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We don’t know what causes each case of lung cancer. But we do know many of the risk factors for these cancers (see Lung Cancer Risk Factors) and how some of them cause normal cells to become cancer cells.

How smoking leads to lung cancer

Smoking tobacco is by far the leading cause of lung cancer. About 80% of lung cancer deaths are caused by smoking, and many others are caused by exposure to secondhand smoke.

Smoking is clearly the strongest risk factor for lung cancer, but it often interacts with other factors. People who smoke and are exposed to other known risk factors, such as radon and asbestos, are at an even higher risk. Not everyone who smokes gets lung cancer, so other factors like genetics probably play a role as well (see below).

Causes in people who don’t smoke

Not all people who get lung cancer smoke. Many people with lung cancer formerly smoked, but many others never smoked at all.

Lung cancer in people who don’t smoke can be caused by exposure to radon, secondhand smoke, air pollution, or other factors. Workplace exposures to asbestos, diesel exhaust, or other chemicals can also cause lung cancers in some people who don’t smoke.

Some people with no known risk factors may develop lung cancer. This may be due to random events that don’t have an outside cause, but it also may be due to factors that we don’t yet know about.

Lung cancers in people who don’t smoke are often different from those that occur in people who do. They tend to develop in younger people and often have certain gene changes that are different from those in tumors found in people who smoke. In some cases, these gene changes can be used to guide treatment.

Gene changes that may lead to lung cancer

DNA is the molecule in our cells that makes up our genes, which control how our cells function. DNA, which comes from both our parents, affects more than just how we look. It also can influence our risk for developing certain diseases, including some kinds of cancer.

Some genes help control when cells grow, divide to make new cells, and die:

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

Cancers can be caused by DNA changes that turn on oncogenes or turn off tumor suppressor genes. Changes in many different genes are usually needed to cause lung cancer. There are primarily two types of gene mutations (changes): germline mutations and somatic mutations.

Inherited gene changes (germline mutations)

Inherited gene changes, or germline mutations, are gene changes that you inherit from your parents. These are the mutations in your DNA that you inherit from the egg and sperm cells when you are conceived.  Some people inherit DNA mutations  from their parents that may increase their risk for developing certain cancers.  Historically, germline mutations were not thought to cause very many lung cancers. However, recent studies have shown there may be a benefit to test all patients with lung cancer for germline mutations. If germline mutations are found, it would not only show that you were at an increased hereditary risk for developing lung cancer, but it could also help guide discussions about the best way to treat your lung cancer. If you have lung cancer and are also found to have a certain germline mutation, you may respond well to that mutation’s targeted therapy.

Examples of possible germline mutations for patients with lung cancer include: CHEK2, ATM, TP53, BRCA1, EGFR, APC, and PALB2. Studies are ongoing to better understand the role of germline mutations in lung cancer. Regardless of whether you carry a higher hereditary risk for lung cancer, doctors recommend that all people avoid tobacco smoke and other exposures that will increase cancer risk.

Acquired gene changes (somatic mutations or “driver mutations”)

Acquired gene changes, or somatic mutations, may occur in any individual cell and cannot be inherited. Somatic mutations refer to DNA changes within cells that were not passed from your parents, but rather were acquired during your lifetime. Certain somatic mutations can affect the cell’s ability to control its own growth, and will eventually transform a non-cancer cell to become a cancer cell. These somatic mutations are also known as “driver mutations.” If your tumor is found to have a driver mutation, you will likely respond well to targeted therapy.

For patients with advanced non-small cell lung cancer, it is recommended that the lung mass or a metastatic mass be tested for driver mutations. It is standard practice to test for the following driver mutations: EGFR, ALK, ROS1, MET, RET, BRAF, and NTRK. If any of these driver mutations are found, initial treatment with a targeted therapy (rather than chemotherapy) would be recommended. Although these mutations can be found in any patient with lung cancer, nonsmokers with lung cancer are more likely to have a driver mutation.