Gastric cancer: New genetic developments

Abstract

Gastric cancer's (GC) incidence shows large geographic differences worldwide with the lowest rates occurring in most Western industrialized countries including the United States and the United Kingdom; in contrast, relatively high rates of GC occur in Japan, Korea, China, and South America, particularly Chile. The Laurén classification system classifies GC under two major histopathological variants: 1) an intestinal type and 2) a diffuse type. The intestinal type is more common in the general population, more likely to be sporadic and related to environmental factors such as diet, particularly salted fish and meat as well as smoked foods, cigarette smoking, and alcohol use. It exhibits components of glandular, solid, or intestinal architecture, as well as tubular structures. On the other hand, the diffuse type is more likely to have a primary genetic etiology, a subset of which, known as hereditary diffuse gastric cancer (HDGC), is due to the E-cadherin (CDH1) germline mutation. The diffuse type pathology is characterized by poorly cohesive clusters of cells which infiltrate the gastric wall, leading to its widespread thickening and rigidity of the gastric wall, known as linitis plastica. Helicobacter pylori infection is associated with risk for both the intestinal and diffuse varieties of gastric cancer. Germline truncating mutations of the CDH1 gene, which codes for the E-cadherin protein, were initially identified in three Maori families from New Zealand that were predisposed to diffuse GC. Since then, similar mutations have been described in more than 40 additional HDGC families of diverse ethnic backgrounds. It is noteworthy that two-thirds of HDGC families reported to date have proved negative for the CDH1 germline mutation. A number of candidate genes have been identified through analysis of the molecular biology of E-cadherin. Patients with evidence of the CDH1 germline mutation in the context of a family history of HDGC must be considered as candidates for prophylactic gastrectomy, given the extreme difficulty in its early diagnosis and its exceedingly poor prognosis when there is regional or distant spread. Specifically, the E-cadherin cytoplasmic tail interacts with catenins, assembling the cell-adhesion complex involved with E-cadherin mediated cell:cell adhesion. Beta-catenin and gamma-catenin compete for the same binding site on the E-cadherin cytoplasmic tail, directly linking the adhesion complex to the cytoskeleton through alpha-catenin. Beta-catenin gene (CTNNB1) mutations have been described predominantly in intestinal-type gastric cancers and CTNNB1 gene amplification and overexpression have recently been described in a mixed-type gastric cancer. This paper reviews the genetics of both intestinal and diffuse types of gastric carcinoma, their differential diagnosis, molecular genetics, pathology, and, when known, their mode of genetic transmission within families.

De novo expression of CD44 variants in sporadic and hereditary gastric cancer

“…HDGC early lesions remain undetected with currently used diagnostic tools. 32 This limitation in cancer detection clinically supports prophylactic gastrectomy as the only reliable medical approach to prevent disease progress in CDH1 mutation carriers belonging to HDGC families. 27 We identified overexpression of CD44 molecules in GC (GC cell lines, primary sporadic gastric carcinoma and HDGC) and its premalignant lesions (intestinal metaplasia and dysplasia).…”

Hereditary diffuse gastric cancer in a Japanese family with a large deletion involving CDH1

“…Clinically, approximately 25 % of families fulfilling the criteria for the diagnosis of HDGC have inactivating CDH1 germline mutations [2,3]. In contrast, in East Asian countries, including Japan, Korea, and China, with high incidences of GCs [4], HDGC has rarely been reported [5,6]. Recently, Yamada et al [7] reported two germline alterations in the CDH1 gene in two Japanese familial GCs.…”

Familial gastric cancer: guidelines for diagnosis, treatment and periodic surveillance

“…In families with clustering of gastric cancer cases, the diffuse type is the most frequent, but not the only, presenting histological type. Familial occurrence of intestinal gastric cancer is rare, but several cases have been reported [9][10][11].…”