Hereditary diffuse gastric and lobular breast cancer syndrome (CDH1)

CDH1 is a gene that carries the instructions for making E-cadherin, a protein that holds neighboring cells together. When a change in this gene is inherited, it causes a condition that raises the lifetime risk of two specific cancers: diffuse gastric cancer, a type of stomach cancer, and lobular breast cancer. The condition is called hereditary diffuse gastric cancer, and because breast cancer is such a prominent part of it, some centers now use the longer name hereditary diffuse gastric and lobular breast cancer syndrome.

This article is different from most in this section. Nearly all biomarker tests answer the question “which drug is likely to work for this cancer?” A CDH1 result answers a different question: “what is my lifetime risk, what can be done to reduce it, and what does this mean for my family?” There is currently no drug that targets CDH1. What the result changes is risk management, and sometimes major preventive surgery.

Many people reading this have not been diagnosed with cancer at all. They have learned they carry an inherited CDH1 change because a relative was tested, or because genetic testing was offered after a family member developed stomach cancer at a young age. This article is written for both groups: people with a cancer diagnosis and people making decisions about a risk that has not yet become a disease.

What the test looks for

The CDH1 gene makes E-cadherin, a protein that sits on the surface of cells and acts as the glue holding them to their neighbors. This is what allows the lining of the stomach, the breast, and other organs to hold together as an organized sheet.

CDH1 is a tumor suppressor gene, meaning its normal job includes restraining uncontrolled cell growth. Everyone carries two copies of the gene. A person with an inherited CDH1 condition is born with one working copy and one that does not work. That single working copy is enough for normal life, but if it is damaged in any individual cell during a lifetime, that cell loses E-cadherin entirely, detaches from its neighbors, and can begin to grow as an isolated cell. This explains the characteristic behavior of the cancers this gene causes: instead of forming a lump, the cancer cells scatter individually through the tissue.

Two quite different tests involve CDH1, and confusing them is common:

Germline genetic testing — A blood or saliva sample is tested for an inherited change in the CDH1 gene. This tests the DNA a person was born with, present in every cell of the body, and it is the test that identifies the hereditary syndrome.
E-cadherin immunohistochemistry — A stain applied to tumor tissue to show whether the E-cadherin protein is present in the cancer cells. This is a test on the tumor, not on inherited DNA, and it is used to help classify the tumor rather than to identify a hereditary condition.

CDH1 by tumor type: diagnostic and treatment implications

Diffuse gastric cancer, including signet ring cell carcinoma

Diffuse gastric cancer is a form of stomach cancer in which the cells do not stick together and spread individually through the stomach wall. When most of the cells contain a droplet of mucus that pushes the nucleus to one side, it is called signet ring cell carcinoma. Loss of E-cadherin is the direct biological cause of this scattered growth pattern, and almost all of these tumors have lost the protein one way or another.

Most of that loss is not inherited. In sporadic diffuse gastric cancer, the CDH1 gene is damaged within the tumor itself, and the person’s other cells are unaffected. An inherited CDH1 change accounts for only a small share of stomach cancers overall, in the range of 1% to 3%, though the proportion is far higher among families with several relatives affected by diffuse gastric cancer at young ages.

CDH1 status does not currently change drug treatment for someone who already has diffuse gastric cancer. Treatment follows the usual pathway of surgery and chemotherapy, guided by the biomarkers used in stomach cancer generally, including HER2, PD-L1, mismatch repair, and claudin 18.2. What a positive germline result does change is the plan for the rest of the stomach if any remains, the person’s breast surveillance, and testing for blood relatives.

Germline testing is offered at the time of diagnosis rather than reserved for advanced disease, because the results affect surgical planning and family members immediately.

Lobular breast cancer

Invasive lobular carcinoma is the second most common type of breast cancer, accounting for roughly one in ten cases. Like diffuse gastric cancer, it grows as single files and small clusters of cells that infiltrate the breast rather than forming a discrete lump, which is why it can be difficult to feel and difficult to see on a mammogram.

Here, E-cadherin testing has a genuinely diagnostic role. Loss of E-cadherin on immunohistochemistry is the standard way pathologists distinguish lobular carcinoma from the more common ductal type, and the large majority of invasive lobular carcinomas show that loss. If your breast pathology report mentions E-cadherin, this is almost certainly why, and on its own it says nothing about whether the change is inherited.

