CDH1 Mutation and Hereditary Diffuse Gastric Cancer (HDGC)

Hereditary diffuse gastric cancer, often abbreviated as HDCG is a rare inherited form of stomach cancer. As the name suggests, the cancer is diffuse and there is no solid tumour. HDGC may affect multiple areas of the stomach which makes the detection and treatment of this type of cancer very tricky. The most common mutation resulting in HDCG is the germline mutation in the CDH1 gene. The gene codes for E-cadherin (commonly known as epithelial cadherin) which is a transmembrane glycoprotein with crucial functions in maintaining cell-cell adhesion. Globally, gastric cancer is the third leading cause of cancer-related mortality. HDGC contributes to roughly 20% of gastric cancer cases. The condition is also known as E-cadherin-associated hereditary cancer, familial diffuse gastric cancer, and hereditary diffuse gastric adenocarcinoma.

Genetic mutations of E-cadherin in Hereditary Diffuse Gastric Cancer

The CDH1 gene located in the short arm of chromosome 16 and comprises 16 exons. The gene transcribes into a 4.5 Kb mRNA which codes for E-cadherin. They participate in a plethora of cellular functions which include cell-cell adhesion, maintenance of cell polarity, maintenance of cell, and cell survival in a calcium-dependent manner. It also modulates the Wnt signalling pathway, Rho GTPases, and NF-kβ pathway. The glycoprotein E-cadherin comprises three structural domains:  an extracellular domain with five tandemly repeating domains which are exclusively present in cadherins, a transmembrane domain and a cytoplasmic domain. Missense mutations in the extracellular domain result in the production of a short and non-functional E-cadherin with alterations in the calcium-binding sites or making the protein more susceptible to proteolytic degradation. This abnormal protein shows impaired interaction with EGFR (epidermal growth factor receptor). E-cadherin normally acts as a tumour repressor and its inactivation impairs the signalling pathways regulated by it, resulting in tumour progression. Several reports have studied somatic mutations of CDH1 in colorectal cancer, breast cancer, prostate cancer, and ovarian cancer.

Inheritance of Hereditary Diffuse Gastric Cancer

HDGC follows an autosomal dominant pattern of inheritance. This means that mutation occurs in one copy of the gene and off-springs of parents with the mutation have a 50% chance of inheriting the mutation. In the majority of the cases, a person with HDGC will have at least one parent with the mutated CDH1 gene. However, 60-70% of HDGC affected individuals do not harbour any identified CDH1 mutation but mutations in other cancer-causing genes may result in HDGC.

Symptoms of Hereditary Diffuse Gastric Cancer

The common symptoms of HDGC are

  • Stomach pain
  • Nausea
  • Vomiting
  • Dysphagia (difficulty in swallowing)
  • Decrease appetite
  • Weight loss

The specialized symptoms of HDGC are

  • Liver enlargement
  • Jaundice (yellowing of skin and eyes)
  • Ascites (fluid built up in the abdominal cavity), etc.

Diagnosis of HDGC

Diagnosis of HDGC is hard as the normal imaging tests which detect other common types of cancer cannot detect HDGC. As a result, HDGC cases are detected only at the later stages where cancer spreads. Most cases of HDGC are diagnosed before the age of 40.

  1. Genetic testing: People with a history of HDGC running in their families can undergo genetic testing to detect the presence of mutations in CDH1 gene or any other mutation which may cause HDGC.
  2. Imaging: If HDGC has spread to other body parts, it can be diagnosed by imaging. Techniques like ultrasound, CT scan and PET scan can be used. Imaging results can reveal information about the size and sites of the tumour.
  3. Biopsy: In a biopsy test, a small amount of tissue is removed using a needle and is checked microscopically. The examination will allow identifying if the tumour is HDGC or not.

Treatment of HDGC

The most common treatment for HDGC is the surgical removal of a part of the stomach or entire stomach to reduce cancer from spreading further. In cases where surgical removal of the affected areas is not possible, chemotherapy can be used to treat HDGC.


  5. Liu X, Chu KM, 2014. E-cadherin and Gastric Cancer: Causes, consequences and applications. Biomed Res Int. DOI: 10.1155/2014/637308
  6. Pharoah PD, Guilford P, Caldas C, 2001. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from HDGC families. Gastroenterology. DOI: 10.1053/gast.2001.29611