Gastric cancer is the fourth most common cancer worldwide. It occurs when the cells in the stomach or intestine begin to grow abnormally into a malignant tumor. In about 10% of cases, multiple family members are affected with gastric cancer, leading to the suspicion that they may have hereditary gastric cancer. Hereditary gastric cancer (HGC) occurs when a person has a genetic change (mutation) that causes their cells to be more likely to become cancerous. The mutation can be passed through generations in a family. Women and men with HGC have a higher risk of developing gastric cancer, and sometimes other cancers or health problems, as well.

Our genes, or DNA, tell the cells in our body how to work correctly. Cancer-risk genes are genes with roles that can impact whether a cell will begin to grow uncontrollably into cancer. We have two copies of every gene, one from our mother and the other from our father. Hereditary gastric cancer is most commonly inherited in an autosomal dominant way. For dominant conditions, having only one copy of a gene mutation is enough to cause symptoms. In the case of HGC, having one mutation leads to an increased risk for cancer. If a person has a mutation in one gene for HGC, there is a 50% risk that each of their children will inherit this mutation. Siblings, parents, and potentially other relatives could also have the mutation. Importantly, not everyone who has a mutation in a cancer-risk gene will develop cancer, but their chances are higher. While rare, it is possible for a person to have a mutation for a dominant condition that is absent from both of their parents. In this situation, the mutation arose early before they were conceived or born. This is called de novo inheritance. Even after de novo inheritance, if a person has a mutation in one gene for hereditary gastric cancer, each of their children will have a 50% risk to inherit the mutation. Less commonly, HGC can be inherited in an autosomal recessive way. For recessive conditions, both copies of a person’s gene must have a mutation before they will have an increased risk for cancer. Typically, an individual with a recessive condition will have inherited one mutation from their mom and one from their dad. Because the mom and dad have another copy of the gene without the mutation, they will usually not show symptoms. For these parents, there is a 25% risk with each pregnancy that the child will inherit both the mom’s and the dad’s mutations, and therefore, will have the recessive condition. Similarly, for a person with recessive HGC to have an affected child, their partner would also need to have a mutation in the same cancer-risk gene. A genetic counselor can help with partner testing in this situation.

Hereditary gastric cancer syndromes are conditions that impact multiple areas of an individual’s body in addition to increasing their risk for gastric cancer. There are many different syndromes that increase the risk for gastric cancer. Several examples are listed below. Of note, all are inherited in an autosomal dominant way.

Hereditary Diffuse Gastric Cancer (HGDC)

Hereditary Diffuse Gastric Cancer is caused by a mutation in the gene CDH1. HGDC accounts for 1-3% of all gastric cancers. The majority occur before the age of 40 years. By age 80, 80% of men and women will develop HGC. Women are also at an increased risk for breast cancer. At present, the only known method for prevention of gastric cancer in people with a CDH1 mutation is surgery to remove the stomach (gastrectomy).

Lynch Syndrome

Lynch syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is caused by a mutation in a gene whose job is to repair the DNA damage that normally occurs as cells grow and divide. People with Lynch syndrome have up to a 13% risk to develop gastric cancer, and an 80% risk to develop colon cancer by age 70 years. Individuals with Lynch syndrome are also at an increased risk for many other types of cancers, such as endometrial, urinary tract, brain, skin and prostate. Mutations in five different genes can cause Lynch syndrome.

APC Associated Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS)

 GAPPS is one of the conditions caused by the cancer-risk gene APC. People with GAPPS develop more than 100 benign growths (polyps) in their stomach. Because these polyps can become cancerous, the chance someone with GAPPS will eventually develop gastric cancer is high. GAPPS was first described in 2012, and therefore, less information is known about GAPPS than many of the other HGC syndromes. Additional research is needed to determine the exact risk for gastric cancer and the best approaches for prevention.

POSITIVE +

 A positive result means that a genetic mutation causing an increased risk for gastric cancer was identified. Your risk for other cancers or health conditions may also be increased, depending on the gene involved. Your doctor can use this information to customize your care, which could include increased screening, preventative surgery, medication, and other steps. A positive result is also important for your family. Your parents, siblings, and children could have as high as a 50% chance to also have the mutation. As a result, sharing your genetic testing results with your relatives is important for their health.

NEGATIVE –

A negative result indicates that a genetic mutation was not identified. A negative result may indicate that there is not a cancer-risk gene mutation in you or your family. However, it can also mean that the gene increasing risk in you or your family was not included on the ordered test. Your doctor can use a negative result to continue your treatment and screening based on your clinical and family history, or they may consider another type of genetic testing.

 

VARIANT OF UNCERTAIN CLINICAL SIGNIFICANCE (VUS)?

The third possible test result is called a Variant of Uncertain Clinical Significance. A gene variant is a genetic difference that could be disease-causing (mutation) or could be a normal finding (benign). More research is needed to determine whether the variant is important or not, and it should usually be treated as a negative result until more information is available.

Stomach cancer, also called gastric cancer, begins when healthy cells in the stomach become abnormal and grow out of control. A tumor can be cancerous or benign. A cancerous tumor is malignant, meaning it can grow and spread to other parts of the body. A benign tumor means the tumor can grow but will not spread. Cancer can begin in any part of the stomach. It can also spread to nearby lymph nodes and other parts of the body, such as the liver, bones, lungs, and a woman’s ovaries.

  • Stomach cancer occurs most commonly in people older than 55.
  • Men are twice as likely to develop stomach cancer as women.
  • A common bacterium called Helicobacter pylori, also called H. pylori, causes stomach inflammation and ulcers. It is also considered one of the main causes of stomach cancer.
  • Family history/genetics. People who have a parent, child, or sibling who has had stomach cancer have a higher risk of the disease. In addition, certain inherited genetic disorders, such as hereditary diffuse gastric cancer, Lynch syndrome, hereditary breast and ovarian cancer (HBOC), and familial adenomatous polyposis (FAP)may increase the risk of stomach cancer.
  • Race/ethnicity.Stomach cancer is more common in black, Hispanic, and Asian people than in white people.
  • Eating a diet high in salt has been linked to an increased risk of stomach cancer.
  • Previous surgery or health conditions. People who have had stomach surgery, pernicious anemia, or achlorhydria have a higher risk of stomach cancer. Pernicious anemia is a severe decrease in red blood cells caused when the stomach is not able to properly absorb vitamin B12.
  • Occupational exposure
  • Tobacco and alcohol
  • Obesity

  • The incidence of stomach cancer varies in different parts of the world. Although stomach cancer has decreased in the United States by 1.5% annually over the last decade, it is still common in other countries and one of the top causes of cancer deaths worldwide.

    If the cancer is diagnosed and treated before it has spread outside the stomach, the 5-year survival rate is 69%. If the cancer has spread to surrounding tissues or organs and/or the regional lymph nodes, the 5-year survival rate is 31%. If the cancer has spread to a distant part of the body, the 5-year survival rate is 5%.