What Connects Cleft Lip and CDH1 Stomach Cancer?

It can seem confusing when a doctor or genetic counselor asks about facial birth defects during a discussion about stomach cancer. The connection between a cleft lip or palate and stomach cancer lies in a single genetic mutation that affects how the cells in our bodies stick to one another ^[1].

The Role of “Cellular Glue”

To understand this connection, it helps to look at a specific gene called CDH1 (cadherin 1) ^[2]. Genes are essentially instruction manuals for our bodies. The CDH1 gene provides the instructions for making a crucial protein known as E-cadherin ^[3][4].

Think of E-cadherin as a heavy-duty cellular glue. It sits on the surface of our cells and binds them tightly to their neighboring cells ^[1][2][5]. This cellular glue is responsible for maintaining the structure and strength of various tissues in the body, ensuring that cells stay exactly where they belong ^[3][6].

When a person has a mutation (a typo in the instruction manual) in their CDH1 gene, their body either does not produce enough E-cadherin or produces a defective version of it ^[7][1]. This loss of cellular glue has distinct effects depending on where and when it happens in the body ^[8][1].

How Missing Glue Affects Fetal Development

When a fetus is developing during pregnancy, various tissues must migrate and fuse together perfectly to form the face ^[2][5]. E-cadherin is essential for this delicate process. The cellular glue ensures that the tissues making up the upper lip and the roof of the mouth (the palate) successfully attach to one another ^[5][9].

If a baby inherits a mutated CDH1 gene, the lack of functioning E-cadherin can prevent these facial tissues from fusing completely ^[2][9]. This failure to connect results in an opening or split in the upper lip or the roof of the mouth—a condition known as a cleft lip or cleft palate ^[2][10]. Because this happens during fetal development, the cleft lip or palate is present at birth.

How Missing Glue Leads to Diffuse Cancers

That exact same cellular glue is also heavily relied upon by the cells lining the stomach and, in women, the milk-producing lobules of the breast ^[1][11]. In a healthy body, E-cadherin keeps these cells tightly packed together in an organized, protective layer ^[12][13].

When the CDH1 mutation causes a loss of this glue, the cells lose their grip on one another ^[7]. Without that structural connection, individual cells can break away from their designated tissue, grow uncontrollably, and invade the surrounding area ^[7][14].

In the stomach, this process causes Hereditary Diffuse Gastric Cancer (HDGC), a rare and aggressive form of cancer where tumors grow in tiny, loose clusters throughout the stomach wall rather than forming a single, solid lump ^[2][11][7]. Because it grows diffusely, it is notoriously difficult to spot during a standard endoscopy. In the breasts, this same loss of glue allows cells to break away and form lobular breast cancer ^[2][11].

Why Genetic Counselors Look for This Clue

Because an altered CDH1 gene can cause both a cleft lip at birth and stomach or breast cancer later in life, the presence of a cleft lip in your family tree acts as a critical red flag for geneticists ^[2][11]. Identifying this visible, developmental clue helps them piece together a family’s silent genetic risk for cancer, allowing for earlier screening and life-saving interventions ^[15][16].

However, it is vital to keep two things in perspective:

• Most people with CDH1 mutations do not have a cleft lip, nor do they have a family history of one ^[2]. If no one in your family has had a cleft lip, it does not mean your cancer risk or diagnosis is incorrect.
• A cleft lip does not mean the cancer will be worse. If a family member does have a cleft lip, it simply points to the same underlying genetic mutation. It does not mean their cancer risk is more severe or aggressive than someone with the mutation who does not have a cleft lip ^[17][2].

If you have been diagnosed with a CDH1 mutation and recognize this pattern of cleft lip or palate in your extended family, it is important to inform your relatives. A cousin with a history of a cleft palate might not know they need to be screened for stomach or breast cancer ^[15].