Hereditary Diffuse Gastric Cancer (HDGC): Symptoms, Causes, Treatment

What are the symptoms of hereditary diffuse gastric cancer?

Hereditary diffuse gastric cancer (HDGC) is a genetic condition associated with an increased risk of developing diffuse-type stomach cancer. Symptoms can vary, but they typically include:

1. Indigestion: Persistent discomfort or pain in the upper abdomen, often mistaken for regular indigestion.
2. Early satiety: Feeling full after eating small amounts of food.
3. Unexplained weight loss: Losing weight without trying.
4. Nausea and vomiting: Especially if these symptoms persist or worsen over time.
5. Difficulty swallowing: Also known as dysphagia, which may indicate more advanced disease.
6. Abdominal pain: Persistent pain or discomfort in the abdomen.
7. Bleeding: Blood in vomit or stools, which can be a sign of advanced gastric cancer.

It’s important to note that these symptoms can be caused by various conditions, and having them does not necessarily mean a person has HDGC. However, individuals with a family history of diffuse gastric cancer or those known to carry mutations like CDH1 gene mutations (associated with HDGC) should be vigilant and undergo regular screening and genetic counseling. Early detection and intervention can significantly improve outcomes.

What are the causes of hereditary diffuse gastric cancer?

Hereditary diffuse gastric cancer (HDGC) is primarily caused by mutations in the CDH1 gene. This gene encodes for E-cadherin, a protein that plays a crucial role in cell adhesion. Mutations in the CDH1 gene can lead to a loss or alteration of E-cadherin function, which in turn contributes to an increased risk of developing diffuse-type stomach cancer.

Key points about the causes of HDGC include:

1. CDH1 Gene Mutations: The majority of HDGC cases are associated with inherited mutations in the CDH1 gene. These mutations are inherited in an autosomal dominant pattern, meaning that a person who inherits one copy of the mutated gene from a parent has a 50% chance of passing it on to their children.
2. Loss of E-cadherin Function: Mutations in the CDH1 gene can result in a loss of normal E-cadherin function. E-cadherin is essential for cell-cell adhesion and maintaining tissue structure. Loss of its function can lead to increased cell proliferation, reduced cell adhesion, and ultimately contribute to the development of cancer.
3. Genetic Predisposition: Individuals with a family history of diffuse gastric cancer are more likely to carry CDH1 gene mutations. Genetic testing can identify these mutations in individuals with a family history of HDGC or those who meet specific clinical criteria.
4. Environmental and Other Factors: While CDH1 gene mutations are the primary cause of HDGC, environmental factors such as diet, smoking, and infection with Helicobacter pylori may also influence the risk of developing gastric cancer. However, these factors are generally more associated with non-hereditary forms of gastric cancer.

Early identification of CDH1 gene mutations through genetic testing and counseling can help individuals and their families make informed decisions about screening, surveillance, and preventive measures to reduce the risk of developing HDGC-related cancers.

How is the diagnosis of hereditary diffuse gastric cancer made?

Diagnosing hereditary diffuse gastric cancer (HDGC) involves several steps, especially when there is a suspected genetic predisposition due to family history or known genetic mutations like CDH1. Here’s how the diagnosis is typically approached:

1. Family History Assessment: A detailed family history is essential to identify any patterns of gastric cancer or other related cancers (such as lobular breast cancer) within the family. This helps determine if there is a hereditary predisposition.
2. Genetic Testing: Genetic testing for mutations in the CDH1 gene is crucial for individuals suspected to have HDGC based on family history or clinical criteria. This involves a blood or saliva test to analyze the DNA for specific mutations associated with HDGC.
3. Endoscopic Evaluation: Individuals identified through genetic testing or high-risk family history may undergo endoscopic evaluation (upper gastrointestinal endoscopy). During this procedure, a flexible tube with a camera is passed through the mouth and into the stomach to visually inspect the lining of the stomach for any abnormalities or signs of cancerous changes.
4. Biopsy: During endoscopy, tissue samples (biopsies) may be taken from suspicious areas of the stomach lining. These samples are examined under a microscope by a pathologist to look for signs of gastric cancer or pre-cancerous changes.
5. Imaging Studies: In some cases, imaging studies such as CT scans or MRI may be performed to evaluate the extent of disease or to check for signs of metastasis (spread) in individuals diagnosed with HDGC.
6. Clinical Criteria: Apart from genetic testing, clinical criteria based on family history and personal medical history are also used to determine the likelihood of HDGC. These criteria help guide decisions regarding genetic testing and surveillance strategies.
7. Multidisciplinary Approach: The diagnosis and management of HDGC often involve a multidisciplinary team including gastroenterologists, genetic counselors, oncologists, and surgeons. This approach ensures comprehensive evaluation, genetic counseling, and appropriate management based on individual risk profiles.

Early detection through genetic testing and surveillance can significantly improve outcomes by allowing for timely interventions such as enhanced surveillance or risk-reducing surgeries in high-risk individuals. Regular follow-up and adherence to screening protocols are critical for those at risk for HDGC.

What is the treatment for hereditary diffuse gastric cancer?

The treatment for hereditary diffuse gastric cancer (HDGC) typically involves a combination of surveillance, risk-reduction strategies, and sometimes surgical intervention. The approach may vary based on individual risk factors, genetic mutations (such as CDH1), and the presence or progression of cancer. Here are the main components of treatment for HDGC:

1. Surveillance and Screening: Regular surveillance is crucial for individuals with a known genetic predisposition to HDGC. This includes periodic endoscopic evaluations (upper gastrointestinal endoscopy) to monitor for any signs of early-stage cancer or pre-cancerous changes in the stomach lining.
2. Prophylactic Gastrectomy: For individuals with a confirmed CDH1 mutation and a significant family history of gastric cancer, prophylactic total gastrectomy (removal of the entire stomach) may be recommended as a preventive measure. This surgery aims to reduce the risk of developing diffuse gastric cancer. The decision to undergo prophylactic gastrectomy is complex and requires careful consideration of individual risk factors, age, and personal preferences.
3. Pathological Evaluation: If a prophylactic gastrectomy is performed, the removed stomach tissue is examined pathologically to detect any early-stage cancer or pre-cancerous lesions that may require additional treatment or monitoring.
4. Adjuvant Therapy: In cases where gastric cancer is detected, treatment may involve chemotherapy, radiation therapy, or a combination of both, depending on the stage and extent of the cancer. Adjuvant therapy aims to reduce the risk of cancer recurrence after surgery.
5. Clinical Trials: Participation in clinical trials may be considered for individuals with HDGC to explore new treatment approaches, targeted therapies, or novel diagnostic methods.
6. Genetic Counseling and Family Screening: Genetic counseling is essential for individuals and families affected by HDGC to understand genetic risks, options for testing, and implications for family members. Family members who are at risk may undergo genetic testing and appropriate surveillance based on their genetic status.
7. Lifestyle and Supportive Care: Supportive care measures, including nutritional support and management of symptoms, are important components of comprehensive care for individuals undergoing treatment for HDGC.

The management of HDGC requires a personalized approach tailored to each individual’s genetic profile, family history, and clinical presentation. It involves close collaboration among healthcare providers specializing in gastroenterology, genetics, oncology, and surgical oncology to optimize outcomes and quality of life for affected individuals and their families.