By Lynne Eldridge, MD 

 Medically reviewed by Doru Paul, MD

While the exact causes of non-small cell lung cancer are uncertain, several risk factors have been identified.1 While smoking is still very important, non-small cell lung cancer is the most common type of lung cancer among never smokers, young adults, and women, and factors such as radon exposure, genetics, indoor and outdoor air pollution, radiation, and secondhand smoke are important.

There are also some potential risk factors that are just beginning to be explored. This is of particular importance as the incidence of non-small cell lung cancer is increasing in young women who have never smoked.2

Common Causes

While the exact causes of non-small cell lung cancer are uncertain, it's understood that normal lung cells are transformed to cancer cells following a series of mutations or other genetic changes to the DNA of the cell.3 This damage can occur due to a combination of environmental exposures and mistakes that occur in the normal division of cells (hence, why cancer is more common with age).

Even when the DNA in cells is damaged, most cells don't become cancer cells. Humans have several genes (tumor suppressor genes4 ) that code for proteins that repair damaged DNA or eliminate cells that can't be repaired (apoptosis). Some people are predisposed to developing cancer if these repair genes are mutated.

For example, the BRCA2 gene mutations may increase the risk of non-small cell lung cancer, at least in women who smoke.5 These mutations, however, don't cause lung cancer—they simply make it more difficult to repair cells that are damaged in other ways.

Lifestyle Risk Factors

There are a number of risk factors that are associated with an increased risk of developing lung cancer. Some of these are lifestyle choices, such as smoking, but some cannot be changed, such as your age. It's important to note that risk factors are not necessarily the causes.6

Even though the risk of lung cancer increases with age, advanced age does not directly cause these tumors.

The following are risk factors that are common to non-small lung cancer.

Age

The risk of non-small cell lung cancer increases with age,7 with the median age of diagnosis being 71 years old. Yet non-small cell lung cancer is the most common type of lung cancer in young adults, and can even (rarely) occur in children.

Personal History of Lung Cancer

People who have had one primary non-small cell lung cancer have an increased risk of developing a second lung cancer,8 and this second cancer may be unique and unrelated to the first.

Smoking

It's thought that roughly 80% of non-small cell lung cancers are associated with smoking, but this can vary with subtype.9 Squamous cell carcinomas are linked most closely with smoking, while lung adenocarcinomas are the most common subtype in never smokers. Carcinoid tumors do not appear to be associated with smoking.

The risk of non-small cell lung cancer is linked to the length of time and number of cigarettes smoked, or pack-years of smoking. The addition of filters has not significantly changed the risk of lung cancer, but the most common types have changed. Small cell lung cancer was once more common, but the addition of filters is thought to cause toxins in cigarettes to be inhaled more deeply into the lungs, to the regions where many non-small cell lung cancers occur.10

The link between smoking and lung cancer, however, varies in different regions of the world. A phenomena known as the Japanese smoking and lung cancer paradox (Japanese men smoke more than men in the United States but have a lower risk of lung cancer) may be due to genetics, fewer carcinogens, better filters in Japanese cigarettes, and more.11

Radon Exposure in the Home

Radon is the second most common cause for non-small cell lung cancer (and the most common cause among never smokers) accounting for roughly 21,000 lung cancer deaths each year.12 Radon gas occurs due to the natural decay of uranium in the soil and can enter homes through cracks in the foundation, sump pumps, wires, and more and become trapped. Since it is an odorless, colorless gas, the only way you can know if your home is safe is to do radon testing.13

Though some regions tend to have higher levels than others, elevated levels have been found in homes in all 50 states and around the world. Radon kits are available at most hardware stores and can usually be purchased for $20 or less. If levels are high, radon mitigation can almost always resolve the problem.14

Occupational Chemicals and Other Substances

Occupational exposures are very significant in non-small cell lung cancer and are thought to play a role in 13% to 29% of these cancers in men in the United States, and roughly 14.5% of cancers in the United Kingdom.15 Some of the culprits include:

• Metals such as arsenic, beryllium, nickel, and cadmium

• Fibers such as silica, wood dust, and asbestos (while asbestos is well known for its role in mesothelioma, it is also a risk for non-small cell lung cancer)

• Chemicals such as vinyl chloride, polycyclic aromatic hydrocarbons (PAHs), and mustard gas

There are many occupations that involve exposures to these substances. As one example, arsenic is used in ceramics, fireworks, textiles, and semiconductors.

