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Aslan F, Almalı N, Kaya Z, Güven M, Şahin ES, Özdemir A, Duran S, Binici S, Karan BM, Uygur S. Linking CDH1 SNPs to gastric cancer risk: a comprehensive analysis of rs16260, rs13689, and rs9929218. Mol Biol Rep 2024; 51:1162. [PMID: 39550749 DOI: 10.1007/s11033-024-10094-7] [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: 09/12/2024] [Accepted: 11/04/2024] [Indexed: 11/18/2024]
Abstract
OBJECTIVE Single nucleotide polymorphisms (SNPs) are linked to carcinogenesis. Pathogenic variants in the CDH1 gene are associated with gastric cancer. This study examines the genotype and allele frequencies of three SNPs (rs16260, rs13689, and rs9929218) in the CDH1 gene and their relationship with gastric cancer risk. MATERIALS AND METHODS The study involved 105 gastric cancer patients with pathology results and 105 healthy controls. Clinical, histopathological, and demographic data were collected and compared between the two groups. RESULTS No significant differences were found for rs16260 (- 160 C > A) and rs9929218 (G > A) between patients and controls (p > 0.05). For rs13689 (T > C), the T allele frequency was 90% in patients versus 69% in controls, while the C allele frequency was 10% in patients versus 31% in controls. A significant difference was observed for this SNP, with a higher T allele frequency in patients (OR = 4.03 CI95% 2.4-6.7, p < 0.0001) compared with controls, suggesting a fourfold increased risk of gastric cancer. Genotype frequencies were 80% wild-type (TT) and 20% heterozygous-type (TC) in patients, and 58% TT, 22% TC, and 20% mutant-type (CC) in controls (p < 0.0001). The frequencies of non-C allele carriers (TT) were present in 80% of patients versus 58.1% of controls (OR = 2.88 CI95% 1.56-5.34, p = 0.0006). CONCLUSION This study is the first to link the rs13689 SNP's T allele and TT genotype with increased gastric cancer risk. Our results suggest that the rs13689 T allele may contribute significantly to disease susceptibility, while the rs16260 CC genotype and rs9929218 GG genotype may influence risk in smokers.
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Affiliation(s)
- Fırat Aslan
- Faculty of Medicine, Department of General Surgery, Van Yuzuncu Yıl University, Van, Turkey.
- Department of General Surgery, Van Education and Research Hospital, Van, Turkey.
| | - Necat Almalı
- Faculty of Medicine, Department of General Surgery, Van Yuzuncu Yıl University, Van, Turkey
| | - Zehra Kaya
- Faculty of Medicine, Department of Medical Biology, Van Yuzuncu Yıl University, Van, Turkey
| | - Mustafa Güven
- Faculty of Medicine, Van Yuzuncu Yıl University, Van, Turkey
| | - Elif Sena Şahin
- Faculty of Medicine, Department of Medical Biology, Van Yuzuncu Yıl University, Van, Turkey
| | - Abdulselam Özdemir
- Faculty of Medicine, Department of General Surgery, Van Yuzuncu Yıl University, Van, Turkey
- Department of General Surgery, Dağkapı State Hospital, Diyarbakır, Turkey
| | - Seren Duran
- Faculty of Medicine, Department of Medical Biology, Van Yuzuncu Yıl University, Van, Turkey
| | - Serhat Binici
- Faculty of Medicine, Department of General Surgery, Van Yuzuncu Yıl University, Van, Turkey
- General Surgery Department, Şırnak State Hospital, Şırnak, Turkey
| | - Burak Muğdat Karan
- Faculty of Medicine, Department of Medical Biology, Van Yuzuncu Yıl University, Van, Turkey
| | - Serhat Uygur
- Faculty of Medicine, Van Yuzuncu Yıl University, Van, Turkey
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Cai HQ, Zhang LY, Fu LM, Xu B, Jiao Y. Mutational landscape of TP53 and CDH1 in gastric cancer. World J Gastrointest Surg 2024; 16:276-283. [PMID: 38463349 PMCID: PMC10921187 DOI: 10.4240/wjgs.v16.i2.276] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 12/26/2023] [Accepted: 01/30/2024] [Indexed: 02/25/2024] Open
Abstract
In this editorial we comment on an article published in a recent issue of the World J Gastrointest Surg. A common gene mutation in gastric cancer (GC) is the TP53 mutation. As a tumor suppressor gene, TP53 is implicated in more than half of all tumor occurrences. TP53 gene mutations in GC tissue may be related with clinical pathological aspects. The TP53 mutation arose late in the progression of GC and aided in the final switch to malignancy. CDH1 encodes E-cadherin, which is involved in cell-to-cell adhesion, epithelial structure maintenance, cell polarity, differentiation, and intracellular signaling pathway modulation. CDH1 mutations and functional loss can result in diffuse GC, and CDH1 mutations can serve as independent prognostic indicators for poor prognosis. GC patients can benefit from genetic counseling and testing for CDH1 mutations. Demethylation therapy may assist to postpone the onset and progression of GC. The investigation of TP53 and CDH1 gene mutations in GC allows for the investigation of the relationship between these two gene mutations, as well as providing some basis for evaluating the prognosis of GC patients.
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Affiliation(s)
- Hong-Qiao Cai
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Yue Zhang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Ming Fu
- Department of Traditional Chinese Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Bin Xu
- Department of Traditional Chinese Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yan Jiao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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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] [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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Salarikia SR, Kashkooli M, Taghipour MJ, Malekpour M, Negahdaripour M. Identification of hub pathways and drug candidates in gastric cancer through systems biology. Sci Rep 2022; 12:9099. [PMID: 35650297 PMCID: PMC9160265 DOI: 10.1038/s41598-022-13052-0] [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: 12/01/2021] [Accepted: 05/10/2022] [Indexed: 11/17/2022] Open
Abstract
Gastric cancer is the fourth cause of cancer death globally, and gastric adenocarcinoma is its most common type. Efforts for the treatment of gastric cancer have increased its median survival rate by only seven months. Due to the relatively low response of gastric cancer to surgery and adjuvant therapy, as well as the complex role of risk factors in its incidences, such as protein-pomp inhibitors (PPIs) and viral and bacterial infections, we aimed to study the pathological pathways involved in gastric cancer development and investigate possible medications by systems biology and bioinformatics tools. In this study, the protein-protein interaction network was analyzed based on microarray data, and possible effective compounds were discovered. Non-coding RNA versus coding RNA interaction network and gene-disease network were also reconstructed to better understand the underlying mechanisms. It was found that compounds such as amiloride, imatinib, omeprazole, troglitazone, pantoprazole, and fostamatinib might be effective in gastric cancer treatment. In a gene-disease network, it was indicated that diseases such as liver carcinoma, breast carcinoma, liver fibrosis, prostate cancer, ovarian carcinoma, and lung cancer were correlated with gastric adenocarcinoma through specific genes, including hgf, mt2a, mmp2, fbn1, col1a1, and col1a2. It was shown that signaling pathways such as cell cycle, cell division, and extracellular matrix organization were overexpressed, while digestion and ion transport pathways were underexpressed. Based on a multilevel systems biology analysis, hub genes in gastric adenocarcinoma showed participation in the pathways such as focal adhesion, platelet activation, gastric acid secretion, HPV infection, and cell cycle. PPIs are hypothesized to have a therapeutic effect on patients with gastric cancer. Fostamatinib seems a potential therapeutic drug in gastric cancer due to its inhibitory effect on two survival genes. However, these findings should be confirmed through experimental investigations.
