Sporadic Gastric Carcinomas Research Articles

Histologic and immunohistochemical differences between hereditary and sporadic diffuse gastric carcinoma

We aimed to identify histopathologic features unique in hereditary diffuse gastric cancer (HDGC) by comparing with its sporadic counterpart (SDGC). 11 patients with confirmed CDH1 mutation who were found to have HDGC in a prophylactic total gastrectomy were collected. Median age of HDGC patients was 39 years (range 24-57). All HDGC cases had intramucosal signet ring cell carcinoma. Twenty-three invasive tumor foci from 7 patients with HDGC were available for ancillary studies, and we evaluated each focus separately. Almost all foci (20/23) showed two distinct tumor cell populations, namely, large signet ring cells and small signet ring cells. The large cells were located just beneath the surface epithelium and were positive for mucicarmine and pCEA, while the small cells were found in the deeper lamina propria and were mostly negative for mucicarmine and pCEA. A subset of small cells (6 foci from two resected stomachs) showed poorly differentiated morphology with p16 positivity. All other tumor cells with well-differentiated signet ring cell morphology were negative for p16. In contrast, 18 of 20 SDGCs were positive for p16. In addition, all HDGCs were negative for CDX2, while 19 of 20 SDGCs were positive. We propose that there are three distinct tumor cell populations in HDGC: well-differentiated large cells, well-differentiated small cells, and poorly differentiated small cells, and that the latter group with aberrant p16 expression may represents a more aggressive phenotype. The absence of CDX2 in HDGC suggests that it may develop along a carcinogenetic pathway different from that of SDGC.

Clinical and biological significance of a -73A>C variation in the CDH1 promoter of patients with sporadic gastric carcinoma.

CDH1 germline mutations lead to hereditary diffuse gastric carcinomas. However, it is unclear whether genetic variations in the CDH1 promoter affect the progression of sporadic gastric carcinomas (SGCs). SGC patients in two independent cohorts with follow-up data were enrolled. The CDH1 genotypes, including the -73A>C polymorphism (rs28372783), were determined by PCR sequencing. The CDH1 promoter activity was determined using reporter assays. SNAIL bound to CDH1 alleles was determined by chromatin immunoprecipitation primer extension PCR. CDH1 DNA methylation was determined by bisulfite-based PCR analyses. Kaplan-Meier analyses showed that the overall survival (OS) of the -73C/C patients was significantly longer than that of the -73A/C or -73A/A patients in a Chinese cohort [n=526; hazard ratio 0.68 (95% CI 0.47-1.00)], which was validated in an independent Korea cohort [n=215; hazard ratio 0.49 (95% CI 0.26-0.94)]. Moreover, the transcription activity of the -73C alleles was significantly higher than that of the -73A alleles in vitro and in vivo. The ratio of SNAIL recruited to the promoter regions of the -73C and -73A alleles was 1:10, indicating a strong influence of this polymorphism on the recruitment of SNAIL to the flanking E-box. The prevalence of DNA methylation of the CpG island and shore within the promoter of the -73C allele was much less than that of the -73A allele in both gastric tissues and cancer cell lines. The -73A>C variation may lead to differences in the overall survival of SGC patients and allele-specific repressions of CDH1.

