No abstract

The initial development of diffuse gastric cancer (DGC) is poorly understood. The study of E-cadherin (CDH1) germ line mutation carriers predisposed to DGC provides a rare opportunity to elucidate the genetic and biological events surrounding disease initiation. Samples from various stages of hereditary and sporadic DGC were investigated to determine general mechanisms underlying early DGC development. Paraffin-embedded tissues from 13 CDH1 mutation carriers and from 10 sporadic early DGC cases were analyzed. Immunofluorescence and immunohistochemistry using differentiation, proliferation, and adhesion markers showed that DGC initiation seems to occur at the proliferative zone (the upper neck) of the gastric epithelium and correlates with absent or reduced expression of junctional proteins (B-actin, p120, Lin-7). Slow proliferation of neoplastic cells at the upper gastric neck leads to the formation of intramucosal signet-ring cell carcinoma (SRCC) displaying differentiated features. As shown by immunolabeling, invasion from SRCC lesions beyond the gastric mucosa is associated with poor differentiation, increased proliferation, activation of the c-Src system, and an epithelial-mesenchymal transition. Our results provide a molecular description of the early development of DGC and explain the relationship between the two main DGC types, poorly differentiated carcinoma and SRCC: both share their origin, but SRCC develops following cancer cell differentiation and seems relatively indolent in its intramucosal stage.

This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

No abstract

The importance of loss of the cell-cell adhesion molecule E-cadherin (encoded by CDH1) to tumor progression is well established. However, CDH1 germ-line mutations predispose to the cancer susceptibility syndrome hereditary diffuse gastric cancer (HDGC), suggesting a role for E-cadherin in tumor initiation. The earliest indications of cancer in the stomachs of CDH1 mutation carriers are microscopic foci of intramucosal signet-ring cell carcinoma (SRCC; designated "eHDGC"). Here, we used N-methyl-N-nitrosourea (MNU) to promote gastric carcinogenesis in wild-type (wt) and cdh1(+/-) mice. MNU induced a variety of gastric tumors; however, intramucosal SRCC developed with an 11 times higher incidence in cdh1(+/-) mice compared with wt mice. The murine SRCC resembled the human eHDGCs in that they were hypoproliferative, lacked nuclear beta-catenin accumulation, and had reduced membrane localization of E-cadherin and its interacting junctional proteins. The down-regulation of E-cadherin in the murine SRCCs confirmed the importance of the second CDH1 hit to the initiation of diffuse gastric cancer. CDH1 promoter hypermethylation has been proposed to be a major second hit in advanced HDGC; however, its contribution to eHDGC was unknown. We thus examined a series of human eHDGC and detected CDH1 promoter methylation in 50% of foci. Promoter methylation was accompanied by reduced wt CDH1 mRNA levels in the foci and had a monoclonal pattern, consistent with an epigenetic initiation of disease. Together, these findings provide compelling evidence for a deficiency in cell-to-cell adhesion being sufficient to initiate diffuse gastric cancer in the absence of hyperproliferation and beta-catenin activation.

No abstract

Background and aims: Germline mutations in the CDH-1/E-cadherin gene are, to date, the only known cause of hereditary diffuse gastric cancer (HDGC). While two recent series of prophylactic gastrectomy described microscopic foci of signet ring cell carcinoma in sample sections from 10 macroscopically normal stomachs, whole stomach phenotype has not been mapped. We aimed to describe the size and distribution of foci in relation to mucosal zones and anatomical location. Methods: Six patients (from three HDGC kindred) were referred for total gastrectomy via three different referral pathways. Following fixation, five stomachs were completely blocked and one extensively sampled. Histopathology was mapped to a mucosal photograph of each stomach, enabling precise localisation of carcinoma foci, benign pathology, and mucosal zones. Results: There were 4-318 microscopic foci of intramucosal signet ring cell adenocarcinoma in the six macroscopically normal stomachs (foci size 0.1-10 mm in diameter). The distal third of the stomach contained 48% of total foci (range 29-75%). The body-antral transitional zone occupied 7.7% of mucosal area (range 3.6-11.8) but had 37% of foci (range 10%-75%). The largest foci were found in the transitional zone and foci density was five times greater in the transitional zone than in body or antral type mucosa. Conclusions: In germline CDH-1 mutation carriers, multiple microscopic foci of intramucosal signet ring cell carcinoma show a predilection for the distal stomach and the body-antral transitional zone. Targeting the transitional zone would maximise the likelihood of finding foci in macroscopically normal gastrectomies, and particular attention should be paid to this area during endoscopy.

Background and aims: Germline mutations in the CDH-1/E-cadherin gene are, to date, the only known cause of hereditary diffuse gastric cancer (HDGC). While two recent series of prophylactic gastrectomy described microscopic foci of signet ring cell carcinoma in sample sections from 10 macroscopically normal stomachs, whole stomach phenotype has not been mapped. We aimed to describe the size and distribution of foci in relation to mucosal zones and anatomical location. Methods: Six patients (from three HDGC kindred) were referred for total gastrectomy via three different referral pathways. Following fixation, five stomachs were completely blocked and one extensively sampled. Histopathology was mapped to a mucosal photograph of each stomach, enabling precise localisation of carcinoma foci, benign pathology, and mucosal zones. Results: There were 4-318 microscopic foci of intramucosal signet ring cell adenocarcinoma in the six macroscopically normal stomachs (foci size 0.1-10 mm in diameter). The distal third of the stomach contained 48% of total foci (range 29-75%). The body-antral transitional zone occupied 7.7% of mucosal area (range 3.6-11.8) but had 37% of foci (range 10%-75%). The largest foci were found in the transitional zone and foci density was five times greater in the transitional zone than in body or antral type mucosa. Conclusions: In germline CDH-1 mutation carriers, multiple microscopic foci of intramucosal signet ring cell carcinoma show a predilection for the distal stomach and the body-antral transitional zone. Targeting the transitional zone would maximise the likelihood of finding foci in macroscopically normal gastrectomies, and particular attention should be paid to this area during endoscopy.