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Affiliation(s)
| | - Mohammad Kashkooli
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Javad Taghipour
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Science, Shiraz, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, P.O. Box 71345-1583, Shiraz, Iran
| | - Mahdi Malekpour
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Manica Negahdaripour
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Science, Shiraz, Iran.
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, P.O. Box 71345-1583, Shiraz, Iran.
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Yun T, Wang S, Jiang B, Wang C, Meng N, Yuan X, Wang Y. Significance of Detection of the HER2 Gene and PD-1/PD-L1 in Gastric Cancer. JOURNAL OF ONCOLOGY 2020; 2020:8678945. [PMID: 33123197 PMCID: PMC7584973 DOI: 10.1155/2020/8678945] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 08/05/2020] [Accepted: 09/29/2020] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To explore the relationship between the HER2 gene and PD-1/PD-L1 in gastric cancer and its significance. METHODS Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were used to detect HER2 protein expression, HER2 gene amplification, and PD-1/PD-L1 expression in 78 cases of gastric cancer. RESULTS The expression rate of HER2 protein was 43.6% (34/78), of which 19.4% (14/78) were HER2 3+, 14.1% (11/78) were HER2 2+, and 11.5% (9/78) were HER2 1+. The results showed that 19.2% (15/78) of samples had HER2 gene amplification, 3.8% (3/78) of samples had a HER2/CEP17 ratio <2.0, and 19.2% (15/78) of samples had HER2 gene amplificationf and HER2 copy/cell ≥6.0, as detected by FISH. The positive rate of PD-L1 was 38.5% (30/78) in gastric cancer cells and 50.0% (39/78) in interstitial lymphocytes. The expression of the HER2 gene, PD-L1, and PD-1 in gastric cancer was correlated with the stage and lymph node metastasis of gastric cancer (P < 0.05). CONCLUSIONS The combined detection of the HER2 gene and PD-1/PD-L1 in gastric cancer provides an important reference index for the prognosis of gastric cancer and the benefit of targeted antitumor drugs.
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Affiliation(s)
- Tian Yun
- People's Liberation Army Joint Logistic Support Force 989th Hospital, LuoYang, Henan 471031, China
| | - Sunan Wang
- ShenZhen Polytechnic, ShenZhen 518110, China
| | - Bo Jiang
- People's Liberation Army Joint Logistic Support Force 990th Hospital, ZhuMaDian, Henan 463000, China
| | - Changsong Wang
- People's Liberation Army Joint Logistic Support Force 989th Hospital, LuoYang, Henan 471031, China
| | - Nianlong Meng
- People's Liberation Army Joint Logistic Support Force 989th Hospital, LuoYang, Henan 471031, China
| | - Xutao Yuan
- People's Liberation Army Joint Logistic Support Force 989th Hospital, LuoYang, Henan 471031, China
| | - Yangkun Wang
- Department of Pathology, ShenZhen Hospital, Southern Medical University, ShenZhen 518110, China
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Machlowska J, Baj J, Sitarz M, Maciejewski R, Sitarz R. Gastric Cancer: Epidemiology, Risk Factors, Classification, Genomic Characteristics and Treatment Strategies. Int J Mol Sci 2020; 21:E4012. [PMID: 32512697 PMCID: PMC7312039 DOI: 10.3390/ijms21114012] [Citation(s) in RCA: 774] [Impact Index Per Article: 154.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 05/31/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies worldwide and it is the fourth leading cause of cancer-related death. GC is a multifactorial disease, where both environmental and genetic factors can have an impact on its occurrence and development. The incidence rate of GC rises progressively with age; the median age at diagnosis is 70 years. However, approximately 10% of gastric carcinomas are detected at the age of 45 or younger. Early-onset gastric cancer is a good model to study genetic alterations related to the carcinogenesis process, as young patients are less exposed to environmental carcinogens. Carcinogenesis is a multistage disease process specified by the progressive development of mutations and epigenetic alterations in the expression of various genes, which are responsible for the occurrence of the disease.
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Affiliation(s)
- Julita Machlowska
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, 31-034 Kraków, Poland;
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (J.B.); (R.M.)
| | - Jacek Baj
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (J.B.); (R.M.)
| | - Monika Sitarz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Ryszard Maciejewski
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (J.B.); (R.M.)
| | - Robert Sitarz
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (J.B.); (R.M.)
- Department of Surgery, Center of Oncology of the Lublin Region St. Jana z Dukli, 20-090 Lublin, Poland
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Aitchison A, Hakkaart C, Whitehead M, Khan S, Siddique S, Ahmed R, Frizelle FA, Keenan JI. CDH1 gene mutation in early-onset, colorectal signet-ring cell carcinoma. Pathol Res Pract 2020; 216:152912. [PMID: 32147272 DOI: 10.1016/j.prp.2020.152912] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 02/25/2020] [Accepted: 02/28/2020] [Indexed: 12/12/2022]
Abstract
AIM Colorectal signet-ring cell carcinomas (SRCC) are highly malignant tumours with poor prognosis that disproportionately affect younger patients. There is growing evidence of a unique set of molecular features that separate SRCC from conventional colorectal adenocarcinoma. Identification of these distinct features may have diagnostic and prognostic significance for patients and families. CDH1, which encodes E-cadherin, a cell adhesion protein, is commonly mutated in gastric SRCC and our study aimed to identify whether CDH1 mutation was also a common phenomenon in colorectal SRCC. METHODS DNA was extracted from formalin-fixed paraffin embedded tumour tissue, the CDH1 gene was analysed by next generation sequencing and the pathogenicity of mutations assessed in silico. Sections cut from the same blocks were immunostained to identify the presence of the E-cadherin protein. RESULTS We found 8 CDH1 mutations that meet our inclusion criteria in seven of 11 samples. Of these, five (from four patients), were likely to be germline mutations. E-cadherin staining was absent or markedly reduced in all of the seven samples with CDH1 mutation. CONCLUSION Our finding of CDH1 mutations in a proportion of signet-ring cell carcinomas and associated reduction in E-cadherin in these tumours supports previous findings of a role for mutation of this gene in the development of this disease. In addition, the finding of likely germline mutations suggests that a subset of these tumours may be familial. Loss of E-cadherin staining in the absence of CDH1 mutations however also suggests a role for environmental factors in a subset of these tumours.
