| Hereditary diffuse gastric cancer | |
|---|---|
| Other names | HDGC |
 | |
| Diagram demonstrating the result of a total gastrectomy, the most common prophylactic treatment of HDGC. In the procedure the esophagus is directly connected to the small intestine. | |
| Specialty | Oncology,Gastroenterology |
| Complications | Lobularbreast cancer |
| Usual onset | 38 years of age (median) |
| Causes | Mutation of theE-cadherin gene (CDH1) |
| Risk factors | Stomach cancer |
| Treatment | Totalgastrectomy |
| Frequency | 1-3% of gastric cancers |
Hereditary diffuse gastric cancer (HDGC) is aninherited genetic syndrome most often caused by an inactivating mutation in theE-cadherin gene (CDH1) located onchromosome 16.[1] Individuals who inherit an inactive copy of theCDH1 gene are at significantly elevated risk for developingstomach cancer. For this reason, individuals with these mutations will often elect to undergo prophylacticgastrectomy, or a complete removal of the stomach to prevent this cancer.[1] Mutations inCDH1 are also associated with high risk oflobular breast cancers, and may be associated with a mildly elevated risk of colon cancer.[2]
The most common form of stomach cancer associated withCDH1 mutations is diffuse-type adenocarcinoma. An estimated 70% of males and 56% of females who inherit an inactivatingCDH1 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.[3] The median age of gastric cancer diagnosis in individuals with aCDH1 inactivating mutation is 38 years of age, but cases have been reported as young as 14 years of age.[4]
Hereditary diffuse gastric cancer is inherited as anautosomal dominant mutation of the E-cadherin gene (CDH1), which is located on chromosome 16q22.1. Because the condition only conveys significantly increased risk of cancer, it can be described as havingincomplete penetrance.[3]
The autosomal dominant nature of the mutations implies that inheriting just one mutated copy of theCDH1 gene is sufficient to induce a disease state. However, in order for cancer to arise in these individuals, bothcopies of theCDH1 gene must be inactive. Therefore, HDGC is developed through aloss of heterozygosity, in which the one unmutated copy of theCDH1 gene undergoes mutation or inactivation in some cells during the lifetime of the individual. This explains why the majority of individuals withCDH1 mutations will develop clinical apparent cancer, but some do not.[3]
The gene mutated in HDGC,CDH1, codes for the E-cadherin protein. This protein serves numerous functions in cell-to-cell interactions, as well as intracellular signaling. Development of cancerous cells and malignancy may be related to several of these functions. One major function includes cell-cell adhesion facilitated by E-cadherin binding. Loss of this function may lead todedifferentiation of cells and/or unregulated cell growth and replication. Another major function includes binding and sequestering of thebeta-catenin transcription factor, keeping it inactive. Loss of this function may lead to overactivity of the transcription factor.[5]
Genetic counseling and testing forCDH1 mutations are advised for families meeting the following criteria:[6]
AlthoughCDH1 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, but possible associated genes includeCTNNA1,BRCA2,STK11,SDHB,PRSS1,ATM,MSR1, andPALB2.[5]
Surgical removal of the stomach (gastrectomy) 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. However, individuals discoveringCDH1 mutations after the age of 40 may still be considered for gastrectomy. The physical and psychological health of each individual should be considered in determining the optimal time to perform this operation. Younger individuals may wish to delay this procedure, and are often monitored withendoscopies and randombiopsies. In addition, all individuals testing positive receive an initial endoscopy, at which any lesion is biopsied, as gastric cancer frequently begins without symptoms.[5]
Females withCDH1 mutations also have an elevated risk of lobular breast carcinoma. Frequent screening for breast cancer with bothmammography andbreast MRI is common and recommended for these individuals.[7]
The risk of colon cancer in those withCDH1 mutations is still unclear. Due to the mild risk that may be associated, individuals often receive screeningcolonoscopies at age 40, five years prior to the recommendation in the general population.[3]
The median age at diagnosis is 38 years. An estimated 1-3% of gastric cancers are associated with hereditary cancer syndromes. HDGC is the most common hereditary cancer syndrome of the stomach.[4]
HDGC was originally discovered through studies ofMaori families in New Zealand that were noted to have increased incidences of gastric cancer.[2] Detection ofCDH1 mutations causing HDGC is highest in countries with low incidences of gastric cancer, such as the United States and Canada. Conversely, detection ofCDH1 mutations is lowest in countries with high rates of gastric cancer, such as Portugal, Italy, and Japan.[8] For this reason, some have pushed for increased genetic screening in countries with high rates of gastric cancer, as the rates may mask the incidence ofCDH1 mutations.[9]