Hereditary diffuse gastric cancer

An estimated 1-3% of gastric cancers are associated with hereditary cancer syndromes. 

HDGC is the most common hereditary cancer syndrome of the stomach. 

Hereditary diffuse gastric cancer (HDGC) is an inherited genetic syndrome most often caused by an inactivating mutation in the E-cadherin gene (CDH1) located on chromosome 16.

HDGC is inherited in an autosomal dominant fashion.

Germline pathogenic variants  in CDH1 are the most common genetic predisposition implicated in hereditary diffuse gastric cancer, and are found in 25 to 50% of families fulfilling the hereditary diffuse gastric cancer criteria.

Individuals who inherit an inactive copy of the CDH1 gene are at significantly elevated risk for developing stomach cancer. 

Patients with these mutations will often elect to undergo prophylactic gastrectomy, or a complete removal of the stomach to prevent this cancer.

Mutations in CDH1 are also associated with high risk of lobular breast cancers, and may be associated with a mildly elevated risk of colon cancer.

Studies suggest 60 to 75% of patients with a pathogenic CDH1 variant will probably not develop life-threatening metastatic diffuse type gastric cancer.

The most common form of stomach cancer associated with CDH1 mutations is diffuse type adenocarcinoma. 

More than 120 inherited mutations in the CDH1 gene have been found to cause a familial cancer disorder called hereditary diffuse gastric cancer.

In the absence of the CDH1 pathogenic variant, the incidence of diffuse gastric cancer is approximately 10 times lower.

An estimated 70% of males and 56% of females who inherit an inactivating CDH1 mutation will develop this form of cancer by age 80. 

Female patients are also estimated to have a 42% lifetime risk of developing lobular breast cancer.

The median age of gastric cancer diagnosis in individuals with a CDH1 inactivating mutation is 38 years of age.

Gastric cancer diagnosis in individuals with a CDH1  cases have been reported as young as 14 years of age.

Hereditary diffuse gastric cancer is inherited as an autosomal dominant mutation of the E-cadherin gene (CDH1), which is located on chromosome 16q22.1. 

It is described as having incomplete penetrance.

The autosomal dominant nature of the mutations implies that inheriting just one mutated copy of the CDH1 gene is sufficient to induce a disease state. 

However, for cancer to arise in these individuals, both copies of the CDH1 gene must be inactive. 

HDGC is developed through a loss of heterozygosity, in which the one unmutated copy of the CDH1 gene undergoes mutation or inactivation in some cells during the lifetime of the individual. 

This explains why the majority of individuals with CDH1 mutations will develop clinical apparent cancer, but some do not. 

The gene mutated in HDGC, CDH1, codes for the E-Cadherin protein, which serves numerous functions in cell to cell interactions, as well as intracellular signaling. 

Development of malignancy may be related to several of these functions: cell-cell adhesion facilitated by E-Cadherin binding. 

The mutations that cause HDGC often lead to the production of an abnormally short, nonfunctional version of the E-cadherin protein or lead to the production of a protein with an altered structure. 

The loss of normal E-cadherin prevents it from acting as a tumor suppressor, contributing to the uncontrollable growth and division of cells. 

A lack of E-cadherin impairs cell adhesion, increasing the likelihood that cancer cells will invade the stomach wall and small clusters of cancer cells will metastasize into nearby tissues. 

In combination, the inherited and somatic mutations lead to a lack of functional E-cadherin and result in HDGC.

Loss of this function may lead to dedifferentiation of cells and/or unregulated cell growth and replication. 

Another major function includes binding and sequestering of the beta-catenin transcription factor, keeping it inactive. 

Loss of this function may lead to overactivity of the transcription.


Families with two or more documented cases of diffuse gastric cancer among first or second degree relatives, with at least one case diagnosed before age 50.

Families with two or more documented cases of lobular breast cancers among first or second degree relatives, with or without diffuse gastric cancer in a first or second degree relative.

Any individual diagnosed with diffuse gastric cancer before 35 years of age from a low incidence population.

Although CDH1 is by far the most common gene associated with HDGC, around 11% of cases arise in individuals who are negative for mutations in this gene. 

No other gene has been proven to cause HDGC.


Surgical removal of the stomach is typically recommended for people after 20 years of age, and before 40 years of age in order to prevent development of diffuse gastric adenocarcinoma. 

Individuals discovering CDH1 mutations after the age of 40 may still be considered for gastrectomy. 

Females with CDH1 mutations also have an elevated risk of lobular breast carcinoma. 

Frequent screening for breast cancer with both mammography and breast MRI is common and recommended for these individuals.

The median age at diagnosis is 38 years. 

Detection of CDH1 mutations causing HDGC is highest in countries with low incidences of gastric cancer, such as the United States and Canada. 

Conversely, detection of CDH1 mutations is lowest in countries with high rates of gastric cancer, such as Porugal, Italy, and Japan.

Random biopsies, enhance the early detection of signet cell ring  carcinoma, and are complementary to targeted biopsies in surveillance of hereditary diffuse gastric cancer.

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