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Affiliation(s)
- Alan Aitchison
- Department of Surgery, University of Otago Christchurch, Christchurch, New Zealand.
| | - Christopher Hakkaart
- Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand
| | - Martin Whitehead
- Anatomical Pathology, Canterbury Health Laboratories, Christchurch, New Zealand
| | - Sadaf Khan
- Aga Khan University Medical College, Karachi, Pakistan
| | | | - Rashida Ahmed
- Aga Khan University Medical College, Karachi, Pakistan
| | - Frank A Frizelle
- Department of Surgery, University of Otago Christchurch, Christchurch, New Zealand
| | - Jacqueline I Keenan
- Department of Surgery, University of Otago Christchurch, Christchurch, New Zealand
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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, MA 02115, USA
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Jutel A. Diagnosis: a critical social reflection in the genomic era. CIENCIA & SAUDE COLETIVA 2019; 24:3619-3626. [DOI: 10.1590/1413-812320182410.34502018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 02/11/2019] [Indexed: 11/22/2022] Open
Abstract
Abstract Diagnosis is a pivotal tool for the work of medicine as they categorise and classify individual ailments via a generalised schema. However diagnosis is also a profoundly social act, which reflects society, its values and how it makes sense of illness and disease. Considering diagnosis critically, as well as practically, is an important job of the sociologist. This paper reviews how a social model can provide a critical tool for viewing diagnosis in the genomic era. It explores how the formulation of diagnosis, be it via genetic explanations or microbiological ones, are the product of social discovery, negotiation, and consensus.
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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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Fewings E, Larionov A, Redman J, Goldgraben MA, Scarth J, Richardson S, Brewer C, Davidson R, Ellis I, Evans DG, Halliday D, Izatt L, Marks P, McConnell V, Verbist L, Mayes R, Clark GR, Hadfield J, Chin SF, Teixeira MR, Giger OT, Hardwick R, di Pietro M, O'Donovan M, Pharoah P, Caldas C, Fitzgerald RC, Tischkowitz M. Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study. Lancet Gastroenterol Hepatol 2018; 3:489-498. [PMID: 29706558 PMCID: PMC5992580 DOI: 10.1016/s2468-1253(18)30079-7] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 02/27/2018] [Accepted: 02/28/2018] [Indexed: 01/24/2023]
Abstract
BACKGROUND Germline pathogenic variants in the E-cadherin gene (CDH1) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make informed decisions about surveillance and risk-reducing surgery. We aimed to identify new candidate genes associated with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic CDH1 variants. METHODS We did whole-exome sequencing on DNA extracted from the blood of 39 individuals (28 individuals diagnosed with hereditary diffuse gastric cancer and 11 unaffected first-degree relatives) in 22 families without pathogenic CDH1 variants. Genes with loss-of-function variants were prioritised using gene-interaction analysis to identify clusters of genes that could be involved in predisposition to hereditary diffuse gastric cancer. FINDINGS Protein-affecting germline variants were identified in probands from six families with hereditary diffuse gastric cancer; variants were found in genes known to predispose to cancer and in lesser-studied DNA repair genes. A frameshift deletion in PALB2 was found in one member of a family with a history of gastric and breast cancer. Two different MSH2 variants were identified in two unrelated affected individuals, including one frameshift insertion and one previously described start-codon loss. One family had a unique combination of variants in the DNA repair genes ATR and NBN. Two variants in the DNA repair gene RECQL5 were identified in two unrelated families: one missense variant and a splice-acceptor variant. INTERPRETATION The results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. We also identified new candidate genes associated with disease risk in these families. FUNDING UK Medical Research Council (Sackler programme), European Research Council under the European Union's Seventh Framework Programme (2007-13), National Institute for Health Research Cambridge Biomedical Research Centre, Experimental Cancer Medicine Centres, and Cancer Research UK.
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Affiliation(s)
- Eleanor Fewings
- Academic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Alexey Larionov
- Academic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - James Redman
- Academic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Mae A Goldgraben
- Academic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - James Scarth
- Academic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Susan Richardson
- Familial Gastric Cancer Study, Department of Oncology, University of Cambridge, Cambridge, UK
| | | | | | - Ian Ellis
- Cheshire and Merseyside Regional Genetic Service, Liverpool, UK
| | | | - Dorothy Halliday
- Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Louise Izatt
- Clinical Genetics Service, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Peter Marks
- West Midlands Regional Genetics Service, Birmingham, UK
| | - Vivienne McConnell
- Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, UK
| | - Louis Verbist
- Department of Gastroenterology, ZNA Jan Palfijn, Antwerp, Belgium
| | - Rebecca Mayes
- Centre for Cancer Genetic Epidemiology, Strangeway's Research Laboratory, University of Cambridge, Cambridge, UK
| | - Graeme R Clark
- Academic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - James Hadfield
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK; Precision Medicine and Genomics, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge, UK
| | - Suet-Feung Chin
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Manuel R Teixeira
- Department of Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal; Institute of Biomedical Sciences, University of Porto, Porto, Portugal
| | - Olivier T Giger
- Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Richard Hardwick
- Department of Oesophago-Gastric Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Massimiliano di Pietro
- Medical Research Council (MRC) Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK
| | - Maria O'Donovan
- Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Paul Pharoah
- Centre for Cancer Genetic Epidemiology, Strangeway's Research Laboratory, University of Cambridge, Cambridge, UK
| | - Carlos Caldas
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Rebecca C Fitzgerald
- Medical Research Council (MRC) Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Marc Tischkowitz
- Academic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
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12
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Abstract
Next-generation sequencing (NGS) technology has led to the ability to test for multiple cancer susceptibility genes simultaneously without significantly increasing cost or turnaround time. With growing usage of multigene testing for inherited cancer, ongoing education for nurses and other health-care providers about hereditary cancer screening is imperative to ensure appropriate testing candidate identification, test selection, and posttest management. The purpose of this review article is to (1) provide an overview of how NGS works to detect germline mutations, (2) summarize the benefits and limitations of multigene panel testing, (3) describe risk categories of cancer susceptibility genes, and (4) highlight the counseling considerations for patients pursuing multigene testing.
