Hereditary Gastric Cancer Research Articles

The evidence on gene mutations in hereditary diffuse gastric cancer is accumulating

The evidence on gene mutations in hereditary diffuse gastric cancer is accumulating

Preemptive Total Gastrectomy for Hereditary Gastric Cancer

Hereditary gastric cancer is a recently described clinical syndrome, associated with truncating mutation of the E-cadherin gene, named CDH1. It is characterized by autosomal dominant transmission, presentation at an early age, and with diffuse type of gastric adenocarcinoma. Clinical management of these patients is challenging and includes intense endoscopic surveillance or prophylactic gastrectomy, which is associated with short- and long-term morbidity. We report four patients submitted to a prophylactic gastrectomy performed in members of three families with hereditary gastric cancer in a tertiary referral center in Mexico City. These are the first Hispanic families with hereditary gastric cancer reported in the literature.

Early Onset Gastric Cancer: On the Road to Unraveling Gastric Carcinogenesis

Gastric cancer is thought to result from a combination of environmental factors and the accumulation of specific genetic alterations due to increasing genetic instability, and consequently affects mainly older patients. Less than 10% of patients present with the disease before 45 years of age (early onset gastric carcinoma) and these patients are believed to develop gastric carcinomas with a molecular genetic profile differing from that of sporadic carcinomas occurring at a later age. In young patients, the role of genetics is presumably greater than in older patients, with less of an impact from environmental carcinogens. As a result, hereditary gastric cancers and early onset gastric cancers can provide vital information about molecular genetic pathways in sporadic cancers and may aid in the unraveling of gastric carcinogenesis. This review focuses on the molecular genetics of gastric cancer and also focuses on early onset gastric cancers as well as familial gastric cancers such as hereditary diffuse gastric cancer. An overview of the various pathways of importance in gastric cancer, as discovered through in-vitro, primary cancer and mouse model studies, is presented and the clinical importance of CDH1 mutations is discussed.

Type Iγ phosphatidylinositol phosphate kinase modulates adherens junction and E-cadherin trafficking via a direct interaction with μ1B adaptin

Assembly of E-cadherin–based adherens junctions (AJ) is obligatory for establishment of polarized epithelia and plays a key role in repressing the invasiveness of many carcinomas. Here we show that type Iγ phosphatidylinositol phosphate kinase (PIPKIγ) directly binds to E-cadherin and modulates E-cadherin trafficking. PIPKIγ also interacts with the μ subunits of clathrin adaptor protein (AP) complexes and acts as a signalling scaffold that links AP complexes to E-cadherin. Depletion of PIPKIγ or disruption of PIPKIγ binding to either E-cadherin or AP complexes results in defects in E-cadherin transport and blocks AJ assembly. An E-cadherin germline mutation that loses PIPKIγ binding and shows disrupted basolateral membrane targeting no longer forms AJs and leads to hereditary gastric cancers. These combined results reveal a novel mechanism where PIPKIγ serves as both a scaffold, which links E-cadherin to AP complexes and the trafficking machinery, and a regulator of trafficking events via the spatial generation of phosphatidylinositol-4,5-bisphosphate.

Napoleon Bonaparte's gastric cancer: a clinicopathologic approach to staging, pathogenesis, and etiology

Numerous hypotheses on the cause of Napoleon Bonaparte's death have been proposed, including hereditary gastric cancer, arsenic poisoning, and inappropriate medical treatment. We aimed to determine the etiology and pathogenesis of Napoleon's illness by a comparison of historical information with current clinicopathologic knowledge. Evaluation of Napoleon's clinical history, original autopsy reports, and of historical documents. The clinicopathologic data from 135 gastric cancer patients were used for comparison with the data available on Napoleon. At least T3N1M0 (stage IIIA) gastric cancer. Napoleon's tumor extended from the cardia to the pylorus (>10 cm) without infiltration of adjacent structures, which provides strong evidence for at least stage T3. The N1 stage was determined by the presence of several enlarged and hardened regional (perigastric) lymph nodes, and the M0 stage by the absence of distant metastasis. Analysis of the available historical documents indicates that Napoleon's main risk factor might have been Helicobacter pylori infection rather than a familial predisposition. Our analysis suggests that Napoleon's illness was a sporadic gastric carcinoma of advanced stage. Patients with such tumors have a notoriously poor prognosis.