An inherited CDH1 change is found in a small minority of women with lobular breast cancer. The likelihood is higher when the cancer occurs at a young age, when it affects both breasts, or when there is a family history of lobular breast cancer or diffuse gastric cancer. Recognizing this matters because guidelines now advise considering CDH1 testing in women with early-onset or bilateral lobular breast cancer even when no one in the family has had stomach cancer. Some families carry a CDH1 change and develop only lobular breast cancer; this pattern is described as hereditary lobular breast cancer.

As with the stomach, a CDH1 result does not currently select a drug. Treatment follows standard breast cancer pathways guided by hormone receptor and HER2 status. What changes is surveillance of the stomach, decisions about the opposite breast, and testing for relatives.

Other cancers

The two cancers above are the established components of this syndrome. Colorectal cancer, particularly the signet ring cell type, has been reported in some families, but the evidence is not strong enough to establish it as part of the syndrome, and current guidelines do not recommend extra colon screening beyond what is advised for the general population or for the family history.

Separately, some CDH1 changes are associated with cleft lip and cleft palate. A family history of clefting alongside diffuse gastric cancer is an additional reason to consider testing.

Why the test is done

Most biomarker tests described on this site are done to match a cancer to a drug, and several of them work regardless of where the cancer started, an approach known as tumor-agnostic treatment. CDH1 testing works differently. It is done to find out whether a cancer, or a family pattern of cancer, has an inherited cause, so that risk to the person and to their relatives can be managed before another cancer develops.

The reason this matters so much for CDH1 in particular is that diffuse gastric cancer is difficult to detect early. It grows beneath a lining that looks normal, produces few symptoms until it is advanced, and is often missed on endoscopy and even on biopsy. Waiting for symptoms is not an effective strategy. Identifying carriers before they develop cancer is currently the most effective tool available.

Who should be tested

Genetic testing for CDH1 is generally offered when a personal or family history fits one of the recognized patterns. In broad terms, testing is considered when:

Diffuse gastric cancer occurs at a young age — Generally under about 50, even without any family history.
Two or more relatives have had gastric cancer — With at least one confirmed as diffuse type.
Diffuse gastric cancer and lobular breast cancer occur in the same person or the same family — Either combination, at any age in some criteria.
Lobular breast cancer occurs before about age 55, or in both breasts — Even with no stomach cancer in the family.
Diffuse gastric cancer occurs alongside a personal or family history of cleft lip or palate.

Only diffuse gastric cancer and lobular breast cancer count toward them. The more common intestinal-type stomach cancers and ductal breast cancers in a family do not, even though they are cancers of the same organs. If you are gathering family history for a genetics appointment, the specific type recorded on each relative’s pathology report is what matters, and obtaining those reports is often the most useful thing a family can do.

How the test is performed

Germline testing is done on a blood sample or, less commonly, a saliva sample. The DNA is analyzed by next generation sequencing, which reads the sequence of the gene letter by letter, together with a separate method that detects larger deletions where whole sections of the gene are missing. Both are needed, because a meaningful minority of CDH1 changes are large deletions that sequencing alone can miss.

CDH1 is almost always tested as part of a panel covering many hereditary cancer genes at once, rather than on its own. This means the result may mention genes you were not expecting, and it is one reason testing is done alongside genetic counseling rather than as a standalone laboratory test.

E-cadherin immunohistochemistry, by contrast, is performed by the pathologist on the tumor tissue already removed at biopsy or surgery, and requires nothing further from the patient.

How results are reported

Germline genetic test results are reported in categories that describe how confident the laboratory is that a change affects the function of the gene:

Pathogenic or likely pathogenic variant — A change known, or strongly expected, to stop the gene working. This is a positive result and is what the management described below is based on.
Variant of uncertain significance — A change was found, but there is not yet enough evidence to say whether it affects the gene. This is not a positive result and should not be used to justify preventive surgery. Most such variants are eventually reclassified as harmless. Laboratories reassess them as evidence accumulates, which is why keeping in contact with the genetics service matters.
Benign or likely benign variant — A harmless difference in the gene. Everyone carries many of these, and they are usually not reported.
No variant identified — No change was found in the genes tested. What this means depends on the family, as explained below.

