, St. Louis, KY, USA
| | - Lesley Mathews-Greiner
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Dandan Li
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes for Health, CCR 4 West/4-3740, 10 Center Drive, Bethesda, MD, 20892-0001, USA
| | - Abisola Abisoye-Ogunniyan
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes for Health, CCR 4 West/4-3740, 10 Center Drive, Bethesda, MD, 20892-0001, USA.,Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL, USA
| | | | - Yansong Bian
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes for Health, CCR 4 West/4-3740, 10 Center Drive, Bethesda, MD, 20892-0001, USA
| | - Vivek Shukla
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes for Health, CCR 4 West/4-3740, 10 Center Drive, Bethesda, MD, 20892-0001, USA
| | - Xiaohu Zhang
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Raj Guha
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Craig Thomas
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | | | - Athina Zacharia
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes for Health, CCR 4 West/4-3740, 10 Center Drive, Bethesda, MD, 20892-0001, USA
| | - Joal D Beane
- Indiana University School of Medicine, Indianapolis, IN, USA
| | - Sarangan Ravichandran
- Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD, USA
| | - Marc Ferrer
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Udo Rudloff
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes for Health, CCR 4 West/4-3740, 10 Center Drive, Bethesda, MD, 20892-0001, USA.
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Abstract
Gastric cancer represents a major cause of cancer mortality worldwide despite a declining incidence. New molecular classification schemes developed from genomic and molecular analyses of gastric cancer have provided a framework for understanding this heterogenous disease, and early findings suggest these classifications will be relevant for designing and implementing new targeted therapies. The success of targeted therapy and immunotherapy in breast cancer and melanoma, respectively, has not been duplicated in gastric cancer, but trastuzumab and ramucirumab have demonstrated efficacy in select populations. New markers that predict therapeutic response are needed to improve patient selection for both targeted and immunotherapies.
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Affiliation(s)
- Matthew S Strand
- Department of Surgery, Barnes-Jewish Hospital and Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8109, St Louis, MO 63110, USA
| | - Albert Craig Lockhart
- Department of Medicine, Barnes-Jewish Hospital and Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8056, St Louis, MO 63110, USA
| | - Ryan C Fields
- Department of Surgery, Barnes-Jewish Hospital and Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8109, St Louis, MO 63110, USA.
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Boland CR, Yurgelun MB. Historical Perspective on Familial Gastric Cancer. Cell Mol Gastroenterol Hepatol 2017; 3:192-200. [PMID: 28275686 PMCID: PMC5331778 DOI: 10.1016/j.jcmgh.2016.12.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 12/25/2016] [Indexed: 12/18/2022]
Abstract
Gastric cancer is a common disease worldwide, typically associated with acquired chronic inflammation in the stomach, related in most instances to infection by Helicobacter pylori. A small percentage of cases occurs in familial clusters, and some of these can be linked to specific germline mutations. This article reviews the historical background to the current understanding of familial gastric cancer, focuses on the entity of hereditary diffuse gastric cancer, and also reviews the risks for gastric cancer related to a number of other familial genetic diseases.
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Affiliation(s)
- C. Richard Boland
- Division of GI, University of California San Diego School of Medicine, San Diego, California,Correspondence Address correspondence to: C. Richard Boland, MD, UCSD School of Medicine, San Diego, California 92110.UCSD School of MedicineSan DiegoCalifornia 92110
| | - Matthew B. Yurgelun
- Dana-Farber Cancer Institute, Boston, Massachusetts,Matthew B. Yurgelun, MD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana 1126, Boston, Massachusetts 02215. fax: (617) 632–5370.Dana-Farber Cancer Institute450 Brookline AvenueDana 1126BostonMassachusetts 02215
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45
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Abstract
Gastric cancer is an aggressive disease. Several risk factors are involved in gastric cancer pathogenesis, likely Helicobacter pylori (H. pylori) infection, genetic factors in hereditary syndromes, lifestyle, and diet. However, well-implemented screening strategies are lacking in most countries, including those in Southern Europe. Nevertheless, gastric cancer outcomes are better in some Southern European countries than in others, likely because of the incidence and distribution of different histologic types. Robotic surgery has been gaining favor as a treatment of early-stage disease, and the need for perioperative chemotherapy or adjuvant chemoradiotherapy (CRT) for locally advanced disease has been debated. In the metastatic setting, trastuzumab in combination with chemotherapy has helped to extend survival compared with chemotherapy alone for HER2-positive disease. This article will describe how gastric cancer is assessed and treated in Southern Europe in an attempt to correlate these approaches from a global perspective.
