Frequency of CDH1 germline mutations in gastric carcinoma coming from high- and low-risk areas: metanalysis and systematic review of the literature

<p>Abstract</p> <p>Background</p> <p>The frequency of E-cadherin germline mutations in countries with different incidence rates for gastric carcinoma has not been well established. The goal of this study was to assess the worldwide frequency of <it>CDH1 </it>germline mutations in gastric cancers coming from low- and high-risk areas.</p> <p>Methods</p> <p>English articles using MEDLINE access (from 1998 to 2011). Search terms included <it>CDH1</it>, E-cadherin, germline mutation, gastric cancer, hereditary, familial and diffuse histotype.</p> <p>The study included all E-cadherin germline mutations identified in gastric cancer patients; somatic mutations and germline mutations reported in other tumors were excluded.</p> <p>The method of this study was scheduled in accordance with the "PRISMA statement for reporting systematic reviews and meta-analyses". Countries were classified as low- or middle/high risk-areas for gastric carcinoma incidence. Statistical analysis was performed to correlate the <it>CDH1 </it>mutation frequency with gastric cancer incidence areas.</p> <p>Results</p> <p>A total of 122 E-cadherin germline mutations have been identified; the majority (87.5%) occurred in gastric cancers coming from low-risk areas. In high-risk areas, we identified 16 mutations in which missense mutations were predominant. (68.8%). We verified a significant association between the mutation frequency and the gastric cancer risk area (<it>p </it>< 0.001: overall identified mutations in low- vs. middle/high-risk areas).</p> <p>Conclusions</p> <p>E-cadherin genetic screenings performed in low-risk areas for gastric cancer identified a higher frequency of <it>CDH1 </it>germline mutations. This data could open new approaches in the gastric cancer prevention test; before proposing a proband candidate for the <it>CDH1 </it>genetic screening, geographic variability, alongside the family history should be considered.</p

Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation

A role for WNT signalling in gastric carcinogenesis has been suggested due to two major observations. First, patients with germline mutations in adenomatous polyposis coli (APC) are susceptible to stomach polyps and second, in gastric cancer, WNT activation confers a poor prognosis. However, the functional significance of deregulated WNT signalling in gastric homoeostasis and cancer is still unclear. In this study we have addressed this by investigating the immediate effects of WNT signalling activation within the stomach epithelium. We have specifically activated the WNT signalling pathway within the mouse adult gastric epithelium via deletion of either glycogen synthase kinase 3 (GSK3) or APC or via expression of a constitutively active β-catenin protein. WNT pathway deregulation dramatically affects stomach homoeostasis at very short latencies. In the corpus, there is rapid loss of parietal cells with fundic gland polyp (FGP) formation and adenomatous change, which are similar to those observed in familial adenomatous polyposis. In the antrum, adenomas occur from 4 days post-WNT activation. Taken together, these data show a pivotal role for WNT signalling in gastric homoeostasis, FGP formation and adenomagenesis. Loss of the parietal cell population and corresponding FGP formation, an early event in gastric carcinogenesis, as well as antral adenoma formation are immediate effects of nuclear β-catenin translocation and WNT target gene expression. Furthermore, our inducible murine model will permit a better understanding of the molecular changes required to drive tumourigenesis in the stomach

Camouflaging in a Complex Environment—Octopuses Use Specific Features of Their Surroundings for Background Matching

Living under intense predation pressure, octopuses evolved an effective and impressive camouflaging ability that exploits features of their surroundings to enable them to “blend in.” To achieve such background matching, an animal may use general resemblance and reproduce characteristics of its entire surroundings, or it may imitate a specific object in its immediate environment. Using image analysis algorithms, we examined correlations between octopuses and their backgrounds. Field experiments show that when camouflaging, Octopus cyanea and O. vulgaris base their body patterns on selected features of nearby objects rather than attempting to match a large field of view. Such an approach enables the octopus to camouflage in partly occluded environments and to solve the problem of differences in appearance as a function of the viewing inclination of the observer

Reduction in membranous expression of β-catenin and increased cytoplasmic E-cadherin expression predict poor survival in gastric cancer

β-catenin, a component of the E-cadherin–catenin cell adhesion complex, also plays a separate intracellular signalling role, interacting with APC protein. Intracellular accumulation of β-catenin is common in colorectal neoplasia. β-catenin abnormalities are associated with poor survival in gastric cancer, but previous studies do not differentiate between membrane-associated and intracellular β-catenin. In this study we aimed to determine which type of expression abnormalities for E-cadherin, β-catenin and α-catenin correlate with clinico-pathological features and survival in gastric cancer. Immunoperoxidase staining of paraffin-embedded sections from 40 gastric cancers was performed for E-cadherin, α- and β-catenins using microwave unmasking and an avidin–biotin technique. Clinical data were obtained from case records and cancer registry records. Reduced membranous expression of β-catenin occurred in 10/12 (83%) diffuse and 8/28 (29%) intestinal tumours (P = 0.0014), and was associated with poor differentiation (P = 0.0015) and short survival (P = 0.032), but not with age, sex, tumour size or nodal status. Nuclear expression of β-catenin was uncommon; cytoplasmic expression was observed in 13/40 cases (33%) but did not correlate with histology, tumour grade or survival. Reduced E-cadherin membrane expression was associated with lymph node metastasis (P = 0.02). Neither E-cadherin or α-catenin expression correlated with survival. Reduced membranous expression of β-catenin predicts poor prognosis in gastric cancer, whilst ectopic intracellular expression is relatively rare. The apparent differences in β-catenin expression from those found in colon cancer merit further study. © 1999 Cancer Research Campaig