Germline mutations and polymorphic variants in MMR, E‐cadherin and MYH genes associated with familial gastric cancer in Jiangsu of China

Germline mutations in MSH2, MLH1, E-cadherin and MutY (MYH) genes have been implicated in the occurrence of gastric cancer (GC). Epidemiological investigation was performed by recruiting patients with GC onset during 2002 in Jiangsu province, China. We identified suspected hereditary GC patients based on either the GC family history or GC onset at early ages. We have screened germline variations in 101 suspected hereditary GC patients at the coding sequences of MSH2, MLH1, E-cadherin and MYH genes with polymerase chain reaction-denaturing high-performance liquid chromatography (PCR-DHPLC) analysis and DNA sequencing. The result showed that about 40% of patients carried germline variations, predominantly with missense mutations. Of the variations detected are 2 base pair substitutions, c.53C > T and c.74G > A, which is predicted to generate missense mutations of p.Pro18Leu and p.Gly25Asp, respectively, and occurred at the same allele of MYH gene. The frequency of variant haplotype T/A in patients was higher than that in the control group (p = 0.021, odds ratio [OR] = 4.43, 95% confidence interval [95% CI] = 1.33-14.72). Difference in the frequency of the silent mutation p.Asn751Asn in E-cadherin gene was also found between patients and controls (p = 0.009, OR = 2.54, 95% CI = 1.30-4.95). Moreover, 6 types of variations were detected in MSH2 and MLH1 genes in 14 of 101 patients. Most of them occurred at exon7 of MSH2, frequently c.1168C > T, resulting in mutation of p.Leu390Phe. In summary, germline mutation at MSH2, MLH1, E-cadherin and MYH genes is a frequent event in the familial GC. They may form a genetic basis for the familial GC susceptibility in Chinese population.

Single nucleotide polymorphisms (SNPs) at CDH1 promoter region in familial gastric cancer

Gastric cancer is the most frequent gastrointestinal malignancy in Mexico and the proportion of patients younger than 40 years is one of the highest reported in the world literature. Recently several families with familial diffuse gastric cancer have been identified at the National Institute of Medical Sciences and Nutrition. Germline mutations in the E-cadherin gene (CHD1) have been described that result in the development of diffuse hereditary gastric cancer in young patients. The complete coding sequence at exons 1 to 16 and the promoter region of CDH1 was amplified by polymerase chain reaction in peripheral blood samples of two patients with early onset familial diffuse gastric cancer. No germline inactivating mutations of CHD1 were found on either patient. Single nucleotide polymorphisms -160 C->A were detected in the promoter region of CDH1 in both patients. The polymorphism -160 C->A theoretically confers an increased risk of developing diffuse gastric cancer. The relatives of these patients may an increased risk of gastric cancer among other tumors. There is presently not enough evidence to consider the -160 C->A polymorphism an etiologic factor of diffuse gastric cancer in these patients since the frequency and type of genetic alterations of CDH1 are largely unknown in the Mexican population. It will be necessary to conduct epidemiologic studies in the Mexican population to determine the influence that genetic alterations have on the genesis of diffuse gastric carcinoma.

The germline mutaion pattern of CDH1 gene in 12 Chinese hereditary diffuse gastric cancer kindred

9548 Background: E-cadherin is responsible for the cell-cell adhesion. Germline mutations in E-cadherin gene (CDH1) was firstly recognized in Maori kindred with hereditary gastric cancer(HGC) in Ne...