Abstract 119: Genomic analysis of remnant gastric adenocarcinoma

Abstract Introduction: Prior to pharmaceutical treatment of gastroduodenal ulcer disease, partial gastrectomy was performed for the management of ulcer disease complicated by bleeding (PUD). The proposed mechanism for the development of gastric cancer in this setting is the chronic irritation of the mucosa by duodenal reflux into the gastric remnant. The aim of this study is to characterize the genetic profile of remnant gastric carcinoma (RGC). Material and Methods: Thirty cases of RGC developed in the setting of prior partial gastrectomy for PUD and without neoadjuvant chemotherapy were retrospectively collected from the institution database. Histopathological evaluation was performed to ensure >80% tumor cellularity with matching normal gastric mucosa prior to DNA extraction. Ultra-deep targeted sequencing of the thirty matched pairs was performed using the MSK-IMPACT assay (Integrated Mutation Profiling of Actionable Cancer Targets) to identify mutations and copy number alterations in a common set of 410 cancer-associated genes. MSK-IMPACT data from previously sequenced 45 sporadic gastric carcinomas (GC) was used as comparison. Results: The cohort consisted of 22 (73%) males and 8 (27%) females with the mean age of 73 years. The median interval between PUD and RGC resections was 34.8 years (7-60 years). By Lauren's classification, 60% of the tumors were intestinal, 23% diffuse and 17% mixed. Most of the tumors (47%) were poorly differentiated and stage II (40%). MSK-IMPACT sequencing revealed 299 total somatic alterations occurring in 148 of 410 targeted genes with a median number of non-synonymous somatic mutations and copy number events of 3 and 1 per patient, respectively. Of the 207 total mutations, 27.5% were hotspot COSMIC and 23.2% were loss-of-function mutations. Recurrent genomic events included mutually exclusive mutations in TP53 (33%) and amplifications in MDM2 (26%), alterations in the ERBB family genes (37%), ARID1A (16%), KMT2D (13%), CDH1 (13%), and CDK4 (13%). In addition, actionable alterations in PIK3CA (10%), FGFR1 (4%), PTEN (4%), and concurrent hotspot KRAS mutations and inactivation of p15/p16 (10%) were observed. Compared to the sporadic GC cases, RGC cases presented differences in the landscape and recurrence of alterations. Conclusion: The pathogenesis of RGC is likely associated with the prolonged exposure of the gastric mucosa to gastroduodenal contents. The mean age of patients may also exert effects on the development of the RGC. Based on our sequencing results, RGC may present a genetic profile distinct from that of sporadic gastric tumors. Assessment of these alterations identified 30% of patients with potential therapeutic targets for the treatment of this disease and deserves further investigation. Citation Format: Edaise M. da Silva, Helen H. Won, Dianne Torrence, Daniel Coit, Michael F. Berger, Laura Tang. Genomic analysis of remnant gastric adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 119.

Gastric Carcinomas in Young (Younger than 40 Years) Chinese Patients

Little is known about clinicopathological characteristics of gastric carcinoma (GC) in young (≤40 years) Chinese patients. We aimed in this study to analyze those features along with family history and prognostic factors after resection. We retrospectively reviewed all 4671 GC resections (surgical and endoscopic) performed at our center from 2004 to 2014 and identified 152 (3.2%) consecutive young patients. Patient demographics, clinical results, family history, and endoscopic-pathological findings were analyzed along with the older (>41 years) GC controls recruited in the same study period. Clinicopathological factors related to postresection outcomes were assessed statistically. The trend of GC resections in young patients was not changed over the study period. Compared to old GCs, the young GC cohort was predominant in women, positive family history, middle gastric location, the diffuse histology type, shorter duration of symptoms, and advanced stage (pIII+pIV, 53.3%). Radical resection was carried out in 90.1% (n = 137) with a better 5-year survival rate (70.3%) than palliative surgery (0%, n = 15). There was no significant difference in clinicopathological characteristics between familial GC (FGC, n = 38) and sporadic GC (SGC, n = 114) groups. Very young patients (≤ 30 years, n = 38) showed lower Helicobacter pylori (Hp) infection and significantly higher perineural invasion rates, compared to older (31-40 years) patients. Hp infection was more commonly seen in the Lauren's intestinal type and early pT stages (T1+T2). Independent prognostic factors for worse outcomes included higher serum CA 72-4, CA 125 levels, positive resection margin, and stage pIII-pIV tumors. The 5-year survival rate was significantly higher in patients with radical resection than those without. GCs in young Chinese patients were prevalent in women with advanced stages but showed no significant differences in clinicopathology between FGC and SGC groups. High serum CA 72-4 and CA 125 levels may help identify patients with worse outcomes. Radical resection improved postresection survival.