CDH1 promoter hypermethylation and E-cadherin protein expression in infiltrating breast cancer

BACKGROUND: The E-cadherin gene (CDH1) maps, at chromosome 16q22.1, a region often associated with loss of heterozygosity (LOH) in human breast cancer. LOH at this site is thought to lead to loss of function of this tumor suppressor gene and was correlated with decreased disease-free survival, poor prognosis, and metastasis. Differential CpG island methylation in the promoter region of the CDH1 gene might be an alternative way for the loss of expression and function of E-cadherin, leading to loss of tissue integrity, an essential step in tumor progression. METHODS: The aim of our study was to assess, by Methylation-Specific Polymerase Chain Reaction (MSP), the methylation pattern of the CDH1 gene and its possible correlation with the expression of E-cadherin and other standard immunohistochemical parameters (Her-2, ER, PgR, p53, and K-67) in a series of 79 primary breast cancers (71 infiltrating ductal, 5 infiltrating lobular, 1 metaplastic, 1 apocrine, and 1 papillary carcinoma). RESULTS: CDH1 hypermethylation was observed in 72% of the cases including 52/71 ductal, 4/5 lobular carcinomas and 1 apocrine carcinoma. Reduced levels of E-cadherin protein were observed in 85% of our samples. Although not statistically significant, the levels of E-cadherin expression tended to diminish with the CDH1 promoter region methylation. In the group of 71 ductal cancinomas, most of the cases of showing CDH1 hypermethylation also presented reduced levels of expression of ER and PgR proteins, and a possible association was observed between CDH1 methylation and ER expression (p = 0.0301, Fisher's exact test). However, this finding was not considered significant after Bonferroni correction of p-value. CONCLUSION: Our preliminary findings suggested that abnormal CDH1 methylation occurs in high frequencies in infiltrating breast cancers associated with a decrease in E-cadherin expression in a subgroup of cases characterized by loss of expression of other important genes to the mammary carcinogenesis process, probably due to the disruption of the mechanism of maintenance of DNA methylation in tumoral cells

Frequent genomic imbalances suggest commonly altered tumour genes in human hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is one of the most frequent-occurring malignant tumours worldwide, but molecular changes of tumour DNA, with the exception of viral integrations and p53 mutations, are poorly understood. In order to search for common macro-imbalances of genomic tumour DNA, 21 HCCs and 3 HCC-cell lines were characterized by comparative genomic hybridization (CGH), subsequent database analyses and in selected cases by fluorescence in situ hybridization (FISH). Chromosomal subregions of 1q, 8q, 17q and 20q showed frequent gains of genomic material, while losses were most prevalent in subregions of 4q, 6q, 13q and 16q. Deleted regions encompass tumour suppressor genes, like RB-1 and the cadherin gene cluster, some of them previously identified as potential target genes in HCC development. Several potential growth- or transformation-promoting genes located in chromosomal subregions showed frequent gains of genomic material. The present study provides a basis for further genomic and expression analyses in HCCs and in addition suggests chromosome 4q to carry a so far unidentified tumour suppressor gene relevant for HCC development. © 2001 Cancer Research Campaign http://www.bjcancer.co

Conceiving “personality”: Psychologist’s challenges and basic fundamentals of the Transdisciplinary Philosophy-of-Science Paradigm for Research on Individuals

Scientists exploring individuals, as such scientists are individuals themselves and thus not independent from their objects of research, encounter profound challenges; in particular, high risks for anthropo-, ethno- and ego-centric biases and various fallacies in reasoning. The Transdisciplinary Philosophy-of-Science Paradigm for Research on Individuals (TPS-Paradigm) aims to tackle these challenges by exploring and making explicit the philosophical presuppositions that are being made and the metatheories and methodologies that are used in the field. This article introduces basic fundamentals of the TPS-Paradigm including the epistemological principle of complementarity and metatheoretical concepts for exploring individuals as living organisms. Centrally, the TPS-Paradigm considers three metatheoretical properties (spatial location in relation to individuals’ bodies, temporal extension, and physicality versus “non-physicality”) that can be conceived in different forms for various kinds of phenomena explored in individuals (morphology, physiology, behaviour, the psyche, semiotic representations, artificially modified outer appearances and contexts). These properties, as they determine the phenomena’s accessibility in everyday life and research, are used to elaborate philosophy-of-science foundations and to derive general methodological implications for the elementary problem of phenomenon-methodology matching and for scientific quantification of the various kinds of phenomena studied. On the basis of these foundations, the article explores the metatheories and methodologies that are used or needed to empirically study each given kind of phenomenon in individuals in general. Building on these general implications, the article derives special implications for exploring individuals’ “personality”, which the TPS-Paradigm conceives of as individual-specificity in all of the various kinds of phenomena studied in individuals

Nature meets nurture: molecular genetics of gastric cancer

The immensity of genes and molecules implicated in gastric carcinogenesis is overwhelming and the relevant importance of some of these molecules is too often unclear. This review serves to bring us up-to-date with the latest findings as well as to look at the larger picture in terms of how to tackle the problem of solving this multi-piece puzzle. In this review, the environmental nurturing of intestinal cancer is discussed, beginning with epidemiology (known causative factors for inducing molecular change), an update of H. pylori research, including the role of inflammation and stem cells in premalignant lesions. The role of E-cadherin in the nature (genotype) of diffuse gastric cancer is highlighted, and finally the ever growing discipline of SNP analysis (including IL1B) is discussed