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PubMed This is a summary of 21 peer-reviewed journal articles Updated
Medical Genetics · Hereditary Diffuse Gastric Cancer

Genetic Testing & Hereditary Risk

At a Glance

Hereditary Diffuse Gastric Cancer (HDGC) is often caused by an inherited CDH1 gene mutation, which significantly increases the lifetime risk of stomach and lobular breast cancers. Families with this mutation manage their risk through preventive total stomach removal or intensive endoscopic surveillance.

While most cases of diffuse gastric cancer happen by chance, a significant number are caused by an inherited genetic “instruction error.” This condition is known as Hereditary Diffuse Gastric Cancer (HDGC) [1]. For families carrying this genetic trait, the risk of developing stomach cancer is much higher than in the general population, but knowing your status allows you to take proactive, life-saving steps [2].

The CDH1 Gene: The Body’s Architectural Blueprint

The most common cause of HDGC is a mutation in the CDH1 gene [3]. This gene is responsible for producing E-cadherin, a protein that acts like “velcro” to keep your stomach cells stuck together in an organized way [4].

When the CDH1 gene is mutated, the body cannot make enough of this velcro. Without it, stomach cells can become disorganized and begin to grow and move abnormally, potentially leading to diffuse gastric cancer [5][6]. Because this is an autosomal dominant condition, if one parent has the mutation, each child has a 50% chance of inheriting it [1].

Who Should Be Tested? (The 2020 IGCLC Criteria)

In 2020, the International Gastric Cancer Linkage Consortium (IGCLC) updated the guidelines for who should undergo genetic testing for CDH1 [1]. You should consider testing if your family meets any of these criteria:

  • Two or more cases of gastric cancer in the family (at any age), with at least one being confirmed diffuse-type [1].
  • A single person diagnosed with diffuse gastric cancer before age 50 [1].
  • A personal or family history of both diffuse gastric cancer and lobular breast cancer [1].
  • Individuals with a family history of cleft lip or cleft palate in combination with diffuse gastric cancer [2].

Note for parents: Testing for children is typically delayed until they reach young adulthood (often 18 or older), depending on the earliest age of onset of cancer in the family. Your genetic counselor will help you map out the safest timeline for pediatric and young adult testing [1][7].

Understanding Your Risk

Carrying a CDH1 mutation does not mean you have cancer, but it does mean you have a higher lifetime risk of developing it. It is very important to understand the nuance here:

  • Incidental Carriers: Recent population studies of people who were tested without a strong family history suggest a lifetime risk of roughly 7% to 10% [8].
  • Families with HDGC: However, for patients who meet the IGCLC clinical criteria with a strong family history, the lifetime risk is much higher—historically estimated between 30% and 70% [9][10]. When cancer does occur in these patients, it is often aggressive [7].
  • Invasive Lobular Breast Cancer (ILBC): Female mutation carriers have an estimated 37% to 40% lifetime risk of developing this specific type of breast cancer [8][10].

The Difficult Choice: Surgery vs. Surveillance

If you test positive for a pathogenic CDH1 mutation and have a strong family history, you face a major decision about how to manage your risk.

1. Prophylactic Total Gastrectomy (PTG)

This is the surgical removal of the entire stomach before cancer is even found [11]. Removing a healthy organ before cancer develops carries a profound psychological toll, but for high-risk families, it provides unmatched peace of mind.

  • Why it’s recommended: Diffuse gastric cancer is “stealthy” and often hides under the surface where biopsies can’t find it until it is advanced [12][13]. Surgery is currently the only way to eliminate the risk [7].
  • The Reality: Living without a stomach is a major life change. It requires permanent changes to how you eat (smaller, more frequent meals) and lifelong vitamin supplements [14][15].

2. Endoscopic Surveillance (The Cambridge Protocol)

For those who are not ready for surgery, an intensive screening program called the Cambridge Protocol is an option [16].

  • The Process: This involves an endoscopy every 6 to 12 months, where a doctor takes a minimum of 30 leaf-like biopsies from specific areas of the stomach [17][18].
  • The Risk: Even with 30+ biopsies, doctors can still miss tiny “foci” (small spots) of cancer because they grow underneath the surface lining [17][19]. Surveillance is generally seen as a “delaying tactic” rather than a permanent solution for those at very high risk [13].

Other Genes (CTNNA1 and CTNND1)

While CDH1 is the most famous, researchers have found that mutations in other genes, like CTNNA1 or CTNND1, can also lead to HDGC [1][20]. If your family meets the criteria but your CDH1 test is negative, your doctor may recommend a broader “multi-gene panel” to look for these other variants [21].

