Gastric Cancer: New Genetic Developments

Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
Journal of Surgical Oncology (Impact Factor: 3.24). 06/2005; 90(3):114 - 133. DOI: 10.1002/jso.20214


Gastric cancer's (GC) incidence shows large geographic differences worldwide with the lowest rates occurring in most Western industrialized countries including the United States and the United Kingdom; in contrast, relatively high rates of GC occur in Japan, Korea, China, and South America, particularly Chile. The Laurén classification system classifies GC under two major histopathological variants: 1) an intestinal type and 2) a diffuse type. The intestinal type is more common in the general population, more likely to be sporadic and related to environmental factors such as diet, particularly salted fish and meat as well as smoked foods, cigarette smoking, and alcohol use. It exhibits components of glandular, solid, or intestinal architecture, as well as tubular structures. On the other hand, the diffuse type is more likely to have a primary genetic etiology, a subset of which, known as hereditary diffuse gastric cancer (HDGC), is due to the E-cadherin (CDH1) germline mutation. The diffuse type pathology is characterized by poorly cohesive clusters of cells which infiltrate the gastric wall, leading to its widespread thickening and rigidity of the gastric wall, known as linitis plastica. Helicobacter pylori infection is associated with risk for both the intestinal and diffuse varieties of gastric cancer. Germline truncating mutations of the CDH1 gene, which codes for the E-cadherin protein, were initially identified in three Maori families from New Zealand that were predisposed to diffuse GC. Since then, similar mutations have been described in more than 40 additional HDGC families of diverse ethnic backgrounds. It is noteworthy that two-thirds of HDGC families reported to date have proved negative for the CDH1 germline mutation. A number of candidate genes have been identified through analysis of the molecular biology of E-cadherin. Patients with evidence of the CDH1 germline mutation in the context of a family history of HDGC must be considered as candidates for prophylactic gastrectomy, given the extreme difficulty in its early diagnosis and its exceedingly poor prognosis when there is regional or distant spread. Specifically, the E-cadherin cytoplasmic tail interacts with catenins, assembling the cell-adhesion complex involved with E-cadherin mediated cell:cell adhesion. β-catenin and γ-catenin compete for the same binding site on the E-cadherin cytoplasmic tail, directly linking the adhesion complex to the cytoskeleton through α-catenin. β-catenin gene (CTNNB1) mutations have been described predominantly in intestinal-type gastric cancers and CTNNB1 gene amplification and overexpression have recently been described in a mixed-type gastric cancer. This paper reviews the genetics of both intestinal and diffuse types of gastric carcinoma, their differential diagnosis, molecular genetics, pathology, and, when known, their mode of genetic transmission within families. J. Surg. Oncol. 2005;90:114–133. © 2005 Wiley-Liss, Inc.