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Mi EZ, Mi EZ, di Pietro M, O'Donovan M, Hardwick RH, Richardson S, Ziauddeen H, Fletcher PC, Caldas C, Tischkowitz M, Ragunath K, Fitzgerald RC. Comparative study of endoscopic surveillance in hereditary diffuse gastric cancer according to CDH1 mutation status. Gastrointest Endosc 2018; 87:408-418. [PMID: 28688938 PMCID: PMC5780354 DOI: 10.1016/j.gie.2017.06.028] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 06/20/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Hereditary diffuse gastric cancer (HDGC) accounts for 1% of gastric cancer cases. For patients with a germline CDH1 mutation, risk-reducing gastrectomy is recommended. However, for those delaying surgery or for families with no causative mutation identified, regular endoscopy is advised. This study aimed to determine the yield of signet ring cell carcinoma (SRCC) foci in individuals with a CDH1 pathogenic variant compared with those without and how this varies with successive endoscopies. METHODS Patients fulfilling HDGC criteria were recruited to a prospective longitudinal cohort study. Endoscopy was performed according to a strict protocol with visual inspection followed by focal lesion and random biopsy sampling to detect foci of SRCC. Survival analysis determined progression to finding of SRCC according to CDH1 mutation status. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and 36-item Short Form Health Survey questionnaires assessed quality of life before surveillance and each endoscopy. RESULTS Eighty-five individuals fulfilling HDGC criteria underwent 201 endoscopies; 54 (63.5%) tested positive for CDH1 mutation. SRCC yield was 61.1% in CDH1 mutation carriers compared with 9.7% in noncarriers, and mutation-positive patients had a 10-fold risk of SRCC on endoscopy compared with those with no mutation detected (P < .0005). Yield of SRCC decreased substantially with subsequent endoscopies. Surveillance was associated with improved psychological health. CONCLUSIONS SRCC foci are prevalent in CDH1 mutation carriers and can be detected at endoscopy using a standardized, multiple biopsy sampling protocol. Decreasing yield over time suggests that the frequency of endoscopy might be reduced. For patients with no CDH1 pathogenic variant detected, the cost-to-benefit ratio needs to be assessed in view of the low yield.
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Key Words
- aei, allelic expression imbalance
- cdh1+, cdh1 pathogenic variant
- cdh1-npvd, cdh1 no pathogenic variant detected
- dgc, diffuse gastric cancer
- eortc-qol-c30, european organization for research and treatment of cancer quality of life questionnaire core 30
- gc, gastric cancer
- hdgc, hereditary diffuse gastric cancer
- ppi, proton pump inhibitor
- qol, quality of life
- rrtg, risk-reducing total gastrectomy
- sf-36, 36-item short form health survey
- srcc, signet ring cell carcinoma
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Affiliation(s)
- Emma Z Mi
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Ella Z Mi
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | | | - Maria O'Donovan
- Department of Histopathology, Cambridge University Hospitals NHS Trust and University of Cambridge, Cambridge, UK
| | - Richard H Hardwick
- Department of Oesophago-Gastric Surgery, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Susan Richardson
- Familial Gastric Cancer Study, Department of Oncology, Cambridge University Hospitals NHS Trust and University of Cambridge, Cambridge, UK
| | | | - Paul C Fletcher
- Department of Psychiatry, University of Cambridge, Cambridge, UK; Cambridge and Peterborough NHS Foundation Trust, Cambridge, UK
| | - Carlos Caldas
- Cancer Research UK Cambridge Institute, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Marc Tischkowitz
- Department of Medical Genetics, University of Cambridge and Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Krish Ragunath
- NIHR Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Rebecca C Fitzgerald
- MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK
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14
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Chenbhanich J, Malone MV, Spigelman Z, Seetharaman K. Gastric Wall Thickening: Do Not Overlook Family History. Am J Med 2017; 130:e69-e70. [PMID: 28117042 DOI: 10.1016/j.amjmed.2016.09.039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 09/28/2016] [Indexed: 10/20/2022]
Affiliation(s)
- Jirat Chenbhanich
- Department of Internal Medicine, Metrowest Medical Center, Framingham, Mass.
| | | | - Zachary Spigelman
- Division of Hematology and Oncology, Department of Internal Medicine, Metrowest Medical Center, Framingham, Mass; Division of Hematology and Oncology, Department of Medicine, Tufts Medical Center, Boston, Mass
| | - Kala Seetharaman
- Division of Hematology and Oncology, Department of Internal Medicine, Metrowest Medical Center, Framingham, Mass
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15
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Gurzu S, Jung I, Orlowska J, Sugimura H, Kadar Z, Turdean S, Bara T. Hereditary diffuse gastric cancer--An overview. Pathol Res Pract 2015; 211:629-32. [PMID: 26150395 DOI: 10.1016/j.prp.2015.06.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 04/20/2015] [Accepted: 06/02/2015] [Indexed: 02/05/2023]
Abstract
The incidence of gastric cancer varies by up to ten fold throughout the world, and the geographic distribution of hereditary cases is not well explored. Familial clustering is seen in 10% of cases, and approximately 3% of all gastric cancers develop due to hereditary diffuse gastric cancer (HDGC). In this review, the characteristics of HDGC are presented according to molecular particularities, geographic distribution, and other parameters. Based on our experience and the data from the literature, we discuss the possibility of applying a mutation signature (spectrum) study and adductomic approaches to a comparative carcinogenesis of HDGC. We also provide a comprehensive, up-to-date review of genetic counseling and criteria for screening and surveillance of eligible families.
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Affiliation(s)
- Simona Gurzu
- Department of Pathology, University of Medicine and Pharmacy of Tirgu-Mures, Romania.
| | - Ioan Jung
- Department of Pathology, University of Medicine and Pharmacy of Tirgu-Mures, Romania
| | - Janina Orlowska
- Department of Pathology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Haruhiko Sugimura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Zoltan Kadar
- Department of Pathology, University of Medicine and Pharmacy of Tirgu-Mures, Romania; Department of Oncology, University of Medicine and Pharmacy of Tirgu-Mures, Romania
| | - Sabin Turdean
- Department of Pathology, University of Medicine and Pharmacy of Tirgu-Mures, Romania
| | - Tivadar Bara
- Department of Surgery, University of Medicine and Pharmacy of Tirgu-Mures, Romania
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16
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Abstract
Hereditary gastric cancer syndromes are a rare but distinct cause of gastric cancers. The genetic mutations underlying most affected families are unknown. Mutations of CDH1 occur in some patients affected by hereditary diffuse gastric cancer, and is the only practical marker for guiding management. Carriers of CDH1 mutations are at risk for a highly penetrant, aggressive and early-onset diffuse-type gastric cancer, and these individuals are usually offered prophylactic total gastrectomy. Further research is required to identify other genetic mutations responsible for these syndromes to improve our understanding of the underlying disease mechanisms and optimize the clinical management of affected individuals.