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Affiliation(s)
- Ramon Andrade De Mello
- From the Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal, and the Department of Medical Oncology, Clatterbridge Cancer Centre, Merseyside, United Kingdom
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46
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Yelskaya Z, Bacares R, Salo-Mullen E, Somar J, Lehrich DA, Fasaye GA, Coit DG, Tang LH, Stadler ZK, Zhang L. CDH1 Missense Variant c.1679C>G (p.T560R) Completely Disrupts Normal Splicing through Creation of a Novel 5' Splice Site. PLoS One 2016; 11:e0165654. [PMID: 27880784 PMCID: PMC5120775 DOI: 10.1371/journal.pone.0165654] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 10/14/2016] [Indexed: 12/22/2022] Open
Abstract
Disease-causing germline mutations in CDH1 cause Hereditary Diffuse Gastric Cancer (HDGC). For patients who meet the HDGC screening criteria, the identification and classification of the sequence variants found in CDH1 are critical for risk management of patients. In this report, we describe a germline CDH1 c.1679C>G (p.T560R) variant identified in a 50 year old man who was diagnosed with gastric cancer with a strong family history of gastric cancer (one living brother was diagnosed with gastric cancer at 63 and another brother died of gastric cancer at 45). cDNA analysis, involving fragment analysis and cloning, indicated that the p.T560R mutation created a novel 5’ splice donor site, which led to a novel transcript with a 32 nucleotide deletion in exon 11. This abnormal transcript putatively produces a truncated CDH1 protein (E-cadherin) of 575 amino acids instead of 882. We also demonstrated that the variant completely abolishes normal splicing as the mutant allele does not generate any normal transcript. Furthermore, the CDH1 c.1679C>G (p.T560R) variant segregated with gastric cancer in all three family members affected with gastric cancer in this family. These results support the conclusion that CDH1 c.1679C>G (p.T560R) variant is a pathogenic mutation and contributes to HDGC through disruption of normal splicing.
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Affiliation(s)
- Zarina Yelskaya
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Ruben Bacares
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Erin Salo-Mullen
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Joshua Somar
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Deborah A. Lehrich
- Department of Hematology Oncology, Walter Reed National Military Medical Center, Bethesda, Maryland, United States of America
| | - Grace-Ann Fasaye
- Department of Surgical Oncology, Walter Reed National Military Medical Center, Bethesda, Maryland, United States of America
| | - Daniel G. Coit
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Laura H. Tang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Zsofia K. Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Liying Zhang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- * E-mail:
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DDR1 promotes E-cadherin stability via inhibition of integrin-β1-Src activation-mediated E-cadherin endocytosis. Sci Rep 2016; 6:36336. [PMID: 27824116 PMCID: PMC5099905 DOI: 10.1038/srep36336] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 10/14/2016] [Indexed: 01/08/2023] Open
Abstract
Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase of collagen, is primarily expressed in epithelial cells. Activation of DDR1 stabilises E-cadherin located on the cell membrane; however, the detailed mechanism of DDR1-stabilised E-cadherin remains unclear. We performed DDR1 knockdown (Sh-DDR1) on Mardin-Darby canine kidney cells to investigate the mechanism of DDR1-stabilised E-cadherin. Sh-DDR1 decreased junctional localisation, increased endocytosis of E-cadherin, and increased physical interactions between E-cadherin and clathrin. Treatment of the dynamin inhibitor Dyngo 4a suppressed Sh-DDR1-induced E-cadherin endocytosis. In addition, the phosphorylation level of Src tyrosine 418 was increased in Sh-DDR1 cell junctions, and inhibition of Src activity decreased Sh-DDR1-induced E-cadherin endocytosis. To characterise the molecular mechanisms, blocking integrin β1 decreased Src activity and E-cadherin junctional localisation in Sh-DDR1 cells. Photoconversion results showed that inhibition of Src activity rescued E-cadherin membrane stability and that inhibition of integrin β1-Src signalling decreased stress fibres and rescued E-cadherin membrane stability in Sh-DDR1 cells. Taken together, DDR1 stabilised membrane localisation of E-cadherin by inhibiting the integrin β1-Src-mediated clathrin-dependent endocytosis pathway.
