Hereditary cancer syndromes and stomach cancer

This page was reviewed under our medical and editorial policy by

Eric Fowler, MS, LCGC, Manager, Clinical Genetics, Western Region & Licensed Certified Genetic Counselor

This page was reviewed on September 21, 2022.

Stomach cancer, also called gastric cancer, can have many causes. Some cases are caused by changes to genes, called genetic mutations, but these are relatively rare. Some genetic mutations are passed down through families (inherited). Others simply develop over time. These changes are called acquired mutations. Cancer-related genetic mutations may affect:

  • Tumor suppressor genes: These genes regulate cell growth and division. When they mutate, cells can grow out of control, potentially leading to a tumor. These changes are not usually passed down in families.
  • DNA repair genes: When DNA repair genes change and don’t work like they should, the body isn’t able to fix other genetic mutations. Changes to DNA repair genes are either acquired or inherited.
  • Oncogenes: These genes can turn a healthy cell into a cancerous one when it mutates. These changes are less likely to be passed down in families.

While rare, there are a few very specific harmful genetic mutations that can build up over time and that are linked to stomach cancer.

Hereditary diffuse gastric cancer

Hereditary diffuse gastric cancer (HDGC) is an inherited condition that carries an increased risk of stomach cancer. It’s called “diffuse'' because it tends to affect several areas of your stomach as opposed to just one. To make a diagnosis, your care team will consider factors like your cancer history, your age at diagnosis and your family cancer history.

If your care team suspects HDGC, they can test to see whether you have a mutation in the CDH1 (also called E-cadherin) gene, a tumor suppressor gene that typically regulates cell growth and division. When the CDH1 gene mutates and doesn’t work like it should, cells may grow and divide uncontrollably, leading to a tumor. Like other cancers, it can spread to other areas of the body. About 30 to 50 percent of people with HDGC have this genetic mutation, according to a study published in Cancer Management and Research. Researchers are still working to identify other gene mutations that may lead to HDGC. So, you may be diagnosed with HDGC even if tests don’t show that you have a CDH1 mutation.

The CDH1 gene is also associated with lobular breast cancers, so your care team may ask about your personal or family history of breast cancer too.

Gastric adenocarcinoma and proximal polyposis of the stomach

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an inherited condition that causes many polyps to form in the lining of the stomach. These stomach polyps may be benign, meaning they don’t lead to cancer, but they may become cancerous.

Some people with GAPPS experience stomach pain before they’re diagnosed, but typically people with GAPPS don’t notice any symptoms. Your care team may discover it during imaging tests conducted for other reasons.

Researchers discovered GAPPS relatively recently, so they’re still learning about how it runs in families. A gene called the APC gene, or adenomatous polyposis coli gene, is associated with GAPPS. A blood test is used to determine the presence of mutations in this gene. But GAPPS affects people differently, even people in the same family. Treatment for GAPPS may include a watch-and-wait approach to monitor for whether polyps develop, or it may involve surgery to remove a tumor that’s already been diagnosed or that’s spread.

Lynch syndrome

Lynch syndrome (once called hereditary non-polyposis colorectal cancer) is a genetic condition that causes a higher risk of several cancers, including stomach cancer. People with Lynch syndrome have a mutation in DNA repair genes, which are genes that help the body fix acquired genetic mutations. Researchers have identified several genes affected by Lynch syndrome, including MLH1, MSH2, MSH6, PMS2 and EPCAM. They may discover more genes that are affected in the future.

Diagnosing Lynch syndrome starts with your doctor’s review of your cancer history, age at diagnosis and family cancer history. The diagnosis may be confirmed with a blood test.

People with Lynch syndrome have a 1 percent to 13 percent chance of developing stomach cancer in their lifetime, according to the American Society of Clinical Oncology (ASCO).

Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an inherited condition. People who have the condition develop tens to hundreds of colon polyps, often at an early age. While FAP most notably leads to an increased risk of colorectal cancer, people with FAP also have an increased chance of developing other types of cancer, including stomach cancer.

Mutations in the APC gene cause FAP, which may trigger the development of colon polyps that may in turn lead to cancer. Your care team can test for changes in the genes affected by FAP with a blood test.

 While 60 percent to 70 percent of people with FAP have a family history of the condition, about 30 percent to 40 percent of people develop the mutation in APC on their own.

People with FAP have a 5 percent chance of developing stomach cancer, according to ASCO.

Li-Fraumeni syndrome

Li-Fraumeni syndrome is an inherited condition that leads to an increased risk of several kinds of cancer. Breast cancer, brain cancer, leukemia, adrenal cancer and sarcomas are associated with the syndrome, but it’s also linked to an increased risk of stomach cancer, among others.

People with Li-Fraumeni syndrome can develop cancer at a young age and may have more than one cancer in their lifetime. They may also be more at risk to develop cancer from radiation therapy.

The gene mutation that leads to Li-Fraumeni syndrome happens in the TP53 gene, a tumor suppressor gene. About 70 percent of families with LFS will have this mutation, according to ASCO. The mutation causes TP53 to stop making a protein that helps keep damaged cells from growing and dividing. Cancer may develop when the damaged cells keep growing and dividing. If your care team suspects you may have Li-Fraumeni syndrome, they can test to see if you have a TP53 gene mutation.

Researchers are still working to better understand the connection between Li-Fraumeni syndrome and all types of cancers, including stomach cancer.

Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is an inherited condition that causes a certain type of polyp to grow in the digestive tract. Called hamartomatous polyps, they are often benign, but may lead to GI blockages or bleeding. People with Peutz-Jeghers syndrome have an increased risk of stomach cancer as well as breast cancer, colorectal cancer, pancreatic cancer, lung cancer and cancers of the reproductive system.

Signs of Peutz-Jeghers syndrome include dark brown or dark blue freckles around the mouth, hands and feet. Those with the syndrome often experience symptoms—such as bleeding or blockage from a hamartomatous polyp—at a young age, typically around 10 years old.

The STK11 gene (a tumor-suppressor gene also called LKB1) is most commonly associated with Peutz-Jeghers syndrome. It makes an enzyme that helps control organized cell growth. When it doesn’t work like it should, cell growth can become disorganized and out of control, possibly leading to cancer. While 75 percent of people with PJS have a family history of it, about 25 percent of people develop the mutation in STK11 on their own, according to ASCO.

If your care team suspects you have Peutz-Jeghers syndrome, they can test for a mutation in your STK11 gene to confirm it, though not everyone with Peutz-Jeghers syndrome have the mutation.

While PJS itself is rare, people with it have a 30 percent chance of developing stomach cancer, according to ASCO.

BRCA genes

People with mutations in their BRCA1 and BRCA2 genes are more likely to develop breast cancer, ovarian cancer and some other cancers. These genes are DNA repair genes. When they don’t work like they should, they can’t repair damaged DNA, leading to abnormal cell growth and possibly cancer.

While stomach cancer isn’t considered one of the main cancers linked to a BRCA gene mutation, some research studies have found a possible association between BRCA and stomach cancer. There are still many unknowns, including how strongly a BRCA mutation may increase the risk of stomach cancer. While some treatments for breast cancer, ovarian cancer and pancreatic treatments target these gene mutations, this approach isn’t currently a treatment option for stomach cancers.

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