Secondhand Smoke

Secondhand smoke is thought to be responsible for around 7,300 lung cancer deaths each year,16 and there is no level of exposure that is safe. People who are exposed to secondhand smoke in the workplace or at home are 20% to 30% more likely to develop non-small cell lung cancer.17

Air Pollution

Both indoor and outdoor air pollution can increase the risk of non-small cell lung cancer.

• Indoor Air Pollution: Worldwide, cooking fumes are a very significant cause of non-small cell lung cancer18 and are considered a major risk factor for never-smoking women in Asia (worldwide, 50% of women who develop lung cancer are never smokers). With cooking, deep frying confers the greatest risk, with coal used in cooking and heating also a concern.

• Outdoor Air Pollution: The influence of outdoor air pollution on lung cancer risk can vary by region with densely populated areas and those located near major roadways of greater risk.19

Overall, air pollution is thought to be responsible for around 5% of lung cancers.

Ionizing Radiation

Ionizing radiation is a significant risk factor for non-small cell lung cancer.20

Radiation therapy to the chest can also increase risk, particularly those who have had radiation for Hodgkin's disease. Radiation therapy after a mastectomy also raises the risk but is of less concern at the current time than in the past due to improvements in delivery. Breast radiation after a lumpectomy, however, does not.

Lung Disease

Several lung diseases share risk factors with lung cancer, but it's thought that the lung disease itself (and inflammation) raises the risk further.

COPD is an independent risk factor for lung cancer, meaning that the risk goes beyond smoking.21 People who have COPD and smoke have a greater risk of developing lung cancer than smokers without COPD, and never smokers who have COPD have a greater risk of lung cancer than never smokers without the disease. Among people who smoke, COPD is actually the greatest risk factor for developing lung cancer.

It's also thought that asthma may raise lung cancer risk especially in people who do not smoke.22 While there is significant overlap, tuberculosis is thought to increase risk as well.

Less Common Risk Factors

There are many risk factors that account for fewer cases of non-small cell lung cancer but are important to note as they are less well known.

Other Medical Conditions

A number of medical conditions are associated with an increased risk of developing lung cancer, including:

• Some autoimmune disorders such as rheumatoid arthritis23

• Thrombocytosis (an elevated platelet count)

• Conditions that result in immunosuppression such as HIV/AIDS and organ transplant recipients24

Medications

Medications known as ACE inhibitors (often used for high blood pressure) are associated with a 14% increase in the risk of non-small cell lung cancer.25

Military Service

People who are currently active duty, as well as veterans, have an increased risk of non-small cell lung cancer. It's thought that this is due to a combination of exposures (such as industrial chemicals and Agent Orange) and smoking.26

Diet

Dietary intake may contribute to either an increased or decreased risk. Arsenic in drinking water from private wells as well as cured meat and deep-fried foods have been linked to a higher risk, whereas a diet rich in fruits and vegetables, particularly cruciferous vegetables may have a protective effect against the disease.27

Dietary Supplements

Noting that a diet rich in phytonutrients such as beta-carotene seemed to have a protective effect against lung cancer, researchers studied the effect of supplements of beta-carotene on risk. Unlike dietary beta-carotene, however, the supplemental form was associated with an increased risk of developing lung cancer.28

Exercise

Inactivity may increase the risk of non-small cell lung cancer to a small degree, with moderate exercise associated with a reduced risk.29

Possible Risk Factors

There are a number of risk factors that are only beginning to be studied or for which any effect on lung cancer risk is uncertain at this time. This includes:

Some Infectious Diseases

Knowing that microorganisms such as viruses are responsible for at least 20% of cancers worldwide, researchers have begun to look at the possible role of these infections in lung cancer.30 This has been of particular interest as the cause of the recent increase in lung cancer in young never-smokers, especially women, is unknown.

Human Papillomavirus (HPV)

In addition to being responsible for the majority of cervical cancers, the fact that HPV is now the responsible agent in many head and neck cancers has some researchers wondering about a potential link with lung cancer, as the type of tissue is similar.31 HPV has been isolated from some lung cancer cells, but this varies significantly with geography.

In Asian countries, an association has been noted between EGFR positive lung cancers and HPV.32 Despite these associations, it's not known whether correlation means causation—there is a possibility that instead of being a cause of lung cancer, lung cancer might predispose people to an HPV infection.

Other Viruses

In a 2016 study published in the British Journal of Cancer, researchers found evidence of a number of viruses in non-small cell lung cancers that were not present in noncancerous lung tissue.33 Again, the finding of viral DNA in lung cancer cells does not prove that these microorganisms cause lung cancer, but we do know that several viruses can contribute to oncogenesis (the formation of cancer).

