Why do some people who are heavy smokers don’t get lung cancer, while others who never smoke get lung cancer?

If lung cancer in never smokers were considered a disease category, it would rank seventh among the most common causes of cancer death and 11th or 12th among the most common cancers.

By Geoffrey Kabat

Compilation | Kestrel

Lung cancer is the second most common cancer in the world, with 1.8 million deaths and 2.2 million new diagnoses in 2020 alone. It is also the most common cancer with a known and preventable cause. Despite this, there are still some mysteries about the cause of lung cancer. Why are some heavy smokers able to avoid the fate of lung cancer? And why do some people who have never smoked get lung cancer?

A study published in Nature Genetics in April this year found that some smokers’ DNA appears to have “adapted” to the carcinogens in cigarettes, which helps them avoid dangerous cancer-causing mutations. [1]

"Heavier smoking does not correspond to higher mutation burden," said the study's authors, from Albert Einstein College of Medicine in New York. "Our data suggest that some heavy smokers survive for a long time because their bodies have ways to suppress the accumulation of mutations. These people should have very efficient DNA damage repair systems or be able to detoxify substances that enter the body during smoking."

This explanation can answer the first question, but the second one remains to be answered: Why are tens of thousands of never-smokers diagnosed with lung cancer every year around the world?

Lung cancer in non-smokers

In the West, smoking explains 80-90% of lung cancer. If all smokers gave up the habit, the vast majority of lung cancer in high-income countries could be avoided, although this is unlikely to happen. Two other common cancers with known major causes are skin cancer and cervical cancer, the latter of which is caused by the human papilloma virus (HPV), so cervical cancer is almost completely preventable through vaccination.

But lung cancer is different. The epidemiological, clinical, and biological characteristics of lung cancer vary dramatically in different parts of the world. In the United States, with nearly 240,000 cases and 130,000 deaths each year, the incidence of lung cancer in men and women is roughly the same and both are declining. In China, the incidence of lung cancer is increasing in both sexes, and the incidence of lung cancer in men is about twice that of women.

In Western countries, most lung cancers are linked to smoking, but it is estimated that around 15% of lung cancer cases in men and 53% of lung cancer cases in women worldwide are never smokers.

Figure 1 Chest X-rays of six non-smoking lung cancer patients, with the location of cancerous tissue marked in red. 丨Image source: The Guardian

Lung cancer in non-smokers is often classified as adenocarcinoma, which is a malignant tumor formed by the canceration of glandular tissue. It can occur in the lungs, breasts, prostate, colon and other parts of the body, and is mainly seen in women and East Asians. In contrast, the most common lung cancers in smokers are squamous cell carcinoma and small cell carcinoma. The former is a malignant tumor formed by the canceration of squamous epithelial cells, such as skin cancer, and the latter is named because the cancer cells look small and round under a microscope.

If lung cancer in never smokers is considered a disease category (LCINS), it ranks seventh among the most common causes of cancer death and 11th or 12th among the most common cancers.

For more than 40 years, scientists have been looking for environmental risk factors that could explain how never-smokers develop lung cancer. Potential factors include passive smoking, exposure to indoor radon gas, exposure to kitchen fumes from burning coal or other fuels (especially in low-income countries), various air pollutants, pre-existing lung disease, hormonal and reproductive factors (which may explain why never-smoking women are more likely to develop lung cancer), and genetic susceptibility. Other potential risk factors include asbestos and cancer-causing viruses.

Although many studies have investigated these factors, their effects appear to be relatively weak and unlikely to explain the majority of cases.

Environment and genetics

A 2012 epidemiological review of lung cancer in never smokers concluded that “the majority of lung cancer cases in never smokers cannot be definitively linked to known environmental risk factors, suggesting that more epidemiological research in this area is urgently needed.” [2]

Although no convincing environmental risk factors have been found, some studies have brought us new insights with potential clinical applications, mainly examining molecular markers and studies on mutations that drive tumor development. There is evidence that "lung cancer in never smokers" is a disease with unique molecular and genetic characteristics .

Chemical mutagens are chemicals that act on DNA, changing its structure and causing genetic mutations. Cancer is generally caused by mutagens binding to important genes on DNA, including tumor suppressor genes, proto-oncogenes, and genes involved in DNA repair. If DNA damage is not repaired, the genetic material will be permanently changed, and the cell will continue to divide, forming a clone - a group of cells with the same genetic material, and then develop into a complete tumor, which is clinically recognized as a tumor. Tobacco smoke contains more than 60 mutagens, which will bind to DNA and introduce chemical modifications to form a lung cancer genome with a special mutational imprint .

