Genetic predisposition to gastric cancer
Section snippets
Background
Gastric cancer is a heterogeneous disease, caused by a variety of genetic and environmental factors, and comprised of several pathologic subtypes with different molecular features and clinical outcomes [1]. The incidence and prevalence of gastric cancer varies widely, but China, Korea, Japan and Portugal bear the highest rates of disease [2]. In the west, although the overall rate of has decreased substantially over the past century, the incidence of adenocarcinomas of the gastroesophageal
Histological characterization
Gastric cancer can be subtyped pathologically according to Lauren’s classification published in 1965 and revised by Carneiro in 1995 [6], [7]. The four histological categories include (1) glandular/intestinal, (2) mixed intestinal/diffuse, (3) border foveal hyperplasia, and (4) solid/undifferentiated.
The worldwide relative proportions of gastric cancer subtypes are 74% intestinal, 16% diffuse, and 10% other [8]. Intestinal type gastric tumors often present as solid masses with atrophic
Etiological characterization
A host of etiological factors are implicated as causes of gastric cancer. Correlations have been shown with chronic ingestion of pickled vegetables, salted fish, excessive salt intake, smoked meat, and smoking. Epstein-Barr virus has been implicated in about 10% of worldwide gastric carcinoma, and Helicobacter pylori has been consistently implicated as a major risk factor, primarily in intestinal type.
About 5%–10% of gastric cancers are associated with strong familial clustering and can be
Hereditary diffuse gastric cancer
To date, the major gene implicated in hereditary diffuse gastric cancer syndrome (HDGC) is CDH1, located on chromosome 16q22.1. Inherited germline mutations in this gene are associated with 1%–3% of all gastric cancers and account for approximately one third of familial associated gastric cancers of the diffuse or signet ring type [9]. The International Gastric Cancer Linkage Consortium (IGCLC) developed diagnostic criteria for HDGC that includes at least two cases of diffuse gastric cancer in
HDGC screening and management
Early-stage diffuse gastric cancer is diagnostically elusive: symptoms are generally nonspecific and do not appear until the disease is advanced. While endoscopy is considered to be the best screening method, it regularly fails to identify diffuse gastric carcinoma as these lesions spread submucosally as single cells or clustered islands of cells. Unfortunately, to date no tests (procedures or biomarkers) have been shown to be clinically useful for screening and/or early detection in
Other hereditary cancer susceptibility syndromes associated with gastric cancer risk
Peutz-Jeghers syndrome (PJS) is a rare disorder with an estimated 1/25,000 to 1/250,000 incidence rate. PJS is characterized by both hamartomatous and adenomatous polyposis throughout the gastrointestinal tract, and confers a high predisposition to gastrointestinal malignancies (Table 1). It may be clinically diagnosed based on histologically confirmed hamartomatous polyps and two of the following: positive family history, hyperpigmentation of the digits and mucosa of the external genitalia,
Challenges in stratifying risk and concluding remarks
With the inclusion of CDH1 on many multi-gene cancer panels due to its high-penetrance breast cancer risk, we are now identifying unexpected CDH1 pathogenic mutations in individuals without a personal or family history of HDGC-related cancers. Currently, there are no defined guidelines for how to interpret a CDH1 mutation in the midst of personal and family history lacking diffuse gastric cancer or lobular breast cancer. Given the poor diagnostic yield of screening endoscopy, it is a major
Conflicts of interest
None.
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