Pathology

E. Strong (ed.). Gastric cancer. Principles and practice. Springer (2015)


Mechanism of tumorigenesis

E-cadherin is involved in cell adhesion, epithelial-to-mesenchymal transition (EMT) and in regulation of Wnt signalling via β-catenin. Although the exact mechanisms by which loss of E-cadherin instigates tumorigenesis remain to be elucidated, it is thought that in HDGC, CDH1 acts as a tumour suppressor gene, with loss of function leading to loss of cell adhesion with subsequent invasion and metastasis. One hypothesis is that loss of E-cadherin and subsequent loss of cell adhesion causes disruption to cell polarity that interferes with cell division and results in daughter cells being deposited in the lamina propria, which then expand forming foci of SRCs [78]. The in vitro and in vivo evidence available suggests that the loss of cell adhesion alone caused by deficient E-cadherin expression is sufficient to initiate DGC.

Loss of E-cadherin expression is one of the hallmarks of EMT [104]. EMT is the process by which epithelial cells assume a more mesenchymal phenotype, including the ability to migrate through the basement membrane and possess some resistance to apoptosis [105]. This process is normal in human development, but is pathological when implicated in tumour progression and metastasis. In addition to disrupting cell adhesion and therefore potentiating an invasive phenotype, loss of E-cadherin expression also promotes dysregulated β-catenin signalling through the canonical Wnt signalling pathway which has been associated with tumorigenesis in a wide variety of cancers [106].

E-cadherin’s role as a suppressor of tumour invasion has been shown in vitro, where loss of expression or function leads to altered cell phenotype and enhanced cell invasiveness [27]. This phenotype can be reverted by restoring Ecadherin protein expression after transfection of E-cadherin coding cDNA [107, 108].

The important role that E-cadherin has in embryogenesis is reflected in the fact that E-cadherin homozygous knockout mice are embryonic lethal [109]. Heterozygous mutant animals are phenotypically normal, and have been used to establish a mouse model of DGC by exposure to a carcinogen (N-methyl-N-nitrosurea) to induce the 2nd hit [79, 109]. It was noted that compared to wild-type treated mice, Cdh1+/mice developed intramucosal SRCCs 11 times more frequently. In addition to loss of E-cadherin expression, the SRCCs showed a low proliferative activity and absence of nuclear β catenin accumulation, suggesting that in the absence of increased proliferation or Wnt signalling activation, loss of cellto-cell adhesion alone was sufficient to initiate a DGC in these models [79]. This is consistent with the clinical observation, where hundreds of independent foci of SRCCs can occur in the stomachs of patients with germline CDH1 mutations, which suggests that it is unlikely that other genes are required to initiate HDGC [78].

It is not known why germline CDH1 mutations predispose to DGC, and LBC, but not significantly to other malignancies. One hypothesis is the higher carcinogen exposure and chronic inflammation that the gastric epithelium is exposed to, another is the high cellular turnover of the gastric epithelium [78]. In these settings, fewer mutational or epigenetic events may be required to generate an invasive malignant phenotype. It is notable, however, that epithelial cell turnover in the intestine is also high, and why colorectal cancer is not more apparent in patients with CDH1 mutations remains unresolved.

Risk modifiers

There has not been a comprehensive analysis of the genetic or environmental factors that impact on penetrance of HDGC. Knowledge of these would be beneficial for genetic counselling on risk behaviours and on genetic risk profile. However, there are a number of lifestyle and environmental factors that have been identified to impact on risk of sporadic GC (see Chaps. 1–3), and it is possible that these factors may also impact on HDGC.

Helicobacter pylori

Helicobacter pylori (H. pylori) was classified as a class I carcinogen by the World Health Organisation in 1994, and has a well-established association with GC [110]. It has been implicated in both sporadic intestinal GC, and DGC, and although it does not appear to be required for oncogenesis in HDGC [66, 111–113], it theoretically may modulate disease risk [114]. Current recommendations for HDGC suggest eradicating H. pylori if found [10], but there are no prospective analyses showing impact of this on progression of HDGC.

Physical activity and diet

Numerous studies have investigated the association of sporadic GC with demographics, diet and physical activity; however, there are no studies that investigate HDGC specifically or as a subgroup.

Diet and food storage have been implicated in the changing incidence of sporadic GC, with the adoption of refrigeration improving access to fresh fruit and vegetables and reducing the need for salt preservation of food being implicated in the decrease in incidence observed in GC [115–118]. The European Prospective Investigation into Cancer and Nutrition (EPIC) study was designed to prospectively investigate relationships between cancer incidence and lifestyle, genetic and environmental factors. It found an inverse association with vegetable intake for intestinal GC, but not diffuse GC, and no association with fruit intake [119]. For sporadic GC, the EPIC study demonstrated an inverse association with physical activity, particularly in non-cardiac GC [120]. Findings of the EPIC study also showed an association between smoking and sporadic GC, with approximately 18% of cases in this study being attributable to smoking [121]. Whether smoking, physical activity, diet or other environmental factors impact on the penetrance of HDGC is unknown, but would be assumed to have similar affects as in sporadic GC.

CDH1 mutations in sporadic GC

E-cadherin gene mutations were identified in sporadic GC prior to the identification of CDH1 as the gene responsible for HDGC [29]. Inactivating somatic mutations in CDH1 are detected in over 50% of sporadic DGC, but not intestinal GC [29, 122]. As with HDGC, promoter methylation of CDH1 has been identified in sporadic DGC as the 2nd hit [122]. The high prevalence of mutation and epigenetic silencing of CDH1 suggests that the inactivation of E-cadherin has a role in the evolution of sporadic DGC as well as HDGC, with the earlier age of onset of GC seen in HDGC kindreds reflecting the fact that only one wild-type CDH1 allele requires mutation to develop a potentially malignant genotype. Interestingly, although mutations in CDH1 are not seen in intestinal GC, promoter methylation has been identified in a subset of intestinal GC [76, 122]. It is likely that silencing of E-cadherin expression has an effect on the later stages of the carcinogenic cascade in intestinal type GCs, whereas it has a role in early pathogenesis of DGC.

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