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Affiliation(s)
- Hugh Colvin
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Ken Yamamoto
- Department of Medical Chemistry, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka 830-0011, Japan
| | - Noriko Wada
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
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17
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Oh MG, Kim JH, Han MA, Park J, Ryu SY, Choi SW. Family history and survival of patients with gastric cancer: a meta-analysis. Asian Pac J Cancer Prev 2015; 15:3465-70. [PMID: 24870741 DOI: 10.7314/apjcp.2014.15.8.3465] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Previous studies have generated conflicting evidence regarding associations between family history and survival after gastric cancer surgery. In this study, we investigated this question using a meta-analysis. MATERIALS AND METHODS To identify relevant studies, PubMed and Embase databases were searched up to June 2013. Two reviewers independently assessed search results and data extraction of included studies. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) were calculated based on fixed- or random- effects models. Homogeneity of effects across studies was assessed using x2 test statistics and quantified by I2. RESULTS A total of five studies were selected according to the inclusion criteria. The total number of patients included was 2,030, which ranged from 145 to 598 per study. There was no significant difference in OS by family history of cancer (HR=0.83, 95%CIs=0.50-1.38), but subgroup analysis of patients with a first-degree family history of cancer (HR=0.74, 95%CIs=0.60-0.93) and gastric cancer family history (HR=0.56, 95%CIs=0.41-0.76) tended to show better OS in these patients. CONCLUSIONS This meta-analysis suggests that a first-degree family history of cancer or gastric cancer family history is associated with better survival of gastric cancer patients after surgery, after a systematic review of five previous studies. These results can be applied by clinicians when counselling patients regarding their risk of death from gastric cancer. Further study is needed to investigate the underlying mechanism between family history and survival in gastric cancer patients.
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Affiliation(s)
- Myueng Guen Oh
- Department of Internal Medicine, Chosun University Hospital, Chosun University, Gwangju, Korea E-mail :
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18
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Pattison S, Boussioutas A. Pathophysiology of Hereditary Diffuse Gastric Cancer. Gastric Cancer 2015. [DOI: 10.1007/978-3-319-15826-6_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
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19
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Moreira-Nunes CA, Barros MBL, do Nascimento Borges B, Montenegro RC, Lamarão LM, Ribeiro HF, Bona AB, Assumpção PP, Rey JA, Pinto GR, Burbano RR. Genetic screening analysis of patients with hereditary diffuse gastric cancer from northern and northeastern Brazil. Hered Cancer Clin Pract 2014; 12:18. [PMID: 25180051 PMCID: PMC4150117 DOI: 10.1186/1897-4287-12-18] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 08/08/2014] [Indexed: 12/15/2022] Open
Abstract
Background Hereditary diffuse gastric cancer (HDGC) is a hereditary autosomal inherited syndrome associated with CDH1 germline mutations. In Brazil, gastrointestinal tumors are among the most prevalent tumor types and constitute a serious public health problem, especially in the northern and northeastern regions. This study aimed to investigate germline mutations, methylation pattern and genomic rearrangements in the CDH1 gene and quantitative changes in the DNA of HDGC patients in northern and northeastern Brazil. Methods Twenty-seven DNA samples from the members of four families affected by HDGC were analyzed using array comparative genomic hybridization (aCGH), DNA sequencing and methylation pattern. Results No evidence of gain and loss events or any rearrangements were found in any of the samples tested using aCGH. No promoter region hypermethylation was observed either. Two of the four families presented different types of germline mutations. The 185G > T and 1018A > G germline mutations detected in this study have been described in Asian and European families, respectively. The ancestors of the two families carrying these mutations had originated from those continents. Conclusion This is the first study to evaluate CDH1 gene germline mutations in Brazilian families with HDGC. In our study, 50% of the families showed no CDH1 gene alterations, and it is possible that in regions with a high incidence of gastric cancer, such as northern and northeastern Brazil, environmental factors might have induced the different genetic alterations analyzed in this study.
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Affiliation(s)
| | | | | | - Raquel Carvalho Montenegro
- Biological Science Institute, Federal University of Para, Belem, PA 66075110, Brazil.,Nucleus of Research in Oncology, Federal University of Para, Belem, PA 66073000, Brazil
| | - Leticia Martins Lamarão
- Center of Hematology and Hemotherapy of Para - HEMOPA Foundation, Belem, PA 66033000, Brazil
| | | | - Amanda Braga Bona
- Biological Science Institute, Federal University of Para, Belem, PA 66075110, Brazil
| | | | - Juan Antonio Rey
- Molecular Neuro-oncogenetics Laboratory, Research Unit-Unidad de Investigación, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Giovanny Rebouças Pinto
- Genetics and Molecular Biology Laboratory, Federal University of Piaui, Parnaiba, PI 64049-550, Brazil
| | - Rommel Rodriguez Burbano
- Biological Science Institute, Federal University of Para, Belem, PA 66075110, Brazil.,Nucleus of Research in Oncology, Federal University of Para, Belem, PA 66073000, Brazil
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20
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Khatami F, Karbakhsh M. Socioeconomic position and incidence of gastric cancer: a systematic review and meta-analysis. J Epidemiol Community Health 2014; 69:818-9. [PMID: 25096810 DOI: 10.1136/jech-2013-203784] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 07/19/2014] [Indexed: 01/09/2023]
Affiliation(s)
- Farnaz Khatami
- Department of Community Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Mojgan Karbakhsh
- Department of Community Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
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21
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Garziera M, Canzonieri V, Cannizzaro R, Geremia S, Caggiari L, De Zorzi M, Maiero S, Orzes E, Perin T, Zanussi S, De Paoli P, De Re V. Identification and characterization of CDH1 germline variants in sporadic gastric cancer patients and in individuals at risk of gastric cancer. PLoS One 2013; 8:e77035. [PMID: 24204729 PMCID: PMC3812172 DOI: 10.1371/journal.pone.0077035] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 09/05/2013] [Indexed: 02/06/2023] Open
Abstract
Objective To screen and characterize germline variants for E-cadherin (CDH1) in non-hereditary gastric cancer (GC) patients and in subjects at risk of GC. Methods 59 GCs, 59 first degree relatives (FDRs) of GC, 20 autoimmune metaplastic atrophic gastritis (AMAGs) and 52 blood donors (BDs) were analyzed for CDH1 by direct sequencing, structural modelling and bioinformatics. Functional impact on splicing was assessed for intronic mutations. E-cadherin/β-catenin immunohistochemical staining and E-cadherin mRNA quantification using RT-PCR were performed. Results In GCs, 4 missense variants (p.G274S; p.A298T; p.T470I; p.A592T), 1 mutation in the 5′UTR (−71C>G) and 1 mutation in the intronic IVS12 (c.1937-13T>C) region were found. First pathogenic effect of p.A298T mutation was predicted by protein 3D modelling. The novel p.G274S mutation showed a no clear functional significance. Moreover, first, intronic IVS12 (c.1937-13T>C) mutation was demonstrated to lead to an aberrant CDH1 transcript with exon 11 deletion. This mutation was found in 2 GCs and in 1 BD. In FDRs, we identified 4 variants: the polymorphic (p.A592T) and 3 mutations in untranslated regions with unidentified functional role except for the 5′UTR (−54G>C) that had been found to decrease CDH1 transcription. In AMAGs, we detected 2 alterations: 1 missense (p.A592T) and 1 novel variant (IVS1 (c.48+7C>T)) without effect on CDH1 splicing. Several silent and polymorphic substitutions were found in all the groups studied. Conclusions Overall our study improves upon the current characterization of CDH1 mutations and their functional role in GC and in individuals at risk of GC. Mutations found in untranslated regions and data on splicing effects deserve a particular attention like associated with a reduced E-cadherin amount. The utility of CDH1 screening, in addition to the identification of other risk factors, could be useful for the early detection of GC in subjects at risk (i.e. FDRs and AMAGs), and warrants further study.