However, which specific mutation(s) can explain the strong carcinogenic effect of smoking? Finding the answer is not easy. The recent study from Albert Einstein College of Medicine mentioned at the beginning of the article [1] used a new method to identify the precursor cells of a type of lung cancer-susceptible cell (i.e., lung basal epithelial cells).

The researchers examined normal lung tissues from 14 never-smokers and 19 smokers. Only one of the 14 never-smokers developed lung cancer, while 13 of the 19 smokers did. The number of mutations in both smokers and never-smokers increased with age. For smokers, the number of mutations increased with the increase in the cumulative smoking dose (according to the smokers' own reports), but for heavy smokers with a cumulative smoking dose of more than 23 pack-years, the number of mutations no longer increased. However, there was no significant difference in the number of mutations in the normal lung tissues of never-smokers - whether they did not develop lung cancer or those who did, that is, the never-smoker who developed cancer did not have more mutations than others. (Translator's note: The unit of smoking dose is "pack-year", and 1 pack-year is defined as smoking 20 cigarettes (a pack) a day for 1 year, which is equivalent to smoking 1 cigarette a day for 20 years)

It is worth mentioning that there is no difference in the number of mutations in normal lung tissue between smokers and those who do not have lung cancer. Therefore, we still do not know which smoking-related mutations determine who will get lung cancer. In addition, genetic susceptibility must also play a significant role, because most smokers do not get lung cancer.

Why are Asians more susceptible?

It has long been recognized that the epidemiology of lung cancer in Asia is different from that seen in the West. The smoking rate among Asian women is much lower than that among Asian men, and lung cancer in women is often adenocarcinoma that occurs in the periphery of the lung, as opposed to squamous cell carcinoma and small cell carcinoma that occur in the main bronchus.

So, lung cancer in smokers and lung cancer in never smokers, especially East Asian women, seem to have two opposite characteristics. In smokers, we have found a strong carcinogen, but it is not clear how it causes cancer. In never smokers, we can find driver mutations in most cases (note: driver mutations are changes in genetic material that cause cancer to appear and develop), but the evidence for environmental factors is either absent or very weak.

Figure 2 The percentage of never-smokers who develop lung cancer at different times. [3]

Other studies have found many striking differences in genomic signatures and driver mutations between smokers’ lung cancer and never-smokers’ lung cancer. [4] For example, mutations in the tumor suppressor gene TP53 are more common in smokers’ lung cancer, and mutations in the oncogene KRAS are common in smokers’ lung cancer but rare in never-smokers’ lung cancer (43% vs. 0%). Conversely, mutations in the epidermal growth factor receptor (EGFR) are common in never-smokers’ lung cancer but rare in smokers’ lung cancer (54% vs. 16% in one large study).

In addition, some studies using next-generation sequencing technology [4] have shown that the total number of mutations involving protein coding regions in smokers is significantly higher than that in never-smokers (median 209 vs. 18), which means that the mutation incidence in never-smokers is 90% lower.

The fact that fewer genetic changes were found in lung cancer from never-smokers overall means that most of these mutations are likely involved in the development of cancer. For this reason, the researchers believe that lung cancer from never-smokers may provide "a relatively enriched and easily identified set of lung cancer driver mutations."

Across different populations and geographic regions, researchers have found that EGFR mutations are more common in “never smokers’ lung cancer” [4]. EGFR (epidermal growth factor receptor) is an epidermal growth factor receptor that is also a tyrosine kinase (TK), and is therefore abbreviated as EGFR-TK. Normal EGFR is activated only after binding to epidermal growth factor (EGF), while EGFR with activating mutations does not need to bind to EGF and can remain activated. Researchers have conducted many randomized clinical trials to compare the effects of various EGFR-TK inhibitors as chemotherapy drugs. Through clinical trials on patients with EGFR-TK mutations, scientists have established that inhibitors can be used as standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) that are positive for EGFR-TK mutations. The name of this drug is erlotinib (trade name Tarceva), and patients with EGFR-TK mutations have an approximately 60% chance of responding to erlotinib.

Two researchers involved in the treatment of never-smokers’ lung cancer wrote in the conclusion of their article, “With the development of sequencing technology and the reduction of its cost, in the near future we will be able to treat advanced never-smokers’ lung cancer mainly with molecular targeted therapy and achieve long-term control of this type of lung cancer, just as we do for chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST).”[4]

Despite these advances, we must emphasize that the mutational landscape of lung cancer is complex and that these cancers have the potential to develop resistance to first-line treatments. Therefore, much work is focused on novel targeted therapies, multi-drug combinations, and complementary immunotherapies.