Germline E-cadherin gene mutation screening in familial gastric cancer kindreds

To evaluate the frequency and nature of E-cadherin gene (CDH1) germline mutations in familial gastric cancer kindreds of china. Five familial gastric cancer kindreds of Chinese origin were screened for germline CDH1 mutations, all of them meeting the clinical criteria for hereditary diffuse gastric cancer (HDGC), by PCR-DHPLC and direct sequencing. A new truncating mutation in exon 10 in B family was identified, producing a stop codon at position 503 (Q503X), resulting in a truncated protein. The proband of this family had metachronous development of lobular breast and diffuse type gastric carcinoma. No protein expression was detected in the lobular breast carcinoma, indicating complete inactivation of the gene. A Chinese gastric cancer family with CDH1 germline truncating mutation is described for the first time, and our findings suggest that lobular breast carcinoma might be part of the tumor spectrum of HDGC.

Geno- and pheno-typic characterization in ten patients with double-primary gastric and colorectal adenocarcinomas.

Although a number of double-primary gastric and colorectal cancers have been known to correlate with the mutator pathway, a possible association with known hereditary cancers regarding geno-pathogenesis has rarely been investigated. This study was intended to identify a possible association of hereditary cancers and the implications of the mutator or tumor-suppressor pathway in double-primary gastric and colorectal cancers. Fresh colorectal tissues and lymphocytes from ten patients with double-primary gastric and colorectal cancers were obtained consecutively. The mutator pathway was evaluated by detecting hMSH2 and hMLH1 mutations, microsatellite instability (MSI) using 12 microsatellite markers, and hMLH1 promoter region methylation. Protein expressions of hMSH2, hMLH1, APC, E-cadherin, and beta-catenin were identified by immune staining. There was no pathogenic mutation in any introns or exons of hMSH2, hMLH1 or CDH1, and in exons 3, 5, 6, and 15 of CTNNB1. Either MSI or methylator phenotype was found in five gastric cancers and in four colorectal cancers. No patients met the Amsterdam criteria of hereditary nonpolyposis colorectal cancer (HNPCC) or its equivalent of hereditary gastric cancer. Two patients with gastric cancers among their first-degree relatives showed no E-cadherin expression. The two of the three patients with rectal cancers among their first-degree relatives showed mutator phenotype either in the gastric or in the colorectal cancer. A subset of double-primary gastric and colorectal cancers may thereby be categorized as variant forms of hereditary gastric or colorectal cancer. Both cytoplasmic and nuclear beta-catenins were expressed in all gastric and colorectal cancers. Among the gastric and colorectal cancers with either MSI or methylator phenotype, four of five gastric cancers showed both APC and E-cadherin expression, whereas one of four colorectal cancers showed them. This may suggest that the mutator pathway and the aberrant tumor suppressor pathway of the APC-E-cadherin may be cooperative or separately activated in the geno-pathogenesis of double-primary gastric and colorectal cancers.

Clinicopathologic characteristics of gastric cancer in a young patient population.

The aim of this study was to analyze the clinicopathologic characteristics of young patients with gastric cancer with special attention to hereditary gastric cancer in a tertiary referral university hospital. Charts from all patients 40 years of age or younger at the time of diagnosis, during the period from January 1, 1987 to December 31, 2001, were retrospectively reviewed. Demographic variables, family history of gastric cancer, clinicopathologic characteristics, and treatment-related variables were analyzed. Overall survival was the main outcome variable. Survival curves were constructed by means of the Kaplan-Meier method, univariate analysis was performed with the log-rank test, and multivariate analysis with Cox regression. Significance was considered at P<0.05. During the study period, 558 cases of gastric cancer were seen at our institution, 83 (14.8%) were in patients 40 years of age or younger. Mean patient age was 33.2 years. Forty-five patients (54.2%) were male. Fourteen patients (16.9%) had a family history of gastric cancer. Five patients (6%) fulfilled the criteria of hereditary gastric cancer. Surgery was performed in 88% of patients, but only 35% of the operations had a curative intent. Operative mortality was 2.4%. On univariate analysis, advanced tumor stage, hypoalbuminemia, low performance status, diffuse type, pangastric tumor location, noncurative surgery, and lack of adjuvant chemotherapy had a significant negative impact on survival. On multivariate analysis, advanced tumor stage, pangastric tumor location, and absence of adjuvant chemotherapy were significantly associated with poor prognosis. Family history of gastric cancer or hereditary gastric cancer did not have any impact on prognosis. There is a high frequency of gastric cancer in young patients at our institution. Most patients present in advanced stages, which favors a poor overall survival. Family history of gastric cancer or hereditary gastric cancer did not have a significant impact on survival. Complete resection and adjuvant chemotherapy appeared to confer the only chance of prolonged survival.

