The CDH1 gene, formally known as Cadherin-1, provides the genetic blueprint for a protein called E-cadherin. This protein is fundamental to the architecture and communication within epithelial tissues, which line the body’s internal and external surfaces. A functioning CDH1 gene is necessary for maintaining tissue structure and regulating cell growth, acting as a tumor suppressor. When a germline mutation is present in this gene, the fundamental cell-to-cell communication is disrupted, leading to a significantly increased lifetime risk of developing specific, aggressive forms of cancer.
The Normal Function of E-Cadherin
The E-cadherin protein is a calcium-dependent cell adhesion molecule that acts as a physical anchor between neighboring cells. It is the core component of adherens junctions, belt-like structures that encircle epithelial cells. These junctions function as cellular glue, holding cells tightly together to maintain the integrity and barrier function of tissues like the stomach lining. The protein connects with E-cadherin molecules on adjacent cells and links internally to the actin cytoskeleton. This structured adhesion coordinates cellular activities and suppresses uncontrolled cell division, classifying it as a tumor suppressor.
CDH1 Mutation and Hereditary Cancer Risk
A pathogenic germline mutation in the CDH1 gene typically results in a non-functional E-cadherin protein, which means the cell loses its ability to adhere properly to its neighbors. This initial inherited mutation represents the “first hit” in the two-hit hypothesis of tumor suppression, leaving the remaining healthy copy vulnerable. Subsequent loss or inactivation of the second copy triggers the complete loss of cell adhesion.
The primary disease linked to this genetic change is Hereditary Diffuse Gastric Cancer (HDGC) syndrome. This form of stomach cancer is characterized by its insidious growth pattern, where poorly cohesive cancer cells, known as signet ring cells, infiltrate the stomach wall individually rather than forming a visible mass. This diffuse growth beneath the mucosal surface is what makes HDGC notoriously difficult to detect during standard endoscopy procedures.
The lifetime risk of developing diffuse gastric cancer for a CDH1 mutation carrier is substantial. Current guidelines from the National Comprehensive Cancer Network (NCCN) estimate the risk to be in the range of 25 to 42 percent for men and 14 to 33 percent for women. The cancer typically presents at a younger age than sporadic gastric cancer, with a median age of diagnosis around 38 years.
Women with a CDH1 mutation face an additional risk of developing Hereditary Lobular Breast Cancer (HLBC). This specific type of breast cancer is also marked by a loss of cell-to-cell cohesion, reflecting the underlying E-cadherin deficiency. The estimated lifetime risk of developing lobular breast cancer for female carriers ranges from 37 to 55 percent.
Genetic Testing and Inheritance Patterns
The inheritance of a pathogenic CDH1 mutation follows an Autosomal Dominant pattern. This means that a person needs to inherit only one copy of the altered gene from either parent to be considered a carrier. Each child of a carrier has a 50 percent chance of inheriting the mutation, underscoring the necessity of genetic testing and cascade screening within affected families.
Genetic counseling is a mandatory first step for any individual considering CDH1 testing. The counselor evaluates a person’s three-generation family history for patterns of diffuse gastric cancer, lobular breast cancer, or associated features like cleft lip or palate. Testing is recommended for individuals who meet specific criteria, such as a diagnosis of diffuse gastric cancer before age 40, or a family history combining DGC and LBC diagnoses.
The genetic test is straightforward, usually performed on a sample of blood or saliva. The analysis determines the presence of a pathogenic variant within the CDH1 gene. Pre-test counseling is vital for discussing the potential emotional, financial, and medical implications of a positive result.
Clinical Management Following a Positive Result
For individuals who test positive for a pathogenic CDH1 mutation, the primary and most definitive risk-reduction strategy is a Prophylactic Total Gastrectomy (PTG). This procedure involves the surgical removal of the entire stomach to eliminate the organ at risk for developing diffuse cancer. PTG is the consensus recommendation because the diffuse, deeply infiltrating nature of HDGC makes it virtually impossible to reliably detect early lesions through endoscopic surveillance.
The rationale for this surgical approach is rooted in the high mortality rate of HDGC once it becomes invasive. Guidelines recommend that PTG be performed in early adulthood, typically between the ages of 20 and 30. The surgery is complex and should be carried out at a high-volume center with a multidisciplinary team experienced in managing these patients.
For carriers who choose to delay or decline PTG, intensive endoscopic surveillance is the only alternative, though it is considered unreliable. This involves an annual upper endoscopy with multiple random biopsies taken from specific areas of the stomach. The goal is to detect signet ring cell foci before they progress beyond the mucosal layer.
Female CDH1 carriers must manage the elevated risk of lobular breast cancer. Annual surveillance with a breast Magnetic Resonance Imaging (MRI) scan is recommended, typically starting at age 30. This is often performed alternately with a mammogram every six months. A prophylactic bilateral mastectomy may also be considered as a risk-reducing option for women with additional risk factors.