New Insights in Histogenetic Pathways of Gastric Cancer.

The aim of this paper was to describe 3 possible histogenetic pathways for poorly cohesive (diffuse) carcinomas and 2 for intestinal-type gastric carcinomas (GCs), which might influence the behavior of GC. In the present observational study, 102 patients with early (n = 50) and advanced GCs (n = 52) were evaluated, and the histogenetic background was analyzed. All of the cases were sporadic GCs. For particular aspects, Maspin, E-cadherin, and SLUG immunostains were performed. For our final conclusions, the results were correlated with literature data. In early stages, poorly cohesive carcinomas can display 3 histogenetic pathways, with particular molecular behaviors: “carcinoma with intraepithelial pagetoid onset” (with or without a switch from E-cadherin to SLUG positivity), “carcinoma with early lymphatic invasion” (carcinoma limited to mucosa but with carcinomatosis of the lymph vessels from subjacent layers), and “microglandular-type poorly cohesive carcinoma” (the onset is similar with adenocarcinoma but abrupt dedifferentiation can be seen in the submucosa, with persistence of a dual component in the deep layers). The intestinal type carcinoma can be developed on the background of superficially located dysplasia (“classic adenocarcinoma”) or in the submucosal heterotopic mucosa (“adenocarcinoma arising from the mucosal infolding in the submucosa”). Based on personal observations correlated with literature data, 5 histopathogenetic pathways are proposed with specific denominations. Each of them can partially explain the aberrant behavior of early gastric cancer.

Genetic variation and gastric cancer risk: a field synopsis and meta-analysis

BackgroundData on genetic susceptibility to sporadic gastric carcinoma have been published at a growing pace, but to date no comprehensive overview and quantitative summary has been available.MethodsWe conducted a systematic...

The normal neuroendocrine cells of the upper gastrointestinal tract lack E-cadherin

Objective. E-cadherin plays a crucial role in the adhesion between epithelial cells and thus epithelial integrity. Moreover, germline mutations in the E-cadherin gene (CDH1) causing loss of E-cadherin function (adhesion) leads to hereditary gastric cancer of the diffuse type, according to Laurén. Even sporadic gastric carcinomas of the diffuse type often lose E-cadherin expression due to mutations. Lack of E-cadherin has been recorded at an early phase in such carcinomas. For 25 years, we have provided evidence for neuroendocrine (NE) cell origin of gastric carcinomas of diffuse type. The present study was, therefore, done to examine whether normal NE cells in the gastrointestinal tract express E-cadherin or not. Methods. During upper gastrointestinal endoscopy, biopsies were taken from normal oxyntic mucosa, gastric carcinoids, gastric carcinomas, and from normal duodenal mucosa. Tissues were examined by immunohistochemistry (IHC) using antibodies toward chromogranin A, synaptophysin, and E-cadherin. Isolated mucosal cells were prepared from biopsies of normal mucosa and examined by antibodies against the same markers by immunofluorescence. Results. Normal gastrointestinal NE cells did not express E-cadherin as assessed by IHC or immunocytochemistry. No expression of E-cadherin was found on tumor cells from gastric carcinoids or cancer of diffuse type examined by IHC. Conclusion. Our findings, which are in contrast to some previous studies, may explain why there is a discrepancy between lack of atypia and malignant biological behavior of such tumors. Since they normally lack the adhesion molecule E-cadherin, reflected in their spread occurrence, only minor changes may result in malignant behavior.