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    • "Anecdotal occurrences of primary malignancies of the colon, lung, prostate, salivary gland and pancreas have been described in CDH-1 associated HDGC families, with rare examples of the signet ring cell variety; none of which occur at a frequency greater than the general population [18]. Colorectal carcinoma has been deemed by some to be an occasional member of the HDGC disease spectrum, with the recommendation that surveillance colonoscopy should commence in this population at age 40, or 10 years younger than the youngest diagnosis of colon carcinoma [1,2,19,20]. In the general population, colorectal carcinoma is thought to be familial in 20% of cases. "
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    ABSTRACT: Hereditary diffuse gastric carcinoma is an autosomal dominant cancer syndrome associated with mutations of the E-cadherin gene (CDH1). E-cadherin is normally involved in cell-cell adhesion, so it not surprising that individuals with this syndrome are predisposed to develop malignancies with dyshesive morphologies at a young age, such as diffuse (signet ring cell) gastric carcinoma and lobular breast carcinoma. Herein we describe the first reported case of primary appendiceal signet ring cell carcinoma arising in a CDH1-associated hereditary diffuse gastric carcinoma kindred with synchronous primary diffuse gastric carcinoma. A 51- year old woman, with known CDH1 mutation carrier status and a prior history of lobular breast carcinoma underwent prophylactic total gastrectomy which revealed multifocal intramucosal signet ring cell carcinoma. An appendectomy was performed at the same time due to a prior episode of presumed appendicitis, with pathologic examination significant for a primary signet ring cell carcinoma of the appendix. As appendiceal signet ring cell carcinoma is exceedingly rare, the occurrence of this neoplasm in this patient, with this particular morphology, provides credence for it being part of the hereditary diffuse gastric carcinoma spectrum of malignancies.
    BMC Gastroenterology 07/2013; 13(1):114. DOI:10.1186/1471-230X-13-114 · 2.37 Impact Factor
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    • "The sequence of events are including: chronic superficial gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, adenoma and adenocarcinoma (gastric cancer) (13). The Lauren's classification is one of the most useful ones, distinguishing two main types of gastric carcinomas, well differentiated (intestinal type) and diffuse types, which show different clinico-pathological profiles and often occur in distinct epidemiological settings (6, 14). Intestinal type is more common and is related to environmental and dietary factors but diffuse type has genetic background and is more aggressive. "
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    ABSTRACT: Objective(s): Gastric cancer is the first and second leading cause of cancer related death in Iranian men and women, respectively. Gastric cancer management is based on the surgery, radiotherapy and chemotherapy. In the present study, for the first time, the beneficial effect of saffron (Crocus sativus L.) aqueous extract (SAE) on the 1-Methyl-3-nitro-1-nitrosoguanidine (MNNG)-induced gastric cancer in rat was investigated. Materials and Methods: MNNG was used to induce gastric cancer and then, different concentrations of SAE were administered to rats. After sacrificing, the stomach tissue was investigated by both pathologist and flow cytometry, and several biochemical parameters was determined in the plasma (or serum) and stomach of rats. Results: Pathologic data indicated the induction of cancer at different stages from hyperplasia to adenoma in rats; and the inhibition of cancer progression in the gastric tissue by SAE administration; so that, 20% of cancerous rats treated with higher doses of SAE was completely normal at the end of experiment and there was no rat with adenoma in the SAE treated groups. In addition, the results of the flow cytometry/ propidium iodide staining showed that the apoptosis/proliferation ratio was increased due to the SAE treatment of cancerous rats. Moreover, the significantly increased serum LDH and decreased plasma antioxidant activity due to cancer induction fell backwards after treatment of rats with SAE. But changes in the other parameters (Ca2+, tyrosine kinase activity and carcino-embryonic antigen) were not significant. Conclusion: SAE inhibits the progression of gastric cancer in rats, in a dose dependent manner.
    Iranian Journal of Basic Medical Science 01/2013; 16(1):27-38. · 1.23 Impact Factor
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    • "Most of these families might carry mutations in other, still to be identified, GC susceptibility genes. As binding partner for E-cadherin, mutated β- and γ-catenin have been considered as candidates for diffuse GC predisposition [37]. The β-catenin gene (CTNNB1) was recently assessed in a series of 40 families with positive history of GC from the Netherlands without finding any mutations [Vogelaar et al., unpublished data, 2012]. "
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    ABSTRACT: Worldwide, gastric cancer is one of the most common forms of cancer, with a high morbidity and mortality. Several environmental factors predispose to the development of gastric cancer, such as Helicobacter pylori infection, diet and smoking. Familial clustering of gastric cancer is seen in 10% of cases, and approximately 3% of gastric cancer cases arise in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at relatively young age. Germline mutations in the CDH1 gene are the major cause of HDGC and are identified in approximately 25-50% of families which fulfill strict criteria. Prophylactic gastrectomy is the only option to prevent gastric cancer in individuals with a CDH1 mutation. However, in the majority of families with multiple cases of gastric cancer no germline genetic abnormality can be identified and therefore preventive measures are not available, except for general lifestyle advice. Future research should focus on identifying new genetic predisposing factors for all types of familial gastric cancer.
    Hereditary Cancer in Clinical Practice 12/2012; 10(1):18. DOI:10.1186/1897-4287-10-18 · 1.47 Impact Factor
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