Key points in lung cancer research

First, epidemiological studies on factors that are difficult to measure or subtle, such as secondhand smoke, radon gas, and asbestos, should focus on reliable people who have never smoked in their lives, because smoking is indeed a strong risk factor for lung cancer, and the risk of lung cancer caused by smoking is much higher than that of asbestos.

Because we know so little about the causes of never-smoker lung cancer, there may be a tendency to overestimate the associations between potential risk factors that have been studied and to overestimate their importance, rather than acknowledging that the findings from these studies are unlikely to explain the majority of never-smoker lung cancer.

Regarding passive smoking, a French study[5] examined the major mutations associated with lung cancer in never-smokers and smokers and did not find a clear association between passive smoking and a “smoker-like mutational signature” in lung cancer patients who had never smoked throughout their lives. Therefore, they concluded that passive smoking alone does not seem to be sufficient to determine a somatic mutational signature for lung cancer.

Secondly, characterizing the similarities and differences in the malignant transformation mechanisms of lung cancer in smokers and never-smokers is helpful for understanding the malignant transformation process and the mechanism of cancer evolution. Some mutations will not coexist, which can strongly prove that former smokers and never-smokers have different genetic pathways for lung cancer.

Third, the difficulty in finding the main cause of “never smoker lung cancer” reminds us that for many types of cancer, despite fifty years of epidemiological studies, we still have not found the cause of many common cancers, which means that we cannot prevent these cancers. This includes colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, brain cancer, leukemia, etc.

This shows how difficult it is to accurately find the external cause of cancer. However, we have found that smoking is the cause of lung cancer and infection with human papillomavirus is the cause of cervical cancer, which are worth mentioning as exceptions.

That is, we have seen that identifying driver mutations that drive specific cancers can lead to the development of effective targeted therapies that can significantly prolong patient survival. These therapies represent a long-sought advance in treating serious cancers that is independent of identifying the cause of cancer.

References

[1] Huang, Z., Sun, S., Lee, M., Maslov, AY, Shi, M., Waldman, S., Marsh, A., Siddiqui, T., Dong, X., Peter, Y., Sadoughi, A., Shah, C., Ye, K., Spivack, SD, & Vijg, J. (2022). Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking. Nature genetics, 54(4), 492–498. https://doi.org/10.1038/s41588-022-01035-w

[2] McCarthy, WJ, Meza, R., Jeon, J., & Moolgavkar, SH (2012). Chapter 6: Lung cancer in never smokers: epidemiology and risk prediction models. Risk analysis : an official publication of the Society for Risk Analysis, 32 Suppl 1(Suppl 1), S69–S84. https://doi.org/10.1111/j.1539-6924.2012.01768.x

[3] Ou, SH, Ziogas, A., & Zell, JA (2009). Asian ethnicity is a favorable prognostic factor for overall survival in non-small cell lung cancer (NSCLC) and is independent of smoking status. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 4(9), 1083–1093. https://doi.org/10.1097/JTO.0b013e3181b27b15

[4] Subramanian, J., & Govindan, R. (2013). Molecular profile of lung cancer in never smokers. EJC supplements : EJC : official journal of EORTC, European Organization for Research and Treatment of Cancer ... [et al.], 11(2), 248–253. https://doi.org/10.1016/j.ejcsup.2013.07.004

[5] Couraud, S., Debieuvre, D., Moreau, L., Dumont, P., Margery, J., Quoix, E., Duvert, B., Cellerin, L., Baize, N., Taviot, B., Coudurier, M., Cadranel, J., Missy, P., Morin, F., Mornex, JF, Zalcman, G., Souquet, PJ, & BioCAST/IFCT-1002 study investigators (2015). No impact of passive smoke on the somatic profile of lung cancers in never-smokers. The European respiratory journal, 45(5), 1415–1425. https://doi.org/10.1183/09031936.00097314

[6] Couraud, S., Zalcman, G., Milleron, B., Morin, F., & Souquet, PJ (2012). Lung cancer in never smokers--a review. European journal of cancer (Oxford, England: 1990), 48(9), 1299–1311. https://doi.org/10.1016/j.ejca.2012.03.007

Compiled from
https://geneticliteracyproject.org/2022/06/14/unraveling-the-mystery-of-who-gets-lung-cancer-and-why/#

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