English

Abstract Introduction Hereditary diffuse gastric cancer is an autosomal inherited syndrome associated with the E-cadherin germline mutations. Different types of CDH1 germline mutations have been reported; the missense alterations are rarely identified when compared with truncating mutations. The identification of missense mutation represents a clinical burden, since its pathogenicity is still under genetic and clinical studies. The aim of this critical review was to discuss E-cadherin germline missense mutations in diffuse gastric cancer. Materials and methods In this paper, we reviewed the literature data about the CDH1 germline missense mutations identified in early-onset and hereditary diffuse gastric tumours. The roles of clinical surveillance and prophylactic gastrectomy were discussed. Mutations reported in breast lobular cancer were excluded. Results We identified a total of 31 CDH1 germline missense mutations with different pathogenic impact on E-cadherin function (pathogenic vs. neutral). The majority of these alterations were localized at the extracellular domain of the CDH1 gene. These mutations affected indifferently hereditary and sporadic diffuse gastric carcinomas. Conclusion In this critical review, we reported all missense mutations identified to date and discussed about the E-cadherin missense mutation function, clinical management for asymptomatic mutation carriers and the roles of prophylactic total gastrectomy and endoscopic surveillance.

Expression of C-X-C chemokine receptor types 1/2 in patients with gastric carcinoma: Clinicopathological correlations and significance.

C-X-C chemokine receptor types 1/2 (CXCR1/2) may play multiple roles in the development and progression of a number of types of tumor. The abnormal expression of CXCR1/2 in various types of malignant tumors has been reported, but less is known with regard to gastric carcinoma. The present study was preliminarily conducted to elucidate the correlation between clinicopathological factors and the immunohistochemical expression of CXCR1/2 in patients with gastric carcinoma. The expression of CXCR1/2 in 69 specimens of sporadic gastric carcinoma and their corresponding non-neoplastic mucosa obtained by gastrectomy was assayed by immunohistochemistry (IHC) using a polyclonal anti-CXCR1/2 antibody. ERK1/2 and AKT phosphorylation and the expression of indicators of proliferation, growth and apoptosis (Bcl-2 and Bax, Cyclin D1, EGFR and Ki-67), angiogenesis (VEGF and CD34), invasion and metastasis (MMP-9, MMP-2, TIMP-2 and E-cadherin) were also detected by IHC. A total of 68 (98.6%) of the 69 patients with gastric carcinoma were found to have positive CXCR1/2 expression, which appeared to be significantly higher in gastric carcinoma compared with corresponding non-neoplastic mucosa tissues. The expression of CXCR1/2 in gastric carcinoma was significantly associated with invasion, metastasis and TNM staging (P<0.001). Correlation analysis between CXCR1/2 and pAKT (P=0.032), pERK (P<0.001), Cyclin D1 (P=0.049), EGFR (P=0.013), Bcl-2 (P=0.003), microvessel density (P=0.001), MMP-9 (P=0.013) and MMP-2 (P=0.027) expression using the Spearman test showed significant correlation in gastric carcinoma. Univariate and multivariate logistic regression analysis showed that, compared with negative or weak expression, overexpression of CXCR1/2 protein was a significant risk factor for TNM stage (P<0.001). These results preliminarily suggest that CXCR1/2 may be a useful maker for progression of the tumors and a promising target for gastric carcinoma therapy.

Refined mapping of loss of heterozygosity in Chinese sporadic gastric carcinoma

The aim of this study is to explore precise deleted regions where the candidate tumor suppressor genes might be located in Chinese sporadic gastric carcinoma. By searching in Genothon, NCBI and GDB databases, 145 polymorphic microsatellite markers were chosen, at a mean density of approximately one marker every 2 - 4 cM, covering 15 chromosomes. These polymorphic microsatellite markers in gastric carcinoma and adjacent tissue were analyzed via PCR. PCR products were submitted to electrophoresis on an ABI 3730 DNA sequencer. Genemapper3.2 software was used for LOH (Loss of Heterozygosity) scanning and analysis. Comparison between LOH frequency and clinicopathological factors was performed by Fisher’s exact test. 26 refined regions were mapped as candidate regions for TSGs (Tumor suppression genes) in Chinese sporadic gastric cancer. Associations between LOH and clinical information indicated that 6 loci was associated with pTNM stage, 5 with Lauren's type, 4 with lymph nodes metastasis and another 2 with distant metastasis. Through refined deletion mapping, 26 candidate regions, where TSGs may be located, were found and 17 loci were proposed to be used as clinical markers in Chinese sporadic gastric cancer. Keywords: Gastric carcinoma, refined mapping, loss of heterozygosity (LOH), tumor suppressor genes (TSGs), tumor markers African Journal of Biotechnology Vol. 9(35), pp. 5754-5761, 30 August, 2010

