Causes and Risk Factors of Non-Small Cell Lung Cancer

While the exact causes of non-small cell lung cancer are uncertain, several risk factors have been identified. 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.

Risk factors for non-small cell lung cancer
Verywell / Nusha Ashjaee 

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. 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 genes ) 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. 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.

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.


The risk of non-small cell lung cancer increases with age, 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, and this second cancer may be unique and unrelated to the first.


It's thought that roughly 80% of non-small cell lung cancers are associated with smoking, but this can vary with subtype. 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.

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.

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. 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.

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.

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. 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, 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.

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 cancer 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.

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.

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. 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. 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 arthritis
  • Thrombocytosis (an elevated platelet count)
  • Conditions that result in immunosuppression such as HIV/AIDS and organ transplant recipients


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.

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.


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.

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.


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

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. 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. 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. 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. 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. 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.


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. 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, 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, 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.

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).


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.

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.

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:

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. 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, and in Japan, the GSTM1 null genotype is associated with an increased risk in never-smoking women.

A Word From Verywell

There are many known as well as some potential causes of non-small cell lung cancer, but more research is needed. Due to the strong association with smoking, other causes have often been overshadowed, such that many people are unaware that never-smokers can and do develop lung cancer. With the recent increase in young, never-smoking women, some of these additional causes will hopefully be explored.

Frequently Asked Questions

  • How long does it take for smoking to lead to lung cancer?

    It can vary from person to person, but in general, the longer and more you smoke, the more you're at risk. For example, lung cancer screening is recommended for people at higher risk, which is defined as a 20 pack-year history of smoking. Pack years are calculated by multiplying the number of packs smoked per day times the number of years smoked.

  • How is non-small cell lung cancer treated?

    Treatment depends on the stage of cancer as well as the type of cancer. Early cancers may be treated with surgery and possibly radiation therapy. More advanced cancers may be treated with surgery, radiation therapy, chemotherapy, immunotherapy, and targeted therapies.

44 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. American Society of Clinical Oncology. Lung cancer - non-small cell: risk factors and prevention.

  2. Polo V, Zago G, Frega S, et al. Non-small cell lung cancer in a very young woman: a case report and critical review of the literatureAm J Case Rep. 2015;16:782–789. doi:10.12659/ajcr.894426

  3. de Groot PM, Wu CC, Carter BW, Munden RF. The epidemiology of lung cancerTransl Lung Cancer Res. 2018;7(3):220–233. doi:10.21037/tlcr.2018.05.06

  4. American Cancer Society. Oncogenes and tumor suppressor genes.

  5. Rafnar T, Sigurjonsdottir GR, Stacey SN, et al. Association of brca2 k3326* with small cell lung cancer and squamous cell cancer of the skin. J Natl Cancer Inst. 2018;110(9):967-974. doi:10.1093/jnci/djy002

  6. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorshipMayo Clin Proc. 2008;83(5):584–594. doi:10.4065/83.5.584

  7. Takayuki N, Keiko T, Junji U, et al. Advanced non-small-cell lung cancer in elderly patients: patient features and therapeutic managementBiomed Res Int. 2018;2018:8202971. doi:10.1155/2018/8202971

  8. Wu GX, Nelson RA, Kim JY, Raz DJ. Non–small cell lung cancer as a second primary among patients with previous malignancy: who is at riskClin Lung Cancer. 2017;18(5):543–550.e3. doi:10.1016/j.cllc.2017.02.007

  9. McCarthy WJ, Meza R, Jeon J, Moolgavkar SH. Chapter 6: Lung cancer in never smokers: epidemiology and risk prediction modelsRisk Anal. 2012;32(1):S69–S84. doi:10.1111/j.1539-6924.2012.01768.x

  10. Song MA, Benowitz NL, Berman M, et al. Cigarette filter ventilation and its relationship to increasing rates of lung adenocarcinomaJ Natl Cancer Inst. 2017;109(12):djx075. doi:10.1093/jnci/djx075

  11. Jung KJ, Jeon C, Jee SH. The effect of smoking on lung cancer: ethnic differences and the smoking paradoxEpidemiol Health. 2016;38:e2016060. doi:10.4178/epih.e2016060

  12. Vogeltanz-Holm N, Schwartz GG. Radon and lung cancer: What does the public really know? J Environ Radioact. 2018;192:26-31. doi:10.1016/j.jenvrad.2018.05.017

  13. Lantz PM, Mendez D, Philbert MA. Radon, smoking, and lung cancer: the need to refocus radon control policyAm J Public Health. 2013;103(3):443–447. doi:10.2105/AJPH.2012.300926

  14. United States Environmental Protection Agency. EPA urges home radon tests this january for National Radon Action Month.

