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Lung cancer is the leading cause of cancer death in the United States and around the world. Almost as many Americans die of lung cancer every year than die of prostate, breast, and colon cancer combined (Fig. 1).1 Siegel and colleagues1 reviewed recent cancer data and estimated a total of 239,320 new cases of lung cancer and 161,250 deaths from lung cancer in the United States in 2010.2 The statistics reflect data from 2007 and, therefore, likely underestimate the current lung cancer burden. Lung cancer has been the most common cancer worldwide since 1985, both in terms of incidence and mortality. Globally, lung cancer is the largest contributor to new cancer diagnoses (1,350,000 new cases and 12.4% of total new cancer cases) and to death from cancer (1,180,000 deaths and 17.6% of total cancer deaths). The 5-year survival rate in the United States for lung cancer is 15.6%, and although there has been some improvement in survival during the past few decades, the survival advances that have been realized in other common malignancies have yet to be achieved in lung cancer. There has been a large relative increase in the numbers of cases of lung cancer in developing countries. Approximately half (49.9%) of the cases now occur in developing countries whereas in 1980, 69% of cases were in developed countries. The estimated numbers of lung cancer cases worldwide has increased by 51% since 1985 (a 44% increase in men and a 76% increase in women). In the United States, cancer of the lung and bronchus ranks second in both genders, with an estimated 115,060 new cases in men (14% of all new cancers) and 106,070 in women (14% of all new cancers).1,2 The age-adjusted incidence rate of lung cancer is 62 per 100,000 men and women per year in the United States, with the incidence rate higher in men than in women (75.2 vs 52.3 per 100,000).3 Lung cancer in both genders tops the list on the number of estimated deaths yearly (85,600, or 28% of all cancer deaths for men, and 71,340, or 26% of all cancer deaths for women)Lung cancer incidence in men in the United States has been decreasing since the early 1980s. The incidence and mortality rates for lung cancer tend to mirror one another because most patients diagnosed with lung cancer eventually die of it. Siegel and colleagues,¹ in their review of cancer statistics in 2011, noted decreases in death rates from lung cancer in men by 2.0% per year from 1994 to 2006 . In women, however, lung cancer death rates continued to increase by 0.3% per year from 1995 to 2005, but more recent data from 2003 to 2006 show a more encouraging trend with a start in decline of 0.9% per year ). The lung cancer incidence among women has declined over the past decades, from 5.6% between 1975 and 1982, to 3.4% between 1982 and 1990, to 0.4% between 1991 and 2006, and more recently to −2.3% between 2006 and 2008 . Because of the change in lung cancer incidence in women, recent figures show that lung cancer death rates decreased in women for the first time, more than a decade after decreases in men. The lag in the decline of lung cancer rates in women compared with men has been attributed to the fact that cigarette smoking in women peaked two decades later than in men. Lung cancer mortality rates thus seem to be reaching a plateau, which is an encouraging change from the steep rise in the 1970s. Lung cancer arises from the cells of the respiratory epithelium and can be divided into two broad categories. Small cell lung cancer (SCLC) is a highly malignant tumor derived from cells exhibiting neuroendocrine characteristics and accounts for 15% of lung cancer cases. Non–small cell lung cancer (NSCLC), which accounts for the remaining 85% of cases, is further divided into 3 major pathologic subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma by itself accounts for 38.5% of all lung cancer cases, with squamous cell carcinoma accounting for 20% and large cell carcinoma accounting for 2.9%.In the past several decades, the incidence of adenocarcinoma has increased greatly, and adenocarcinoma has replaced squamous cell carcinoma as the most prevalent type of NSCLC. The 5-year total survival rate for lung cancer in the United States from 2001 to 2007 was 15.6%. Patients with localized disease at diagnosis have a 5-year survival rate of 52%; however, the more than 52% of patients with distant metastasis at diagnosis have a dismal 5-year survival rate of 3.6%, which begs for the need for better screening methods to detect early-stage cancers. Lung cancer was the most commonly diagnosed cancer and the leading cause of cancer death in men in 2008 globally.² For women, lung cancer was the fourth most commonly diagnosed cancer and the second leading cause of cancer death. Overall, lung cancer accounted for 13% or 1.6 million of total cancer cases and 18% or 1.4 million cancer-related deaths worldwide in 2008. Lung cancer incidence and mortality rates are highest in the United States and the developed countries. In contrast, lung cancer rates in underdeveloped geographic areas, including Central America and most of Africa, are lower, except the rates are slowly increasing  More developed countries have higher incidence and mortality rates from lung cancers in both genders than less developed countries. The World Health Organization estimates that lung cancer deaths worldwide will continue to rise, largely as a result of an increase in global tobacco use, especially in Asia. Tobacco use is the principal risk factor for lung cancer, and a large proportion of all pulmonary carcinomas are attributable to the effects of cigarette smoking. Despite efforts to curb tobacco smoking, there are approximately 1.1 billion smokers worldwide, and if the current trends continue, that number would increase to 1.9 billion by 2025. As of 2008, 20.6% (46.0 million) of American adults smoke. Of these, 79.8% (36.7 million) smoke every day and 20.2% (9.3 million) smoke some days. During the past decade, there has been a 3.5% point decrease in the number of US adults who smoke (20.6% in 2008 and 24.1% in 1998).
Despite the availability of new diagnostic and genetic technologies, advancements in surgical techniques, and the development of new biologic treatments, the overall 5-year survival rate for lung cancer in the United States remains at a dismal 15.6%.⁹ The situation globally is even worse, with 5-year survival in Europe, China, and developing countries estimated at only 8.9%.