Methylation ofGATA-4andGATA-5and development of sporadic gastric carcinomas

To understand the implication of GATA-4 and GATA-5 methylation in gastric carcinogenesis. Methylation status of GATA-4 and GATA-5 CpG islands in human gastric mucosa samples, including normal gastric biopsies from 45 outpatients, gastric dysplasia [low-grade gastric intraepithelial neoplasia (GIN), n = 30; indefinite, n = 77], and 80 paired sporadic gastric carcinomas (SGC) as well as the adjacent non-neoplastic gastric tissues was analyzed by methylation specific polymerase chain reaction (MSP) and confirmed by denatured high performance liquid chromatography (DHPLC). Immunohistochemical staining was used to detect protein expression. The correlation between GATA-4 and GATA-5 methylation and clinicopathological characteristics of patients including Helicobacter pylori (H. pylori) infection was analyzed. GATA-4 and GATA-5 methylation was frequently observed in SGCs (53.8% and 61.3%, respectively) and their corresponding normal tissues (41.3% and 46.3%) by MSP. The result of MSP was consistent with that of DHPLC. Loss of both GATA-4 and GATA-5 proteins was associated with their methylation in SGCs (P = 0.01). Moreover, a high frequency of GATA-4 and GATA-5 methylation was found in both gastric low-grade GIN (57.1% and 69.0%) and indefinite for dysplasia (42.9% and 46.7%), respectively. However, GATA-4 and GATA-5 methylation was detected only in 4/32 (12.5%) and 3/39 (7.7%) of normal gastric biopsies. GATA-4 methylation in both normal gastric mucosa and low-grade GIN was also significantly associated with H. pylori infection (P = 0.023 and 0.027, two-sides). Epigenetic inactivation of GATA-4 (and GATA-5) by methylation of CpG islands is an early frequent event during gastric carcinogenesis and is significantly correlated with H. pylori infection.

Aberrant methylation of DNA mismatch repair genes in elderly patients with sporadic gastric carcinoma: A comparison with younger patients

Hypermethylation of promoters that regulate the expression of DNA repair genes is associated with gastric carcinoma (GC). Little is known regarding the association between age of disease onset and differences in molecular profiles. The two study groups consisted of 100 elderly patients and 100 younger patients. The aberrant DNA methylation patterns of four mismatch repair genes, hMLH1, hMSH2, hMSH3, and MGMT, were compared by bisulfite modification and methylation-specific PCR (MSP). The methylation frequencies for hMLH1 and hMSH3 were significantly higher for the elderly than for the younger GC patients (P < 0.001 and P = 0.031, respectively). A significant correlation was observed between aberrant hMLH1, hMSH3, and MGMT methylation and the loss of hMLH1, hMSH3, and MGMT protein expression (P < 0.001, P = 0.002, and P = 0.001, respectively). The prevalence of aberrant hMLH1 and hMSH3 methylation increased significantly with age. These results suggest that the methylation of hMLH1 and hMSH3 is age related and thus may play an important role in gastric carcinogenesis in the elderly. Screening for hMLH1 and hMSH3 methylation may have clinical significance for the evaluation of elderly patients with GC.