What the result means

A pathogenic or likely pathogenic CDH1 variant confirms the hereditary syndrome. It means an increased lifetime risk of diffuse gastric cancer and, for women, of lobular breast cancer, and it means each of the person’s children, siblings, and parents has a 50% chance of carrying the same change.

A negative result needs careful interpretation and means different things in different situations. If a specific CDH1 variant has already been identified in the family and you tested negative for that exact variant, this is a true negative: you did not inherit it, your risk returns to that of the general population, and your children cannot inherit it from you. If no variant has been identified in anyone in the family, a negative result is less conclusive. It rules out the genes tested but does not rule out an inherited cause, since some families have a clear hereditary pattern with no identifiable gene change. These families are described as having an HDGC-like syndrome and are usually offered surveillance based on family history alone.

A variant of uncertain significance is managed as though the result were negative, with surveillance guided by family history rather than by the variant. Waiting without an answer is difficult. The genetics service can tell you what would need to happen for the classification to change, and how you would be informed if it does.

Germline versus somatic CDH1 changes

This distinction causes more confusion than any other aspect of CDH1, and getting it right matters.

A germline change is present in the DNA a person was born with, is in every cell of the body, and can be passed to children. This is the inherited syndrome.

A somatic change arises within a tumor during a person’s lifetime. It is present only in the cancer cells, cannot be inherited by children, and carries no implications for relatives. Somatic CDH1 changes are common in diffuse gastric cancer and in lobular breast cancer, and they are one of the main reasons those cancers grow the way they do.

Comprehensive tumor sequencing panels test the cancer, not inherited DNA. If such a panel reports a CDH1 mutation, it does not by itself mean the change is inherited. Confirming that requires a separate germline test on blood or saliva. If a tumor panel has reported a CDH1 mutation and no one has discussed germline testing with you, you can ask whether it would be appropriate, because a proportion of these do turn out to be inherited.

Cancer risk for people with an inherited CDH1 change

The risk figures for this syndrome have changed substantially over the past decade, and anyone searching online will encounter both the old and the new numbers. Understanding why they differ is important, because the difference is large.

The earliest estimates came from families identified precisely because they had many affected members across several generations. Those studies suggested a lifetime risk of stomach cancer by age 80 of roughly 70% for men and 56% for women. As genetic testing became cheaper and was offered more widely, carriers began to be identified in families with far less dramatic histories, and the estimates fell. Current figures from larger and less selected groups put the lifetime risk of stomach cancer in the range of 25% to 42%, and the most recent large study of over 200 families estimated the risk of advanced stomach cancer by age 80 at around 10% for men and 7% for women.

Those newer figures come with two important qualifications. First, they count advanced cancers. When small early cancers found incidentally at preventive surgery are included, the figures roughly double. Second, and most importantly, risk depends heavily on family history. In the same study, carriers with three or more first-degree relatives affected by stomach cancer had an estimated risk of around 38%, far higher than carriers without that history. A single number does not describe every carrier, and a genetics service can give an estimate that reflects your own family.

For women, the lifetime risk of lobular breast cancer has been more consistent across studies, estimated in the range of 37% to 55% by age 80. The average age at diagnosis is around 50, later than the average age for stomach cancer in this syndrome, which falls in the late thirties to forties in the older studies and around 50 in more recent ones.

These numbers point in two directions at once. The risk is high enough to justify serious preventive measures, and low enough that most carriers in families without a strong history will never develop stomach cancer. Both of those things are true, and holding them together is the central difficulty of decision-making in this condition.

Managing the risk of stomach cancer

Two approaches are available, and current guidance treats the choice between them as a decision to be made with the care team rather than an automatic recommendation.

Preventive removal of the stomach, called prophylactic total gastrectomy, eliminates the risk of stomach cancer almost entirely. It has long been the standard recommendation for carriers, usually offered in early adulthood. Almost every stomach removed this way contains small early cancers that were invisible on endoscopy, which is the strongest argument in its favor. It is also a major, irreversible operation with permanent effects: eating changes permanently to small frequent meals, weight loss is usual, vitamin B12 injections are needed for life, and most people have some digestive symptoms a year afterward.