The particular viruses varied based on subtype, with a significant number of squamous cell carcinomas being positive for HPV and hepatitis B, whereas lung adenocarcinomas were more likely to carry evidence of a sarcoma virus or bovine leukemia virus. Hepatitis B has a known role as a carcinogen in liver cancer, and since treatments to eradicate the virus are now available, this is of particular interest.

To gain further understanding of these findings, a 2018 study published in BMC Cancer looked at gene expression patterns in tumors that carried the different viruses and found that these were different.34 They hypothesized that these viruses may play a role in the development of non-small cell lung cancers by regulating gene expressions in cancer cells as tumors form and spread.

The conclusion was that that the viruses found likely interact with the tumor cells in some way (they weren't just passengers in the cells) and that this concept needs to be studied further.

Marijuana

The fact that smoking marijuana results in the inhalation of many of the toxins present in cigarettes would imply that marijuana would likewise increase lung cancer risk; however, studies have failed to confirm this, and some have even found a reduced risk.35 Unfortunately, the legal issues associated with studying marijuana have left the question unanswered as to whether marijuana causes lung cancer or not.

Electronic Cigarettes

There has been concern over the use of electronic cigarettes and lung cancer risk,36 but due to the latency period associated with most carcinogens, it's simply too soon to tell.

Hookah Smoking

Similarly, there is reason to be concerned with regard to Hookah,37 but the cancer risks of Hookah smoking are still uncertain.

Hormone Replacement Therapy

The issue surrounding the association of estrogen and lung cancer is confusing and still uncertain. It's known that some non-small cell lung cancers have estrogen receptors and that the incidence (and survival rate) from lung cancer can vary based on parity (number of children born), use of estrogen replacement therapy, and more.38

There appear to be varied effects, however, when it comes to causation (the risk of developing lung cancer), and progression (how well someone does after being diagnosed with the disease).

Genetics

While genetics appears to play a lesser role in the development of non-small cell lung cancer than some other cancers, we do know that family history, as well as some specific genetic variations, are associated with an elevated risk.39

Family History

Lung cancer can run in families, though it has sometimes been challenging to separate hereditary factors from common environmental factors shared by a family. People who have a first-degree relative (parent, sibling, or child) with the disease have roughly twice the risk, and those who have a second degree relative with non-small cell lung cancer have a risk around 30% higher than average.40

However, women who have lung cancer are more likely than men to have a genetic component.

Genetic Syndromes, Mutations, and Susceptibility

The science looking at the genetics of non-small cell cancer is relatively young. Some of the mutations or alterations in signaling proteins (biomarkers) in lung cancer that are detectable with genetic testing today include:

• EGFR mutations

• KRAS mutations

• ALK rearrangements

• ROS1 rearrangements

• MET amplification

• BRAF mutations

• RET mutations

• NTRK mutations

With regard to specific gene mutations, it's been noted that women who have BRCA2 mutations and smoke have around twice the risk of developing lung cancer.41 People who have the uncommon Li-Fraumeni syndrome related to a mutation in the p53 gene also have an increased risk.

There are also regions on chromosomes that have been associated with susceptibility, including major susceptibility locus on chromosome 6 and another on chromosome 15. More recently, NF-kB2 genetic variations have been found to be significantly associated with non-small cell lung cancer risk,42 and in Japan, the GSTM1 null genotype is associated with an increased risk in never-smoking women.

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Additional Reading

Centers for Disease Control and Prevention. What are the risk factors for lung cancer?

Centers for Disease Control and Prevention. Health effects of secondhand smoke.

Kim Y, Pierce CM, Robinson LA. Impact of viral presence in tumor on gene expression in non-small cell lung cancer. BMC Cancer. 2018;18(1):843. doi:10.1186/s12885-018-4748-0

Malhotra J, Malvezzi M, Negri E, La Vecchia C, Boffetta P. Risk factors for lung cancer worldwide. Eur Respir J. 2016;48(3):889-902. doi:10.1183/13993003.00359-2016

Robinson LA, Jaing CJ, Pierce Campbell C, et al. Molecular evidence of viral DNA in non-small cell lung cancer and non-neoplastic lung. Br J Cancer. 2016;115(4):497-504. doi:10.1038/bjc.2016.213

By Lynne Eldridge, MD
 Lynne Eldrige, MD, is a lung cancer physician, patient advocate, and award-winning author of "Avoiding Cancer One Day at a Time."