Refined mapping of loss of heterozygosity of 1q43 regions in the patients with sporadic gastric carcinoma

Objective To screen the candidate tumor suppressor genes(TSGs)related to gastric cancer(GC)in 1 q43 region.Methods Four fluorescent labeled polymorphie markers were analvzed in the samples of GC and adjacent normal tissues obtained during operation performed on 96 GC patients,60 males and 36 females.The PCR products were eleetrophresed for loss of heterozygosity(LOH)scanning and analysis.Results The average LOH frequency in the 1 q43 region was 17.9%,with the highest LOH frequency of 26.5%at the D1S1594 locus,and lowest LOH frequency of 7.7%at DISl594 locus.There was no relationship between LOH frequency and cliniepathologcial data such aft the age and sex of the patients,the size and TNM stage of the tumor.Conclusion One high LOH region between D1 S1 594 and D1 S2785(1 q43,about 1 em)had been detected in GC,suggesting the existence of TSGs related to GC. Key words: Gastric carcinoma; LoSS of heterozygosity; Chromosome

Genetic Polymorphisms of the E-Cadherin Promoter and Risk of Sporadic Gastric Carcinoma in Chinese Populations

Frequent mutations and loss of expression of E-cadherin have been reported in a number of cancers. E-cadherin germ line mutations lead to a high risk of familial diffused gastric carcinoma. In the present study, to evaluate the effect of genetic polymorphisms in the E-cadherin promoter on the risk of sporadic gastric carcinoma (SGC), a comprehensive study was conducted in two populations with high and low risk of SGC in China, respectively. Five hundred seventy-two SGC cases and 625 controls from low-risk area and 589 individuals enrolled in a long-term follow-up survey in high-risk area were studied. Polymorphisms of E-cadherin around transcription start site (-437 to +314) were analyzed by sequencing. Five variations of -347del>A, -160C>A, -73A>C, +178T>C, and +234 13N ins>del were linked tightly. The -347del/del and its strongly linked +178T/T, +234 13N ins/ins genotypes increased male SGC risk in the high-risk area significantly [odds ratio (OR), 2.22; 95% confidence intervals (95% CI), 1.10-4.46] and correlated with the severity of gastric lesions. A synergetic effect was also observed between -347del/del genotype and Helicobacter pylori infection (OR, 4.93; 95% CI, 1.65-14.71). Compared with -347del-containing haplotypes, the -347A-containing haplotype [A((-347))-C((-160))-A((-73))-C((+178))-13N del((+234))] decreased the risk of SGC among male subjects (OR, 0.61; 95% CI, 0.37-1.01). Such correlation could not be observed among subjects from the low-risk area. The present data suggest that the -347del allele of E-cadherin strongly links with the +178T and +234 13N ins alleles. The -347del/del genotype may increase the susceptibility of SGC among males in the high-risk area of China.

M1622 Loss of Heterozygosity of PTEN Tumor Supressor Gene and Expression Pattern of E-Cadherin in Sporadic Gastric Carcinoma

M1622 Loss of Heterozygosity of PTEN Tumor Supressor Gene and Expression Pattern of E-Cadherin in Sporadic Gastric Carcinoma

Somatic mutations in mismatch repair genes in sporadic gastric carcinomas are not a cause but a consequence of the mutator phenotype

In hereditary nonpolyposis colorectal cancer (HNPCC), patients' mismatch repair (MMR) gene mutations cause MMR deficiency, leading to microsatellite instability (MSI-H). MSI-H is also found in a substantial fraction of sporadic gastric carcinomas (SGC), mainly due to MLH1 promoter hypermethylation, although somatic mutations in MMR genes have been described. We aimed to investigate which MMR defects are present in SGC. Twenty-nine MSI-H SGC investigated previously for MLH1 promoter hypermethylation were screened for somatic mutations in MLH1, MSH2, MSH6, MLH3, and MBD4 by denaturing gradient gel electrophoresis and sequencing. Five truncating mutations (three in MSH6, one in MLH3, and one in MBD4) and one missense mutation ( MLH1) were identified. Of these, three truncating mutations were in MSI-H cases that lack MLH1 hypermethylation. As all truncating mutations were found in the coding poly-A tracts, it seems likely that they result from the MSI phenotype rather than cause it. In summary, somatic mutations in MMR genes are rare in SGC and do not explain the development of these tumors reflecting, rather than causing, the mutator phenotype. Other MMR genes are probably involved in MSI-H gastric cancer without MLH1 hypermethylation.