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Affiliation(s)
- Marica Garziera
- Departement of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Pordenone, Italy
| | - Vincenzo Canzonieri
- Pathology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Pordenone, Italy
| | - Renato Cannizzaro
- Gastroenterology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Pordenone, Italy
| | - Silvano Geremia
- CEB-Centre of Excellence in Biocrystallography, Department of Chemical Sciences, University of Trieste, Trieste, Italy
| | - Laura Caggiari
- Departement of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Pordenone, Italy
| | - Mariangela De Zorzi
- Departement of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Pordenone, Italy
| | - Stefania Maiero
- Gastroenterology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Pordenone, Italy
| | - Enrico Orzes
- Gastroenterology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Pordenone, Italy
| | - Tiziana Perin
- Pathology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Pordenone, Italy
| | - Stefania Zanussi
- Microbiology-Immunology and Virology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Pordenone, Italy
| | - Paolo De Paoli
- Scientific Director, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Pordenone, Italy
| | - Valli De Re
- Departement of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Pordenone, Italy
- * E-mail:
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22
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McVeigh TP, Choi JK, Miller NM, Green AJ, Kerin MJ. Lobular breast cancer in a CDH1 splice site mutation carrier: case report and review of the literature. Clin Breast Cancer 2013; 14:e47-51. [PMID: 24333020 DOI: 10.1016/j.clbc.2013.10.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 10/03/2013] [Indexed: 12/25/2022]
Affiliation(s)
- Terri P McVeigh
- Discipline of Surgery, National University of Ireland Galway, Galway, Ireland.
| | - Joon K Choi
- Discipline of Surgery, National University of Ireland Galway, Galway, Ireland
| | - Nicola M Miller
- Discipline of Surgery, National University of Ireland Galway, Galway, Ireland
| | - Andrew J Green
- National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Ireland
| | - Michael J Kerin
- Discipline of Surgery, National University of Ireland Galway, Galway, Ireland
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23
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Uthman OA, Jadidi E, Moradi T. Socioeconomic position and incidence of gastric cancer: a systematic review and meta-analysis. J Epidemiol Community Health 2013; 67:854-60. [PMID: 23929615 DOI: 10.1136/jech-2012-201108] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Low socioeconomic position (SEP) has been associated with increased risks of morbidity and mortality from many diseases. We investigated the associations between gastric cancer incidence and education, occupation and income as indicators for SEP. METHODS We searched the PubMed and EMBASE databases for studies on SEP and gastric cancer incidence published from 1966 through February 2013. We used a random-effect model to pool the risk estimates from the individual studies. The relative indexes of inequality (RIIs) with their 95% CIs were used as summary estimates. We stratified the analysis by SEP indicators, sex, country's income group, geographical area, level of adjustment for an established risk factor, publication year, study design, type of control and length of follow-up. RESULTS Of 1549 citations, 36 studies met our inclusion criteria. We observed an increased risk of gastric cancer among the lowest SEP categories in education (RII=2.97; 95% CI 1.923 to 4.58), occupation (RII=4.33; 95% CI 2.57 to 7.29) and combined SEP (RII=2.64; 95% CI 1.05 to 6.63) compared with the highest SEP categories. Although the association between the incidence of gastric cancer and the level of income is evident, it did not reach a statistically significant level (RII=1.25; 95% CI 0.93 to 1.68). CONCLUSIONS We found that the risk of gastric cancer incidence is higher among low SEP groups.
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Affiliation(s)
- Olalekan A Uthman
- Warwick-Centre for Applied Health Research and Delivery (WCAHRD), Division of Health Sciences, Warwick Medical School, The University of Warwick, Coventry, CV4 7AL, United Kingdom
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24
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Piazuelo MB, Correa P. Gastric cáncer: Overview. Colomb Med (Cali) 2013; 44:192-201. [PMID: 24892619 PMCID: PMC4002033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 02/02/2013] [Accepted: 07/02/2013] [Indexed: 12/03/2022] Open
Abstract
Gastric cancer ranks fourth in incidence and second in mortality among all cancers worldwide. Despite the decrease in incidence in some regions of the world, gastric cancer continues to present a major clinical challenge due to most cases being diagnosed in advanced stages with poor prognosis and limited treatment options. The development of gastric cancer is a complex and multifactorial process involving a number of etiological factors and multiple genetic and epigenetic alterations. Among the predisposing factors are: Helicobacter pylori infection, high salt intake, smoking, and in a small percentage of patients, a familial genetic component. More than 95% of stomach cancer cases are adenocarcinomas, which are classified into two major histologic types: intestinal and diffuse. Intestinal type adenocarcinoma is preceded by a sequence of gastric lesions known as Correa´s cascade and is the histologic type associated with the global decrease in gastric cancer rates. Diffuse type adenocarcinomas have a more aggressive behavior and worse prognosis than those of the intestinal type. According to the anatomical location, adenocarcinomas are classified as proximal (originating in the cardia) and distal (originating in the body and antrum). This classification seems to recognize two different clinical entities. Surgical resection of the tumor at an early stage is the only effective treatment method. Therefore, the identification and surveillance of patients at risk may play a significant role in survival rates. Anti-Helicobacter pylori therapy has been shown to be an effective measure in the prevention of gastric cancer.
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Affiliation(s)
- M. Blanca Piazuelo
- Division of Gastroenterology, Department of Medicine,Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Pelayo Correa
- Division of Gastroenterology, Department of Medicine,Vanderbilt University School of Medicine, Nashville, TN, USA
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25
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Abstract
The vast majority of gastric cancers are sporadic. However, 1-3% arise as a result of inherited gastric cancer predisposition syndromes, generally referred to as hereditary diffuse gastric cancer (HDGC). Of those families that fulfill the clinical criteria for HGDC only 25% have a CDH1 germline mutation. No reliable surveillance technique exists for individuals with HDGC. Difficult decisions have therefore to be made by mutation carriers to proceed with prophylactic total gastrectomy, or undergo lifelong annual surveillance. We present a case of the management of a patient with a documented CDH1 mutation and briefly review the available literature.
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Affiliation(s)
- A Daunton
- University Hospital Birmingham, Birmingham, UK
| | - S Puig
- University Hospital Birmingham, Birmingham, UK
| | - P Taniere
- University Hospital Birmingham, Birmingham, UK
| | - C Forde
- University Hospital Birmingham, Birmingham, UK
| | - D Alderson
- University Hospital Birmingham, Birmingham, UK
| | - On Tucker
- University Hospital Birmingham, Birmingham, UK
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26
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Abstract
This article focuses on the diagnosis and management of familial gastric cancer, particularly hereditary diffuse gastric cancer (HDGC). First, existing consensus guidelines are discussed and then the pathology and genetics of HDGC are reviewed. Second, patient management is covered, including surveillance gastroscopy, prophylactic total gastrectomy, and management of the risk of breast cancer.