Endoscopic surveillance involves regular endoscopy at a center experienced in this condition, with many biopsies taken from set locations according to a defined protocol. It is now considered a reasonable option for carriers who wish to postpone or decline surgery, particularly those from families without a strong history of stomach cancer. Its limitation is real and should be understood: the early cancer foci in this condition usually sit beneath a normal-looking lining, so endoscopy can miss them. Balanced against that, recent long-term studies have found that progression to advanced cancer while under active surveillance is uncommon.

Where surveillance finds signet ring cell carcinoma on biopsy, that finding usually moves the discussion decisively toward surgery.

Managing the risk of breast cancer

For women carrying a CDH1 change, annual breast MRI is generally recommended beginning around age 30, often alongside mammography. MRI matters particularly here because lobular breast cancer is one of the harder types to see on a mammogram, growing in strands rather than forming a distinct mass.

Preventive removal of both breasts is not routinely recommended but is considered on an individual basis, taking into account family history, other risk factors, and personal preference. Because the lifetime breast cancer risk in this syndrome is comparable to that in some other hereditary breast cancer conditions, the discussion resembles the one families have around BRCA1 and BRCA2, though the type of breast cancer involved is different.

Men who carry a CDH1 change are not considered to have a meaningfully increased risk of breast cancer, and no breast surveillance is recommended for them.

Testing family members

This syndrome is inherited in an autosomal dominant pattern, which means a single altered copy of the gene is enough to cause it, and each child, sibling, and parent of a carrier has a 50% chance of carrying the same change. It affects men and women, and it can be inherited from either parent.

Once a specific variant has been identified in one family member, relatives can be tested for that exact change, a process called cascade testing. This is simpler, cheaper, and far more definitive than the original test, because the laboratory knows precisely what to look for and the result is a clear yes or no.

Testing is usually offered to adult relatives. For children, testing is generally deferred, commonly until the late teens or early twenties, because nothing about management changes before then and preventive surgery is not considered until adulthood. Families differ in how they approach this, and genetics services are experienced at helping work through the timing and at supporting the difficult conversations that follow a positive result.

A related gene, CTNNA1, causes a similar though apparently lower risk of diffuse gastric cancer in a small number of families. Carriers of a CTNNA1 change are generally offered surveillance rather than preventive surgery, reflecting how much less is known about it.

What happens next

What follows a CDH1 result depends on the situation it was found in.

For someone with a new diagnosis of diffuse gastric cancer, cancer treatment proceeds as planned; the germline result does not delay or alter it. What it adds is a decision about the remaining stomach if only part was removed, the start of breast surveillance for women, and a referral for family testing.

For a woman with lobular breast cancer, the result adds stomach risk management to an existing breast cancer plan, and may influence decisions about the opposite breast.

For an unaffected carrier, the work is entirely about prevention: a discussion of preventive gastrectomy against endoscopic surveillance, breast MRI from around age 30 for women, and cascade testing for relatives. Referral to a center with specific experience in this condition is usual, since both the endoscopic surveillance protocol and the surgery are done best by teams who do them often. Support from a dietitian is part of care for anyone who proceeds to gastrectomy, and psychological support is commonly offered, since these decisions are made young and affect the rest of a person’s life.

Questions to ask your doctor

Was my CDH1 result from a germline test on blood or saliva, or from a test on my tumor?
Was the variant classified as pathogenic, likely pathogenic, or of uncertain significance?
Did the testing look for large deletions as well as sequence changes?
Based on my own family history, what is my estimated lifetime risk of stomach cancer?
What are the arguments for and against preventive removal of my stomach in my particular situation?
If I choose surveillance instead, how often would I have endoscopy, and does this center follow a defined biopsy protocol?
What would life be like after a total gastrectomy, and who would support me with eating and nutrition?
When should I start breast MRI, and will I have mammograms as well?
Which of my relatives should be offered testing, and how is that arranged?
At what age should my children be tested?
If my result was a variant of uncertain significance, how will I find out if the classification changes?
Should I be seen at a center that specializes in this condition?
Is there support available for making these decisions, including counseling or a patient group?