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We do not yet know exactly what causes most esophageal cancers. However, there are certain risk factors that make getting esophageal cancer more likely. (See Esophageal Cancer Risk Factors.)

Scientists believe that some risk factors, such as the use of tobacco or alcohol, may cause esophageal cancer by damaging the DNA in cells that line the inside of the esophagus. Long-term irritation of the lining of the esophagus, as happens with reflux, Barrett’s esophagus, achalasia, Plummer-Vinson syndrome, or scarring from swallowing lye, may also lead to DNA damage.

Cancer is caused by changes in the DNA inside our cells. DNA is the chemical in each of our cells that makes up our genes – which control how our cells function. We usually look like our parents because they are the source of our DNA. But DNA affects more than how we look.

Some genes control when cells grow, divide into new cells, and die.

• Certain genes that help cells grow, divide, and stay alive are called oncogenes.
• Genes that help keep cell division under control or cause cells to die at the right time are called tumor suppressor genes.

Cancers can be caused by DNA mutations (changes) that turn on oncogenes or turn off tumor suppressor genes. This leads to cells growing out of control. Changes in many different genes are usually needed to cause esophageal cancer.

The DNA of esophageal cancer cells often shows changes in many different genes. However, it’s not clear if there are specific gene changes that can be found in all (or most) esophageal cancers.

For more about how genes changes can lead to cancer, see Genes and Cancer.

Inherited gene ?mutations

Some DNA mutations can be passed on in families and are found in all of a person's cells. These are called inherited mutations. A very small number of esophageal cancers are caused by inherited gene mutations. Some of these DNA changes and their effects on the growth of cells have been discovered and are being studied further. For example:

• Tylosis with esophageal cancer (sometimes called Howel-Evans syndrome) is caused by inherited changes in the RHBDF2 gene. People with changes in this gene are more at risk of developing the squamous cell type of esophageal cancer.
• Bloom syndrome is caused by changes in the BLM gene. The BLM gene is important in making a protein that stabilizes DNA as a cell divides. Without this protein, the DNA can become damaged, which can lead to cancer. People with Bloom syndrome are at a higher risk of developing squamous cell esophageal cancer, as well as AML, ALL, and other cancers involving the lymph system. For this syndrome, an abnormal gene is usually inherited from both parents, not just one.
• Fanconi anemia is a rare syndrome that involves abnormal genes that cannot repair damaged DNA. Mutations (changes) in certain FANC genes can lead to a higher risk of many cancers including AML and squamous cell cancer of the esophagus.   
• Familial Barrett’s Esophagus is a syndrome that includes families with Barrett’s esophagus and adenocarcinoma of the esophagus and GE junction. The exact genes associated with this are still being studied.

Special genetic tests can find some of the gene mutations linked to these inherited syndromes. If you have a family history of esophageal cancer or other symptoms linked to these syndromes, you may want to ask your doctor about genetic counseling and genetic testing. The American Cancer Society recommends discussing genetic testing with a qualified cancer genetics professional before any genetic testing is done. For more on this, see Understanding Genetic Testing for Cancer and What Happens during Genetic Testing for Cancer?

Acquired gene mutations

Most gene mutations that lead to cancer are ?acquired mutations. They happen during a person’s lifetime and are not passed on to their children.

In most cases of esophageal cancer, the DNA mutations that lead to cancer are acquired during a person’s life rather than having been inherited.

Certain risk factors, such as tobacco and alcohol use, probably play a role in causing these acquired mutations, but so far it’s not known what causes most of them.