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Affiliation(s)
- Vanessa R Blair
- Department of Surgery, Faculty of Medicine and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
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Hackenson D, Edelman DA, McGuire T, Weaver DW, Webber JD. Prophylactic laparoscopic gastrectomy for hereditary diffuse gastric cancer: a case series in a single family. JSLS 2011; 14:348-52. [PMID: 21333186 PMCID: PMC3041029 DOI: 10.4293/108680810x12924466007449] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Hereditary diffuse gastric carcinomas (HDGCs) are particularly troubling because of autosomal dominant heritance, high penetrance, early age of onset, and a lack of effective treatment once symptomatic. HDGC is further complicated by difficulty of effective screening. Gastrectomy provides definitive treatment for CDH1 mutation-positive patients. Attempting to minimize the morbidity and mortality of this procedure via a laparoscopic approach is appropriate. METHODS Six consanguineous patients, 21 to 51 years of age, were identified as carriers of the CDH1 gene mutation. All of the patients' gastric mucosa was normal by endoscopic appearance and biopsy. After appropriate multispecialty counseling, all patients elected to undergo a laparoscopic total gastrectomy. Demographics, genealogy, operative approach, outcomes, and pathology were reviewed. RESULTS All gastrectomies were completed using a laparoscopic approach. Gross examination of resected stomachs was unremarkable. Histological examination demonstrated multiple foci of invasive signet ring adenocarcinoma in all patients. There were no anastomotic leaks, one small bowel obstruction requiring reoperation, and one esophageal stricture requiring dilation. CONCLUSIONS This series demonstrates the utility and safety of the laparoscopic approach for prophylactic total gastrectomy for carriers of the CDH1 gene mutation. It serves to highlight that patients with CDH1 mutations may be more likely to undergo gastrectomy if they are offered the lower risk laparoscopic approach.
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Affiliation(s)
- David Hackenson
- Department of Surgery, Wayne State University, Detroit, Michigan 48201, USA
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Jacobs G, Hellmig S, Huse K, Titz A, Franke A, Kwiatkowski R, Ott S, Kosmahl M, Fischbach W, Lucius R, Klapper W, Fölsch UR, Hampe J, Schreiber S, Rosenstiel P. Polymorphisms in the 3'-untranslated region of the CDH1 gene are a risk factor for primary gastric diffuse large B-cell lymphoma. Haematologica 2011; 96:987-95. [PMID: 21459793 DOI: 10.3324/haematol.2010.033126] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Primary gastric B-cell lymphomas arise from mucosa-associated lymphatic tissue (MALT) in patients with chronic Helicobacter pylori infection. We investigated whether germline variants in the CDH1 gene, coding for E-cadherin, genetically predispose patients to primary gastric B-cell lymphoma. DESIGN AND METHODS Single marker analyses of the CDH1 gene were conducted in patients with primary gastric B-cell lymphoma (n=144), in patients with primary gastric high-grade lymphoma (n=61), and in healthy blood donors (n=361). Twelve single nucleotide polymorphisms were genotyped by TaqMan(®) technology. Allelic imbalance was tested by pyrosequencing and clone direct sequencing of heterozygote genomic and cDNA. Mutation detection was conducted around the poly-A signal of the CDH1 3'-untranslated region. The influence of the 3'-untranslated region on protein translation was determined by a luciferase reporter assay. RESULTS Single marker analyses identified two single nucleotide polymorphisms in strong linkage disequilibrium located in the CDH1 3'-untranslated region. One of them was significantly associated with primary gastric diffuse large B-cell lymphomas after correction for multiple testing and this association was confirmed in an independent sample set. Patients homozygous for the rare T allele (rs1801026) had a 4.9-fold increased risk (95% CI: 1.5-15.9) of developing primary gastric diffuse large B-cell lymphoma. Allelic imbalance and reporter gene assays indicated a putative influence on mRNA stability and/or translational efficacy. CONCLUSIONS We identified variants in CDH1 as the first potential genetic risk factors for the development of primary gastric diffuse large B-cell lymphomas. One of the potentially causative variants affects allelic CDH1 expression. These findings support the hypothesis that besides somatic alterations of B-cells, germline variants in the CDH1 gene contribute to a predisposition to the development of primary gastric diffuse large B-cell lymphomas.
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Affiliation(s)
- Gunnar Jacobs
- Institute of Clinical Molecular Biology, Christian-Albrechts University, Kiel, Germany
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Jakubowska A, Lawniczak M, Wojnarska B, Cybulski C, Huzarski T, Byrski T, Tołoczko-Grabarek A, Jaworska K, Durda K, Starzyńska T, Lubiński J. CDH1 gene mutations do not contribute in hereditary diffuse gastric cancer in Poland. Fam Cancer 2011; 9:605-8. [PMID: 20842455 PMCID: PMC2980631 DOI: 10.1007/s10689-010-9381-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome characterized by a high risk of diffuse stomach cancer and lobular breast cancer. HDGC is caused by germline mutations in the CDH1 gene encoding the E-cadherin which is a member of the transmembrane glycoprotein family responsible for calcium-dependent, cell-to-cell adhesion and plays a fundamental role in the maintenance of cell differentiation and the normal architecture of epithelial tissues. Mutations in the CDH1 gene are detected in 30-46% of families that fulfil strong clinical criteria for HDGC and in about 11% of families fulfilling the modified criteria. In the present study, we investigated germline mutations in the CDH1 gene in Polish patients with HDGC. The entire coding sequence of CDH1 gene was analyzed by sequencing in 86 Polish cancer patients from families fulfilling the modified criteria of HDGC. We found several silent mutations including one common variant (c.2076T>C) present in 56 patients, and three rare variants (c.2253C>T, c.1896C>T, c.2634C>T) detected in 2 patients. In addition, we found four rare sequence variants of unknown significance localized in introns. We did not detect any deleterious mutations of the CDH1 gene. CDH1 gene mutations are not present in Polish families with HDGC defined by the modified clinical criteria. Further studies of families with HDGC matching the restrictive criteria for HDGC are needed.
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Affiliation(s)
- Anna Jakubowska
- International Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Medical University, ul Połabska 4, 70-115 Szczecin, Poland.