Nuclear Pedigree Criteria for the Identification of Individuals Suspected to Be at Risk of an Inherited Predisposition to Gastric Cancer

Gastric cancer is the second most frequently diagnosed malignancy worldwide and therefore represents a significant healthcare burden. Environmental and genetic factors are involved in the development of gastric cancer. To date only one clear genetic predisposition has been identified involving mutations in the E-cadherin gene. The disease phenotype in patients harbouring E-cadherin mutations appears to be specifically related to diffuse gastric cancer. Little is known genetically about the other forms of gastric cancer. Since there is a growing awareness about the necessity of early intervention criteria have been developed that aid the identification of hereditary forms of gastric cancer. The aim of the current study was to identify minimal inclusion criteria so that nuclear pedigree families can be provided with risk assessment and/or genetic testing.The results reveal that inclusion features described herein such as (a) gastric cancer diagnosed before 46 years of age; (b) two gastric cancers among first degree relatives diagnosed over the age of 50 are useful in identifying suspected hereditary gastric cancer patients.

Genetic Screening for Familial Gastric Cancer

Approximately 10% of gastric cancer cases show familial clustering but only 1-3% of gastric carcinomas arise as a result of inherited gastric cancer predisposition syndromes. Direct proof that Hereditary Gastric Cancer a genetic disease with a germline gene defect has come from the demonstration of co-segregation of germline E-cadherin (CDH1) mutations with early onset diffuse gastric cancer in families with an autosomal dominant pattern of inheritance (HDGC). E-cadherin is a transmembrane calcium-dependent cell-adhesion molecule involved in cell-junction formation and the maintenance of epithelial integrity. In this review, we describe frequency and type of CDH1 mutations in sporadic and familial gastric cancer. Further we demonstrate the functional significance of some CDH1 germline missense mutations found in HDGC. We also discuss the CDH1 polymorphisms that have been associated to gastric cancer. We report other types of malignancies associated to HDGC, besides diffuse gastric cancer. Moreover, we review the data available on putative alternative candidate genes screened in familial gastric cancer. Finally, we briefly discuss the role of low-penetrance genes and Helicobacter pylori in gastric cancer. This knowledge is a fundamental step towards accurate genetic counselling, in which a highly specialised pre-symptomatic therapeutic intervention should be offered.

Genetic alterations and polymorphisms in gastric cancer.

The etiology of gastric cancer (GC) is multifactorial, and is likely to involve the actions of genes at multiple levels along the multistage carcinogenesis process. This article reviews the considerable progress that has been achieved in understanding the genetics of GC. The genetic effects consist of inherited genetic factors that predispose to GC, and the genetic targets of neoplastic progression that confer altered growth capacity to neoplastic cells. Inherited genotypes include germline mutations of high-penetrance genes directly associated with hereditary GC syndromes and genetic polymorphisms that indirectly affect the susceptibility to GC after exposure to carcinogens or Helicobacter pylori infection. Based on accumulation of different oncogenes or tumor suppressor genes alterations, 2 broad classes of genetic pathways called suppressor and mutator phenotypes are defined that participate in the development and progression of GC. Examples of genes involved in pathogenesis of GC include p53, adenomatous polyposis coli (APC), beta-catenin, E-cadherin, transforming growth factor (TGF)-betaRII, and hMLH1. Delineating genes involved in different subtypes of GC can reflect the heterogeneity and biologic characteristics of GC. Elucidation of the role of inherited genotypes and genetic alterations at different stages of gastrocarcinogenesis may provide a more coherent picture of the mechanism of this devastating disease and facilitate the development of novel approaches to effective prevention and intervention. Advances in high throughput technologies and functional genomics have rapidly increased our understanding of gene structure and function and its role in disease.

