Hereditary Diffuse Gastric Cancer

Hereditary diffuse gastric cancer, or HDGC, is an inherited condition. It raises the risk of a specific stomach cancer, called diffuse-type gastric cancer. It also raises the risk of a specific breast cancer, called lobular breast cancer. HDGC comes from a change, or pathogenic variant, in a gene. Most often this is CDH1. Sometimes it is CTNNA1 instead. It passes down in a pattern doctors call autosomal dominant. That means a child of someone with the variant has a 50% chance of inheriting it.

CDH1 makes a protein called E-cadherin. E-cadherin normally helps cells stick together properly. When CDH1 does not work right, cells can lose this normal structure. That allows abnormal cells to grow and spread more easily. CDH1 variants show up in roughly 30 to 40% of families that meet the clinical criteria for HDGC.

CTNNA1 makes a related protein, called catenin alpha-1. It also helps cells stick to each other. CTNNA1 variants explain a smaller share of HDGC families. Not all genetic testing labs test for this gene. Ask your genetic counselor whether it was included in your panel.

For CDH1 carriers, the lifetime risk of diffuse-type gastric cancer by age 80 is substantial. It runs roughly 37 to 70% for men, and 25 to 83% for women. Estimates vary between studies and family groups. The cancer typically develops between the late 30s and 80s. It has been reported as early as age 14, though that is rare.

Women with a CDH1 variant also carry real breast cancer risk. Their lifetime risk of lobular breast cancer runs 39 to 55%. The average age at diagnosis is the late 40s. Most breast cancers in women with a CDH1 variant are this lobular type, rather than the more common ductal type.

For CTNNA1 carriers, one European registry reported gastric cancer risk up to 57%. Onset ranged from the early 20s to early 70s. Breast cancer risk for CTNNA1 carriers is not yet well defined.

The cancer linked to HDGC starts small. It forms scattered, microscopic clusters of abnormal cells called signet ring cells. These clusters are extremely hard to see. Doctors can perform endoscopy and take targeted biopsies of anything that looks unusual — ulcers, redness, bumps, polyps, or scars. Even then, those samples find the abnormal clusters less than 10% of the time. Taking many random biopsies helps more. In one surveillance study, thirty or more random biopsies were taken from each person. But even this cannot rule out hidden disease. Early lesions typically look completely normal to the eye. That is why endoscopy alone, without surgery, cannot fully replace other risk-reducing options for a CDH1 carrier.

Because surveillance has these limits, many current guidelines describe a specific standard for confirmed CDH1 carriers. That standard is risk-reducing total gastrectomy: surgically removing the entire stomach before cancer becomes advanced. In one series of people who chose this surgery, the results were striking. In 85.4% of the removed stomachs, cancer cells were already present — even though nothing had shown up on prior testing. In 72.6%, the signet ring cell pattern specifically was found. In 12.8%, the tumors had already grown invasively.

This surgery is significant. People lose 15 to 20% of their body weight on average. They need lifelong adjustments to how and what they eat. The risk of dying from the surgery itself is estimated at 3 to 6%. Most people report a good quality of life several years out. But nutritional deficiencies, leaks where the intestine is reconnected, and digestive symptoms are real risks. Discuss them beforehand.

Endoscopic surveillance instead of surgery is an increasingly accepted choice for people who decline gastrectomy. Newer, more thorough biopsy protocols support this option. Still, this is a decision to make with a specialist team, not a default.

Ask whether your genetic variant has been formally classified as disease-causing. Ask whether your family history fits the HDGC pattern. Ask about referral to a multidisciplinary center experienced with HDGC — this condition benefits from a team that has managed it before. Ask what surveillance would look like if you delay or decline surgery, and what its real limits are. Ask how breast cancer risk will be monitored separately. Ask when family members should consider their own genetic counseling and testing.

• NCI PDQ — Hereditary Diffuse Gastric Cancer (Health Professional Version)