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Zou D, Yoon HS, Anjomshoaa A, Perez D, Fukuzawa R, Guilford P, Humar B. Increased levels of active c-Src distinguish invasive from in situ lobular lesions. Breast Cancer Res 2009; 11:R45. [PMID: 19583841 PMCID: PMC2750104 DOI: 10.1186/bcr2332] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2009] [Revised: 06/15/2009] [Accepted: 07/07/2009] [Indexed: 01/16/2023] Open
Abstract
Introduction Mounting molecular evidence suggests that invasive lobular carcinoma (ILC) is developing from in situ lesions, atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). However, little is known about the mechanisms promoting the progression of lobular breast cancer (LBC) to invasive disease. Here, we investigated whether c-Src kinase, an established inducer of invasive states, contributes to the progression from ALH/LCIS to ILC. Methods Immunochemistry for c-Src and other cancer-related molecules was performed on archived tissue specimens from 57 LBC patients. Relative c-Src activity was estimated by comparing fluorescence intensity of ILC with that of adjacent ALH/LCIS and nonneoplastic epithelia after staining with an antibody against active c-Src. Expression of active c-Src was correlated with markers of invasion and malignancy and with relapse among LBC patients. Results Levels of activated c-Src were increased in ILC relative to ALH/LCIS (1.63-fold ± 0.24 SD) and nonneoplastic epithelia (1.47 ± 0.18 SD). Increased c-Src levels correlated with the activation of c-Src downstream targets (Fak, Stat-3) and the expression of mesenchymal markers. ILC cells with activated c-Src co-expressed metastatic markers (Opn, Cxcr4) and included cells positive for the cancer stem cell marker Aldh1. A tendency for high c-Src levels (P = 0.072) was observed among the seven LBC patients with relapsed disease. Conclusions Our data indicate elevated c-Src activity in ILC relative to noninvasive neoplastic tissue. The associated molecular changes suggest that c-Src promotes LBC invasiveness by inducing an epithelial-mesenchymal transition. Therefore, c-Src antagonists might counteract the acquisition of invasiveness during LBC progression. Inhibition of c-Src may also affect ILC cells thought to have a high metastatic potential and to be capable of initiating/maintaining tumor growth. Together with the possible association between high c-Src levels and disease recurrence, our findings encourage the evaluation of c-Src antagonists for the treatment of LBC.
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Affiliation(s)
- Donghui Zou
- Cancer Genetics Laboratory, Biochemistry Department, University of Otago, 710 Cumberland St, Dunedin 9054, Aotearoa New Zealand.
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Zou D, Yoon HS, Perez D, Weeks RJ, Guilford P, Humar B. Epigenetic silencing in non-neoplastic epithelia identifies E-cadherin (CDH1) as a target for chemoprevention of lobular neoplasia. J Pathol 2009; 218:265-72. [PMID: 19294736 DOI: 10.1002/path.2541] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Invasive lobular carcinoma (ILC) of the breast is believed to develop from in situ lesions, atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). Down-regulation of the cell-cell adhesion protein E-cadherin is a defining feature of lobular breast cancer (LBC) and already occurs in ALH and LCIS. Apart from mutational mechanisms, epigenetic silencing of the E-cadherin gene (CDH1) is thought to be involved in E-cadherin down-regulation and has been observed at a high frequency in ILC. Whether CDH1 promoter methylation is already present in in situ lesions and thus contributes to the initiation of LBC is not established. We thus examined microdissected archived tissue from 20 LBCs by methylation-specific PCR to determine the CDH1 methylation status of lobular lesions. Nineteen of the 20 LBCs had a hypermethylated CDH1 promoter, including 13/14 ILCs and 13/13 ALHs or LCIS. Bisulphite sequencing indicated that methylation was complete within the investigated promoter fragment. Intriguingly, CDH1 methylation was likewise present in 8/8 adjacent non-neoplastic epithelia, but not in 6/6 mammary epithelia from healthy subjects. E-cadherin protein and mRNA were down-regulated in in situ lesions relative to adjacent epithelia. Together, these results indicate that CDH1 promoter methylation occurs in LBC prior to E-cadherin down-regulation and neoplastic formation. We thus propose that epigenetic silencing represents the first of the two hits required to silence both CDH1 alleles for LBC to develop. Because promoter methylation is in principle reversible, our findings suggest that chemoprevention of LBC by epigenetic drugs should be feasible. Furthermore, the presence of CDH1 methylation in pre-neoplastic epithelia suggests the existence of mammary regions with increased disease susceptibility, providing an explanation for the often multifocal presentation of LBC.
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Affiliation(s)
- Donghui Zou
- Cancer Genetics Laboratory, Biochemistry Department, University of Otago, Aotearoa, New Zealand
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Lynch HT, Silva E, Wirtzfeld D, Hebbard P, Lynch J, Huntsman DG. Hereditary diffuse gastric cancer: prophylactic surgical oncology implications. Surg Clin North Am 2008; 88:759-78, vi-vii. [PMID: 18672140 DOI: 10.1016/j.suc.2008.04.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominantly inherited syndrome attributed to mutations of the E-cadherin gene, CDH1. There is no proven effective screening for early HDGC, and symptomatic disease is almost universally fatal. The only available effective option for CDH1 carriers is prophylactic total gastrectomy, but the variable age of onset of HDGC and the reduced penetrance (about 70%) of the CDHI gene further complicate patients' decision making.
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Affiliation(s)
- Henry T Lynch
- Department of Preventive Medicine and Public Health, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA
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Nasri S, More H, Graziano F, Ruzzo A, Wilson E, Dunbier A, McKinney C, Merriman T, Guilford P, Magnani M, Humar B. A novel diffuse gastric cancer susceptibility variant in E-cadherin (CDH1) intron 2: a case control study in an Italian population. BMC Cancer 2008; 8:138. [PMID: 18482459 PMCID: PMC2412889 DOI: 10.1186/1471-2407-8-138] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2007] [Accepted: 05/15/2008] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Inherited genetic factors such as E-cadherin (CDH1) promoter variants are believed to influence the risk towards sporadic diffuse gastric cancer (DGC). Recently, a new regulatory region essential for CDH1 transcription has been identified in CDH1 intron 2. METHODS We genotyped all known polymorphisms located within conserved sequences of CDH1 intron 2 (rs10673765, rs9932686, rs1125557, rs9282650, rs9931853) in an Italian population consisting of 134 DGC cases and 100 healthy controls (55 patient relatives and 45 unrelated, matched individuals). The influence of individual variants on DGC risk was assessed using chi2-tests and logistic regression. The relative contribution of alleles was estimated by haplotype analysis. RESULTS We observed a significant (p < 0.0004) association of the CDH1 163+37235G>A variant (rs1125557) with DGC risk. Odds ratios were 4.55 (95%CI = 2.09-9.93) and 1.38 (95%CI = 0.75-2.55) for AA and GA carriers, respectively. When adjusted for age, sex, smoking status, alcohol intake and H. pylori infection, the risk estimates remained largely significant for AA carriers. Haplotype analysis suggested the 163+37235A-allele contributes to disease risk independently of the other variants studied. CONCLUSION The CDH1 163+37235G>A polymorphism may represent a novel susceptibility variant for sporadic DGC if confirmed in other populations. Considering the broad expression of E-cadherin in epithelia, this exploratory study encourages further evaluation of the 163+37235A-allele as a susceptibility variant in other carcinomas.
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Affiliation(s)
- Soroush Nasri
- Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin 9054, Aotearoa New Zealand.
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