Hereditary diffuse gastric cancer

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. Individuals who inherit an inactive copy of the CDH1 gene are at significantly elevated risk for developing stomach cancer. For this reason, individuals with these mutations will often elect to under go 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. 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. Individuals who inherit an inactive copy of the CDH1 gene are at significantly elevated risk for developing stomach cancer. For this reason, individuals with these mutations will often elect to under go 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. The most common form of stomach cancer associated with CDH1 mutations is diffuse type adenocarcinoma. 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, but 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. Because the condition only conveys significantly increased risk of cancer, it can be 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, in order for cancer to arise in these individuals, both copies of the CDH1 gene must be inactive. Therefore, 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. 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 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 factor. Genetic counseling and testing for CDH1 mutations are advised for families meeting the following criteria: 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, but possible associated genes include CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2. 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 discovering CDH1 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 with endoscopies and random biopsies. In addition, all individuals testing positive receive an initial endoscopy, at which any lesion is biopsied, as gastric cancer frequently begins without symptoms. 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.