Original Research Article
Gastric cancer patients less than 50 years of age exhibit significant downregulation of E-cadherin and CDX2 compared to older reference populations

https://doi.org/10.1016/j.advms.2014.03.002Get rights and content

Abstract

Purpose

There is an increasing need to identify molecular markers, which can be used to prognosticate patient populations in gastric cancer. Whereas a significant number have been identified, very few have been characterized in the context of their ability to discriminate between young and old age groups in which a survival difference clearly exists.

Material/methods

In this study, using immunohistochemistry, we evaluated three markers with proven involvement in gastric cancer. The p53 tumor suppressor, the cell adhesion glycoprotein epithelial cadherin (CDH1) and the caudal-related homeobox transcription factor (CDX2) all of these have important roles in the aetiopathogenesis and/or progression of gastric cancer.

Results

After adjustments for TNM stage, tumor grade, histopathological characteristics (Lauren classification), we found significant differences in the expression of these proteins, particularly E-cadherin and CDX2 between young and elderly patients. However, these differences did not amount to a significant difference in survival.

Conclusions

This study demonstrates that the protein expression of p53, CDH1 and CDX2 significantly discriminates young patients with gastric cancer who have a better prognostic outlook from older patients, but this difference in expression does not contribute to a survival benefit.

Introduction

Worldwide, gastric cancer, including carcinomas of the gastro-esophageal junction, constitutes the 4th and 5th most prevalent cancer in males and females, respectively [1]. According to recent presentations, this cancer type still accounts for an overall poor prognosis [1], [2]. Several investigators have attempted to define risk categories that clearly delineate prognostic subgroups including tumor stage and chronological age amongst others with varying degrees of success [3], [4], [5], [6], [7], [8]. Clinically, immunohistochemical markers are frequently being explored to support diagnosis and patient stratification, and in certain cases prognosticate especially amongst age groups [7], [9], [10], [11].

Interestingly, relative to the number of molecules implicated in gastric carcinogenesis, those that have been explored as potential immunohistochemical markers with possible prognostic implications that discriminate between age groups are few. Very recently, we demonstrated that TFF1, Src and COX-2 could be explored in this regard and showed that young patients with gastric carcinoma had a significantly better age corrected 5-year survival rate compared to an older reference population [7]. However, further molecules with equally significant implications in gastric cancer progression exist. For instance, several reports have demonstrated a strong involvement of E-cadherin, p53 and CDX2 in gastric cancer development, especially in advanced cancers [12], [13], [14], [15], [16], [17], [18].

TP53 is one of the most extensively studied tumor suppressor genes in human carcinogenesis. It is located on the short arm of chromosome 17, and encodes a 53 kDa protein that has established roles in cell cycle regulation, apoptosis, genome stabilization and angiogenesis [19], [20]. The mutational continuum of p53 in gastric cancer is extensive. An increasing occurrence of p53 aberrations has been observed in the progression of gastric cancer, from gastritis all the way to advanced cases, with the highest frequency of abnormalities seen in metastatic lesions [21].

The caudal type homeobox 2 [CDX2] is a transcription factor belonging to the caudal-related homeobox gene family. It plays a role in determining trophoectoderm differentiation in embryogenesis; however, it also functions as a ‘master switch’ for intestinal differentiation, with expression in adults restricted to the small and large intestine [22]. CDX2 is also involved in the development and progression of gastric cancer [23], [24]. Several studies have demonstrated that CDX2-positive expression in gastric cancer significantly correlates with better differentiation and a lower rate of lymph node metastasis [25], [26], [27].

The human E-cadherin gene encodes a calcium-dependent cell-cell adhesion glycoprotein that is essential for development, cell differentiation and maintenance of epithelial polarity and structural integrity [28]. The suppression of E-cadherin is commonly observed in many sporadic tumors, and loss of function is thought to contribute to cancer progression by increasing proliferation, invasion, and metastasis. Around 25–40% of hereditary diffuse gastric cancers are caused by heterozygous E-cadherin. Reduced expression of E-cadherin correlates with an infiltrative and metastatic ability in gastric cancer [29].

In this study, we evaluated the protein expression of these three markers using immunohistochemistry and attempted to relate our findings to prognosis of patients older and younger than 50 years of age.

Section snippets

Patient information

From 1st January 1995 to 31st December 2005, 423 chemotherapy naïve gastric cancer cases encompassing carcinomas of the gastroesophageal junction (AEG II-III) were operated on at the surgical Department of the Erlangen University Hospital, Germany. Patients had a gastrectomy, transhiatal oesophagogastrectomy, or distal gastric resection. Adequate safety margins were taken into consideration with DII–III lymph node dissection, as well as reconstruction according to Billroth I, II or Roux Y. Data

Results

This evaluation established that E-cadherin was weakly expressed in young patients and in comparison to the older age group, significantly downregulated (p < 0.001). The marker was weakly expressed in 39 out of 40 patients (Table 1). E-cadherin is a special case, because it is also known that heritable diffuse gastric cancer (HDGC) involves a mutation of the E-cadherin gene CDH1. Downregulation of E-cadherin is associated with a poor prognosis.

In the case of p53, no significant inter-group

Discussion

Gastric cancer is not a homogeneous disease and the clinical course of patients with similar disease stages or tumor profiles does not always tally [22]. Furthermore, in evaluating patient cohorts, clinico-pathological variables including chronological age are often taken into consideration, but seldom have these studies been used to distinguish prognostic indices on the basis of chronological age. This is further confounded by the fact that age categories are not distinct. While individuals

Conclusions

Taken together, the data from this study clearly demonstrate that even young patients do not constitute a homogeneous group. Especially, we observed aberrant expression of E-cadherin and CDX2 in patients less than 50 years of age that would normally be linked to a poorer outcome, however, we did not find any significant effects on survival for all patients including the young group. This could be due, certainly at least in part, to the small population of 80 patients which we analyzed. This

Conflict of interests

The authors declare no conflict of interests.

Financial disclosure

The authors have no financing to disclose.

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      In fact, a reduced/lack of E-cadherin expression or/and loss of function contributes to cancer progression by increasing proliferation, invasion and metastasis (Berx and van Roy, 2009; Gheldof and Berx, 2013; Schneider and Kolligs, 2014; van Roy, 2014). Disruption of E-cadherin expression and loss of its function(s) has been extensively documented in several ST. Examples are breast (Sinn et al., 2014), ovarian (Cowden Dahl et al., 2008), gastric (Schildberg et al., 2014), endometrial (Wójcik-Krowiranda et al., 2013), colorectal (Deng et al., 2014) and bladder (Bryan 2015) cancers. Several mechanisms of E-cadherin inactivation have been reported, among them are loss of heterozygosity at the 16q22.1 chromosome region (Chalmers et al., 2001), presence of inactivating mutations (Berx et al., 1998; Corso et al., 2014), CpG-island hypermethylation of the CDH1 promoter (Caldeira et al., 2006; Gall and Frampton, 2013; Kanazawa et al., 2002), gene expression silencing by binding of specific transcription factors to sequences in the CDH1 promoter (Zhang et al., 2014), and post-translational modifications (i.e. proteinase processing/phosphorylation/glycosylation) that negatively regulate E-cadherin functions (Rashid et al., 2001).

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    These authors contributed equally to this work.

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