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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. Smokers 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.

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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 cells to become cancer.

Smoking

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. Smokers 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 non-smokers

Not all people who get lung cancer are smokers. Many people with lung cancer are former smokers, but many others never smoked at all. And it is rare for someone who has never smoked to be diagnosed with small cell lung cancer (SCLC), but it can happen.

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

A small portion of lung cancers occur in people with no known risk factors for the disease. Some of these might just be random events that don't have an outside cause, but others might be due to factors that we don't yet know about.

Lung cancers in non-smokers are often different from those that occur in smokers. They tend to occur in younger people and often have certain gene changes that are different from those in tumors found in smokers. In some cases, these gene changes can be used to guide treatment.

Gene changes that may lead to lung cancer

Scientists know how some of the risk factors for lung cancer can cause certain changes in the DNA of lung cells. These changes can lead to abnormal cell growth and, sometimes, cancer. DNA is the chemical 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.

Inherited gene changes

Some people inherit DNA mutations (changes) from their parents that greatly increase their risk for developing certain cancers. But inherited mutations alone are not thought to cause very many lung cancers.

Still, genes do seem to play a role in some families with a history of lung cancer. For example, people who inherit certain DNA changes in a particular chromosome (chromosome 6) are more likely to develop lung cancer, even if they don't smoke or only smoke a little.

Some people seem to inherit a reduced ability to break down or get rid of certain types of cancer-causing chemicals in the body, such as those found in tobacco smoke. This could put them at higher risk for lung cancer.

Other people inherit faulty DNA repair mechanisms that make it more likely they will end up with DNA changes. People with DNA repair enzymes that don't work normally might be especially vulnerable to cancer-causing chemicals and radiation.

Some non-small cell lung cancers (NSCLCs) make too much of the EGFR protein (which comes from an abnormal EGFR gene). This specific gene change is seen more often with adenocarcinoma of the lung in young, non-smoking, Asian women, but the excess EGFR protein has also been seen in more than 60% of metastatic NSCLCs.

Researchers are developing tests that may help identify such people, but these tests are not yet used routinely. For now, doctors recommend that all people avoid tobacco smoke and other exposures that might increase their cancer risk.

Acquired gene changes

Gene changes related to lung cancer are usually acquired during life rather than inherited. Acquired mutations in lung cells often result from exposure to factors in the environment, such as cancer-causing chemicals in tobacco smoke. But some gene changes may just be random events that sometimes happen inside a cell, without having an outside cause.

Acquired changes in certain genes, such as the RB1 tumor suppressor gene, are thought to be important in the development of SCLC. Acquired changes in genes such as the p16 tumor suppressor gene and the K-RAS oncogene, are thought to be important in the development of NSCLC. Changes in the TP53 tumor suppression gene and to chromosome 3 can be seen in both NSCLC and SCLC. Not all lung cancers share the same gene changes, so there are undoubtedly changes in other genes that have not yet been found.

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Lung Cancer Causes | Lung Cancer in Non-Smokers

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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 cells to become cancer. Smoking tobacco is by far the leading cause of lung cancer.