Common questions in this guide

How do I know if I should be tested for a CDH1 mutation?
Testing is recommended if you have a family history of two or more gastric cancer cases, a personal diagnosis of diffuse gastric cancer before age 50, or a family history combining diffuse gastric cancer with lobular breast cancer or cleft lip and palate.
What is the CDH1 gene and how does it relate to stomach cancer?
The CDH1 gene produces a protein called E-cadherin, which acts like velcro to keep your stomach cells organized and stuck together. When this gene is mutated, the body lacks this protective 'velcro', allowing stomach cells to grow and spread abnormally.
What is a prophylactic total gastrectomy?
Prophylactic total gastrectomy is a preventive surgery to remove the entire stomach before cancer develops. Because diffuse gastric cancer grows underneath the stomach lining where it is difficult to detect early, this surgery is currently the only way to entirely eliminate the risk for gene carriers.
What is the Cambridge Protocol for stomach cancer surveillance?
If you decline or delay surgery, your doctor may recommend the Cambridge Protocol. This intensive screening involves an endoscopy every 6 to 12 months, during which a doctor takes a minimum of 30 biopsies from specific areas of your stomach to look for hidden cancer cells.
Does a CDH1 mutation increase my risk of breast cancer?
Yes. Female carriers of a CDH1 gene mutation have an estimated 37% to 40% lifetime risk of developing a specific type of breast cancer known as invasive lobular breast cancer.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Do I meet the 2020 IGCLC criteria for genetic testing based on my family history?
  2. 2.If I have a CDH1 mutation, what is your recommended age range for considering a prophylactic total gastrectomy?
  3. 3.Can you explain the difference between a 'pathogenic' mutation and a 'variant of uncertain significance' (VUS) in my results?
  4. 4.If I choose surveillance over surgery, how many biopsies will be taken during the 'Cambridge protocol' endoscopy, and how often must I have it?
  5. 5.What is the specific risk of lobular breast cancer for me or my female relatives, and what is the screening protocol?
  6. 6.At what age should my children be tested for the CDH1 mutation?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

Related questions

Can I Choose Endoscopy Over Stomach Removal for HDGC?Did H. pylori Cause My Stomach Cancer?Does CDH1 Mutation Increase Lobular Breast Cancer Risk?

References

References (21)
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    Hereditary Diffuse Gastric Cancer-Update Based on the Current Consort Recommendations.

    Treese C, Siegmund B, Daum S

    Current oncology (Toronto, Ont.) 2022; (29(4)):2454-2460 doi:10.3390/curroncol29040199.

    PMID: 35448173
  2. 2

    First report of a Mexican family with mutation in the CDH1 gene.

    Martínez Valenzuela C, Castelán-Maldonado EE, Carvajal-Zarrabal O, Calderón-Garcidueñas AL

    Molecular genetics & genomic medicine 2020; (8(11)):e1208 doi:10.1002/mgg3.1208.

    PMID: 32886433
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    Inherited CDH1 pathogenic variant: is there a place for surveillance of esophageal gastric inlet patch?

    Leclercq P, Jadot V, Bours V, et al.

    Therapeutic advances in gastroenterology 2020; (13()):1756284820916399 doi:10.1177/1756284820916399.

    PMID: 32523621
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    The Identification of Large Rearrangements Involving Intron 2 of the CDH1 Gene in BRCA1/2 Negative and Breast Cancer Susceptibility.

    Ben Aissa-Haj J, Pinheiro H, Cornelis F, et al.

    Genes 2022; (13(12)) doi:10.3390/genes13122213.

    PMID: 36553480
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    The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction.

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    Communications biology 2023; (6(1)):1132 doi:10.1038/s42003-023-05482-x.

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    E-cadherin-deficient cells have synthetic lethal vulnerabilities in plasma membrane organisation, dynamics and function.

    Godwin TD, Kelly ST, Brew TP, et al.

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    Total Gastrectomy for Hereditary Diffuse Gastric Cancer at a Single Center: Postsurgical Outcomes in 41 Patients.

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    Germline CDH1 Variants and Lifetime Cancer Risk.

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    Early genetic counseling and detection of CDH1 mutation in asymptomatic carriers improves survival in hereditary diffuse gastric cancer.

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    Hereditary diffuse gastric cancer: the evolution of a cancer syndrome.

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    Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer.

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    Significance of E-cadherin Gene Mutations in Patients With Hereditary Diffuse Gastric Cancer Syndrome: A Systematic Review.

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    Laparoscopic Prophylactic Total Gastrectomy for Hereditary Diffuse Gastric Cancer in CDH1 Mutation Carriers.

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    The Psychological Impact of Prophylactic Total Gastrectomy in Patients Who Are High Risk for Hereditary Diffuse Gastric Cancer: A Review of the Literature.

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This page provides educational information about Hereditary Diffuse Gastric Cancer and genetic testing. It is not intended to replace professional medical advice. Always consult a genetic counselor or oncologist regarding testing criteria and risk management for your family.

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