After Helicobacter pylori, Genetic Susceptibility to Gastric Carcinoma Revisited

Genetically, it is possible to distinguish two main forms of gastric carcinoma (GC): a hereditary form in which the initiating genetic alteration is inherited and the remaining mutations are acquired somatically; and a sporadic form in which every mutation is of somatic origin and where the environment is thought to play a major role. Although rare, the identification of germline mutations is proving invaluable in the clinical management of GC families. In the setting of sporadic-type GC it has been shown that individuals infected with Helicobacter pylori have an increased risk of developing GC. Recently, abundant evidence has been collected showing that the risk for sporadic GC development also depends on host genetic factors. Despite providing important insights into the understanding of the disease pathogenesis, the genetic markers we have at present are not sensitive/specific enough to form the basis of a screening strategy.

Deletion of exon 8 increases cisplatin-induced E-cadherin cleavage

E-Cadherin-mediated cell–cell adhesion plays a key role in epithelial cell survival and loss of E-cadherin or β-catenin expression is associated with invasive tumor growth. Somatic E-cadherin mutations have been identified in sporadic diffuse-type gastric carcinoma. Here, we analysed the fate of E-cadherin with an in frame deletion of exon 8 compared to wild-type E-cadherin and the involved signalling events during cisplatin-induced apoptosis. We report that mutant E-cadherin was more readily cleaved during apoptosis than the wild-type form. Also β-catenin, an important binding partner of E-cadherin, was processed. E-cadherin cleavage resulted in disconnection of the actin cytoskeleton and accumulation of E-cadherin and β-catenin in the cytoplasm. Inhibitor studies demonstrated that E-cadherin cleavage was caused by a caspase-3-mediated mechanism. We identified the Akt/PKB and the ERK1/2 signalling pathways as important regulators since inhibition resulted in increased E-cadherin cleavage and apoptosis. In summary, we clearly demonstrate that somatic E-cadherin mutations affect apoptosis regulation in that way that they can facilitate the disruption of adherens junctions thereby possibly influencing the response to cisplatin-based chemotherapy. Elucidating the mechanisms that regulate the apoptotic program of tumor cells can contribute to a better understanding of tumor development and potentially be relevant for therapeutic drug design.

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.

MDM2 Promoter Polymorphism Is Associated With Both an Increased Susceptibility to Gastric Carcinoma and Poor Prognosis

Recently, a single-nucleotide polymorphism in the MDM2 promoter (SNP309) has been found to lower the age of onset of tumors and increase the occurrence of multiple primary tumors in Li-Fraumeni syndrome, and accelerate the development of sporadic adult soft tissue sarcoma. The aim of this study was to determine whether SNP309 is associated with susceptibility to gastric carcinoma and its prognosis. In a case-control study including 438 controls and 410 patients with sporadic gastric carcinoma, MDM2 SNP309 was genotyped. Serum pepsinogens (PGs) I and II were measured in 438 control subjects and 253 cases selected from 410 patients. Tumor tissue was immunostained with p53 and examined for mutations in exons 5 to 8 of p53 using polymerase chain reaction-based single strand conformational polymorphism analysis and direct sequencing. The risk of overall gastric carcinoma for SNP309 (G/G) was significantly increased when compared with T carriers (P = .039), especially carcinomas with extragastric tumors (P = .005), carcinoma with severe atrophic gastritis positive for PG assay (PG I level < 70 ng/mL and PG I/II < 3.0; P = .005), antral carcinoma (P = .020), intestinal-type carcinoma (P = .023), p53-immunopositive carcinoma (P = .007), and carcinoma with p53 mutations (P = .007). No significant difference in age at diagnosis was observed among genotypes. SNP309 (G/G) was an independent marker of poor overall survival in advanced carcinoma (hazard ratio, 3.16; 95% CI, 1.22 to 8.20; P = .018). This study provides evidence supporting the association of SNP309 with gastric carcinogenesis via p53 tumor suppressor pathway, extragastric tumorigenesis, and poor prognosis.