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48
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Hugen S, Thomas RE, German AJ, Burgener IA, Mandigers PJJ. Gastric carcinoma in canines and humans, a review. Vet Comp Oncol 2016; 15:692-705. [PMID: 27549077 DOI: 10.1111/vco.12249] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 05/06/2016] [Accepted: 05/20/2016] [Indexed: 02/06/2023]
Abstract
Gastric carcinoma (GC) is the most common neoplasm in the stomach of dogs. Although incidence in the general population is reported to be low, breed-specific GC has a high incidence. Median age at presentation ranges from 8 to approximately 10 years. The disease is mostly located in the lesser curvature and antropyloric region of the stomach. Unfortunately, diagnosis is usually made when the disease is at an advanced stage and, therefore, prognosis is poor. Due to similarities in clinical presentation, diagnosis, histology and prognosis, canine GC may serve as a valuable model for human GC. Extensive pedigrees of canine gastric carcinoma cases could reveal insights for human gastric carcinoma. Putative species differences include the role of Helicobacter in pathogenesis, the wide array of genetic data and screening available for humans, and treatment protocols that are available for human GC.
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Affiliation(s)
- S Hugen
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - R E Thomas
- Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - A J German
- School of Veterinary Science, University of Liverpool, Neston, UK
| | - I A Burgener
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - P J J Mandigers
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
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Baniak N, Senger JL, Ahmed S, Kanthan SC, Kanthan R. Gastric biomarkers: a global review. World J Surg Oncol 2016; 14:212. [PMID: 27514667 PMCID: PMC4982433 DOI: 10.1186/s12957-016-0969-3] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 08/02/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gastric cancer is an aggressive disease with a poor 5-year survival and large global burden of disease. The disease is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Despite the many prognostic, predictive, and therapeutic biomarkers investigated to date, gastric cancer continues to be detected at an advanced stage with resultant poor clinical outcomes. MAIN BODY This is a global review of gastric biomarkers with an emphasis on HER2, E-cadherin, fibroblast growth factor receptor, mammalian target of rapamycin, and hepatocyte growth factor receptor as well as sections on microRNAs, long noncoding RNAs, matrix metalloproteinases, PD-L1, TP53, and microsatellite instability. CONCLUSION A deeper understanding of the pathogenesis and biological features of gastric cancer, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers, hopefully will provide improved clinical outcomes.
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Affiliation(s)
- Nick Baniak
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Jenna-Lynn Senger
- Department of Surgery, University of Alberta, 116 St & 85 Ave, Edmonton, T6G 2R3, T6G 2B7 AB Canada
| | - Shahid Ahmed
- Division of Medical Oncology, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - S. C. Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Rani Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
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Skierucha M, Milne ANA, Offerhaus GJA, Polkowski WP, Maciejewski R, Sitarz R. Molecular alterations in gastric cancer with special reference to the early-onset subtype. World J Gastroenterol 2016; 22:2460-2474. [PMID: 26937134 PMCID: PMC4768192 DOI: 10.3748/wjg.v22.i8.2460] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 11/06/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC.
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