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Lung cancer in never smokers — a different disease

Key Points

  • About 25% of lung cancer cases worldwide are not attributable to tobacco smoking. Thus, lung cancer in never smokers is the seventh leading cause of cancer deaths in the world, killing more people every year than pancreatic or prostate cancers.

  • Globally, lung cancer in never smokers demonstrates a marked gender bias, occuring more frequently among women. In particular, there is a high proportion of never smokers in Asian women diagnosed with lung cancer.

  • Although smoking-related carcinogens act on both proximal and distal airways inducing all the major forms of lung cancer, cancers arising in never smokers target the distal airways and favour adenocarcinoma histology.

  • Environmental tobacco smoke (ETS) is a relatively weak carcinogen and can only account for a minority of lung cancers arising in never smokers.

  • Although multiple risk factors, including environmental, hormonal, genetic and viral factors, have been implicated in the pathogenesis of lung cancer in never smokers, no clear-cut dominant factor has emerged that can explain the relatively high incidence of lung cancer in never smokers and the marked geographic differences in gender proportions.

  • Molecular epidemiology studies, in particular of the TP53, KRAS and epidermal growth factor receptor (EGFR) genes, demonstrate strikingly different mutation patterns and frequencies between lung cancers in never smokers and smokers.

  • There are major clinical differences between lung cancers arising in never smokers and smokers and their response to targeted therapies. Indeed, non-smoking status is the strongest clinical predictor of benefit from the EGFR tyrosine kinase inhibitors.

  • The above-mentioned facts strongly suggest that lung cancer arising in never smokers is a disease distinct from the more common tobacco-associated forms of lung cancer.

  • Further efforts are needed to identify the major cause or causes of lung cancers arising in never smokers before successful strategies for prevention, early diagnosis and novel therapies can be implemented.

Abstract

Although most lung cancers are a result of smoking, approximately 25% of lung cancer cases worldwide are not attributable to tobacco use, accounting for over 300,000 deaths each year. Striking differences in the epidemiological, clinical and molecular characteristics of lung cancers arising in never smokers versus smokers have been identified, suggesting that they are separate entities. This Review summarizes our current knowledge of this unique and poorly understood disease.

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Figure 1: Epidemiological and histological features of lung cancer in never smokers.
Figure 2: Pathogenesis of lung cancer in never smokers: targeting a specific anatomical compartment.
Figure 3: Distinct features of EGFR, KRAS and TP53 mutations in lung cancers in never smokers.
Figure 4: Two pathways to adenocarcinoma.

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Acknowledgements

We thank Xian-Jin Xie for his help with the statistical analyses.

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UMD p53 mutation database

Glossary

Lung cancer

A malignant tumour arising from the cells of the respiratory epithelium. By definition, tumours arising from the non epithelial cells (sarcomas and lymphomas) or the mesothelial lining (mesotheliomas) of the lung are excluded.

Small cell carcinoma of the lung

(SCLC) A highly malignant type of carcinoma consisting of small cells expressing neuroendocrine features. Almost all cases arise in ever smokers.

Squamous cell carcinoma

Tumours that arise from multilayered squamous lining cells. Squamous cells are not normally present in the respiratory epithelium, but may arise from glandular or secretory cells by metaplastic change as a result of exposure to tobacco products, inflammation, irritation etc.

Adenocarcinoma

A tumour arising from cells that have glandular or secretory properties.

Nicotine

An alkaloid compound found in certain plants, especially in tobacco. Nicotine constitutes 0.3 to 5% of the tobacco plant by dry weight, with biosynthesis taking place in the roots and accumulating in the leaves. It acts as a stimulant and is one of the main factors responsible for the dependence-forming properties of tobacco smoking.

Environmental tobacco smoke

(ETS). A combination of the smoke that comes from the burning of a tobacco product and smoke that is exhaled by smokers (second-hand smoke). Inhaling ETS is called involuntary or passive smoking.

Nitrosamines

Any of a class of organic compounds with the general formula R2NNO or RNHNO, present in various foods, tobacco and other products. Many nitrosamines are carcinogenic.

Polycyclic aromatic hydrocarbons

(PAHs). A group of over 100 different stable organic molecules made up of only carbon and hydrogen. They are large, flat molecules built of a collection of fused benzene-like rings. They are formed during the incomplete burning of coal, oil and gas, garbage, or other organic substances like tobacco or charbroiled meat.

DNA adducts

Altered forms of DNA that occur as the result of exposure to carcinogens (in the case of smokers these would be the carcinogens present in cigarette smoke). A DNA adduct may have several possible outcomes: it may lead to cell death by apoptosis; it may be repaired, resulting in a return to the original DNA structure; or it may be mis-repaired, resulting in a mutation.

Base excision repair

A DNA repair pathway that operates on small DNA lesions such as oxidized or reduced bases, fragmented or non-bulky adducts, or those produced by methylating agents; includes XRCC and OGG1.

DNA double-strand break repair

DNA double-strand breaks (DSBs) occur as intermediates in DNA metabolic functions and from exogenous agents such as ionizing radiation; two pathways for DSB repair include homologous recombination and non-homologous end-joining.

Mismatch repair

Corrects DNA replication errors (base–base or insertion/deletion mismatches) caused by DNA polymerase errors.

Bronchioloalveolar carcinoma

(BAC). As strictly defined, a non-invasive form of peripherally arising adenocarcinoma. However, often incorrectly applied to adenocarcinomas of mixed histology that have a prominent bronchioloalveolar component.

Missense mutation

A mutation that causes an amino acid substitution.

CpG island

A part of the genomic DNA in which the frequency of the cytosine (C)–guanine (G) sequence is higher than predicted. The p indicates that C and G are connected by a phosphodiester bond. Methylation only occurs at the C nucleotide of CpG sites. CpG islands are located around the promoters of about half of all genes.

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Sun, S., Schiller, J. & Gazdar, A. Lung cancer in never smokers — a different disease. Nat Rev Cancer 7, 778–790 (2007). https://doi.org/10.1038/nrc2190

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