  15. 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

  16. Naeem Z. Second-hand smoke - ignored implicationsInt J Health Sci (Qassim). 2015;9(2):V–VI.

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

  18. Xue Y, Jiang Y, Jin S, Li Y. Association between cooking oil fume exposure and lung cancer among Chinese nonsmoking women: a meta-analysisOnco Targets Ther. 2016;9:2987–2992. doi:10.2147/OTT.S100949

  19. Lamichhane DK, Kim HC, Choi CM, et al. Lung cancer risk and residential exposure to air pollution: a Korean population-based case-control studyYonsei Med J. 2017;58(6):1111–1118. doi:10.3349/ymj.2017.58.6.1111

  20. Gilbert ES. Ionising radiation and cancer risks: what have we learned from epidemiologyInt J Radiat Biol. 2009;85(6):467–482. doi:10.1080/09553000902883836

  21. Durham AL, Adcock IM. The relationship between COPD and lung cancerLung Cancer. 2015;90(2):121–127. doi:10.1016/j.lungcan.2015.08.017

  22. Qu Y-L, Liu J, Zhang L-X, et al. Asthma and the risk of lung cancer: a meta-analysisOncotarget. 2017;8(7):11614-11620. doi:10.18632/oncotarget.14595

  23. Kallberg H. Rheumatoid arthritis and lung cancer: you probably heard it before. J Rheumatol. 2008;35(9):1695-6.

  24. Aerts JG, Lievense LA, Hoogsteden HC, Hegmans JP. Immunotherapy prospects in the treatment of lung cancer and mesotheliomaTransl Lung Cancer Res. 2014;3(1):34–45. doi:10.3978/j.issn.2218-6751.2013.11.04

  25. Hicks BM, Filion KB, Yin H, Sakr L, Udell JA, Azoulay L. Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study. BMJ. 2018;363:k4209. doi:10.1136/bmj.k4209

  26. Institute of Medicine (US) Committee on Blue Water Navy Vietnam Veterans and Agent Orange Exposure. Blue Water Navy Vietnam Veterans and Agent Orange Exposure. Washington (DC): National Academies Press (US). 6, LONG-TERM ADVERSE HEALTH EFFECTS. Available from:

  27. Anand P, Kunnumakara AB, Sundaram C, et al. Cancer is a preventable disease that requires major lifestyle changesPharm Res. 2008;25(9):2097-2116. doi:10.1007/s11095-008-9661-9

  28. Tanvetyanon T, Bepler G. Beta-carotene in multivitamins and the possible risk of lung cancer among smokers versus former smokers: a meta-analysis and evaluation of national brands. Cancer. 2008;113(1):150-7. doi:10.1002/cncr.23527

  29. Cannioto R, Etter JL, LaMonte MJ, et al. Lifetime physical inactivity is associated with lung cancer risk and mortalityCancer Treat Res Commun. 2018;14:37-45. doi:10.1016/j.ctarc.2018.01.001

  30. Vandeven N, Nghiem P. Pathogen-driven cancers and emerging immune therapeutic strategiesCancer Immunol Res. 2014;2(1):9–14. doi:10.1158/2326-6066.CIR-13-0179

  31. Argyri E, Tsimplaki E, Marketos C, Politis G, Panotopoulou E. Investigating the role of human papillomavirus in lung cancer. Papillomavirus Res. 2017;3:7-10. doi:10.1016/j.pvr.2016.12.002

  32. Liang H, Pan Z, Cai X, et al. The association between human papillomavirus presence and epidermal growth factor receptor mutations in Asian patients with non-small cell lung cancer. Transl Lung Cancer Res. 2018;7(3):397-403. doi:10.21037/tlcr.2018.03.16

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

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

  35. Huang YH, Zhang ZF, Tashkin DP, Feng B, Straif K, Hashibe M. An epidemiologic review of marijuana and cancer: an updateCancer Epidemiol Biomarkers Prev. 2015;24(1):15–31. doi:10.1158/1055-9965.EPI-14-1026

  36. Korfei M. The underestimated danger of E-cigarettes - also in the absence of nicotineRespir Res. 2018;19(1):159. doi:10.1186/s12931-018-0870-4

  37. Mamtani R, Cheema S, Sheikh J, Al Mulla A, Lowenfels A, Maisonneuve P. Cancer risk in waterpipe smokers: a meta-analysisInt J Public Health. 2017;62(1):73–83. doi:10.1007/s00038-016-0856-2

  38. Rodriguez-Lara V, Hernandez-Martinez JM, Arrieta O. Influence of estrogen in non-small cell lung cancer and its clinical implicationsJ Thorac Dis. 2018;10(1):482–497. doi:10.21037/jtd.2017.12.61

  39. Kanwal M, Ding XJ, Cao Y. Familial risk for lung cancerOncol Lett. 2017;13(2):535–542. doi:10.3892/ol.2016.5518

  40. Jonsson S, Thorsteinsdottir U, Gudbjartsson DF, et al. Familial risk of lung carcinoma in the Icelandic population. JAMA. 2004;292(24):2977-83. doi:10.1001/jama.292.24.2977

  41. McKay JD, Hung RJ, Han Y, et al. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypesNat Genet. 2017;49(7):1126–1132. doi:10.1038/ng.3892

  42. Dimitrakopoulos FD, Antonacopoulou AG, Kottorou AE, et al. NF-kB2 genetic variations are significantly associated with non-small cell lung cancer risk and overall survivalSci Rep. 2018;8(1):5259. doi:10.1038/s41598-018-23324-3

  43. Tindle H, Stevenson Duncan M, Greevy R et al. Lifetime smoking history and risk of lung cancer: Results from the Framingham heart studyJNCI: Journal of the National Cancer Institute. 2018;110(11):1201–7. doi:10.1093/jnci/djy041

  44. American Cancer Society. Treatment choices for non-small cell lung cancer, by stage.

Additional Reading

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."