Hereditary gastric cancer: Clinicopathologic characteristics in a young hispanic patient population

Hereditary gastric cancer: Clinicopathologic characteristics in a young hispanic patient population

Genetic epidemiologic aspects of gastric cancer in Iceland.

Association between gastric cancer and environmental factors (diet and infections) has been established, and genetic changes are well described in adenocarcinomas of the stomach. Less is known about clinical features of hereditary gastric cancer and whether the disease is associated with family clustering. Family trees of patients diagnosed with gastric cancer in Iceland between 1955 and 1999 were identified in the Genealogical Database of the University of Iceland. All probands with age of onset younger than 60 years were used in the study. Families of all probands (n = 455 men and 161 women) were traced to third degree. Through linkage of the genealogic data obtained by the Icelandic Cancer Registry (between 1955 and 1999), all reported cancers were identified in those families. The expected number of cases was calculated using age-specific population rates in Iceland. A relative risk (RR) of 2.2 (95% confidence interval [CI] = 1.6-3.0) and 1.3 (95% CI = 1.0-1.7) for the gastric cancer risk was observed among 2,846 first- and 8,658 second-degree relatives of male probands. For female probands the corresponding relative risks were 1.6 (95% CI = 1.1-2.6, n = 7,396) and 1.4 (95% CI = 0.9-2.0, n = 2,764). The increased risk was more pronounced for relatives of men and women diagnosed with gastric cancer before the age of 50 years. A minor difference in relative risk was found between relatives of probands who were diagnosed with intestinal type or diffuse type gastric cancer. Fifty-eight families with two or more relatives with cancer were identified. In 32 families 2 relatives with gastric cancer were identified and in 26 families 3 or more relatives had gastric cancer. Relatives of gastric cancer patients have two- to three-fold increased risk of developing gastric cancer. The risk is elevated for both genders.

E-Cadherin Gene (CDH1) Mutations for Detection of Familial Occult Gastric Cancer

This article has no abstract.

Hereditary Gastric Cancer

Hereditary Gastric Cancer

Report on the first meeting of the International Collaborative Group on Hereditary Gastric Cancer.

Report on the first meeting of the International Collaborative Group on Hereditary Gastric Cancer.

Image quantitation of intestinal metaplasia in entire gastrectomy specimens from Swedish and Japanese patients.

The aim of this work was to investigate the extension of intestinal metaplasia (IM), as well as to quantitate various components of IM (namely sialomucins, sulfomucins and Paneth cells), in entire gastrectomy specimens from Swedish and Japanese patients. The length of the gastric mucosa was assessed by morphometry. The percent of sections with IM was regarded as the extension of IM in the specimens. Histochemically labeled sialomucins, sulfomucins and Paneth cells (the 3 main findings in gastric IM) were quantified in separate sections with the aid of an image analyzer. In total, 1,321 sections corresponding to 6 gastrectomy specimens were quantified. Sialomucins and sulfomucins were more extensively distributed in the 4 specimens with carcinoma than in the 2 without carcinoma (one having a peptic ulcer and the other, hereditary gastric cancer syndrome (HGCS) without carcinoma). On the other hand, quantitative analysis in Swedish specimens indicated that the highest values for sialomucins, sulfomucins and Paneth cells were present in HGCS. When Swedish and Japanese specimens with adenocarcinoma were compared, only sulfomucins (denoting Types II and III IM) were significantly higher in those carrying an intestinal‐type carcinoma (ITC) than in those with diffuse‐type carcinoma (DTC). The results substantiate those obtained with gastric biopsies by other authors. On the other hand, the mucosal extension and the amount of sulfomucins are not comparable parameters (since that mucin was not equally distributed, but “concentrated” in certain areas in the mucosa). One possible conclusion is that the focal distribution of acidic mucins and of Paneth cells in the gastric mucosa may strongly influence their detection rate in gastric biopsies. Thus, haphazard biopsy of the gastric mucosa may fail to sample areas with sulfomucins in population studies aiming to detect individuals at risk. Such sampling errors in gastric biopsies may explain the conflicting results on this subject appearing in the literature.