Lung carcinoma: pathogenesis and precursors
- Mechanism
Tobacco carcinogens mutate the airway lining step by step. Each type of lung cancer has its own driver genes and precursor lesions.
What it is
Most lung cancers are caused by tobacco smoke, with risk rising almost linearly with pack-years; other carcinogens include radon, asbestos, arsenic, chromium, nickel, uranium and air pollution. Driver mutations accumulate stepwise in a field of exposed epithelium. Never-smokers make up a sizable share worldwide, mostly women with adenocarcinoma carrying targetable mutations such as EGFR.
Structure
- Squamous sequence: basal cell hyperplasia, squamous metaplasia, mild to severe dysplasia, carcinoma in situ, invasive carcinoma.
- Atypical adenomatous hyperplasia: a small focus of mildly atypical pneumocytes lining slightly thickened alveolar walls.
- Adenocarcinoma in situ: atypical cells growing only along existing alveolar septa (lepidic), mucinous or non-mucinous, no invasion.
- Minimally invasive adenocarcinoma: lepidic-predominant tumour of 3 cm or less with 5 mm or less of invasion.
Step by step
- Polycyclic hydrocarbons and nitrosamines in smoke are activated by P-450 enzymes and form DNA adducts.
- Typical smoking mutations (G to T transversions) appear in TP53, KRAS and other genes.
- Losses of 3p and 9p (CDKN2A) are among the first events, found even in normal-looking smokers' mucosa.
- Activating mutations in receptor tyrosine kinases (EGFR, ALK) drive growth signalling in many adenocarcinomas.
- TP53 and RB1 loss remove the cell-cycle brakes, especially in small cell carcinoma.
- Clones with enough complementary drivers acquire the hallmarks of cancer and invade.
Driver alterations by type
| Type | Typical alterations | Who |
|---|---|---|
| Adenocarcinoma (smoker) | KRAS, TP53, STK11 | Current or former smokers |
| Adenocarcinoma (never-smoker) | EGFR, ALK, ROS1, RET fusions | Women, East Asian ancestry |
| Squamous cell carcinoma | TP53, CDKN2A loss, 3p loss, SOX2 gain | Heavy smokers |
| Small cell carcinoma | TP53 and RB1 loss, MYC family gain | Heavy smokers |
Markers
- EGFR
- ALK
- ROS1
- KRAS
- PD-L1
Clinical notes
- Stopping smoking lowers risk over time but not to baseline; second-hand smoke also causes lung cancer.
- Molecular testing of non-small cell carcinoma guides targeted therapy (EGFR and ALK inhibitors) and immunotherapy.
- Low-dose CT screening of heavy smokers finds early tumours; in Colombia lung cancer is a leading cause of cancer death.
Test yourself
Think of the answer, then tap the question to see it.
Which two tumour suppressor genes are lost in almost all small cell carcinomas?
TP53 and RB1.
What is adenocarcinoma in situ of the lung?
A tumour of 3 cm or less made of atypical cells growing only along pre-existing alveolar septa (lepidic pattern) without invasion.
Which mutation is more common in lung adenocarcinoma of never-smokers, and which in smokers?
EGFR mutations in never-smokers (especially women of East Asian ancestry); KRAS mutations in smokers. They rarely occur together.
Connections
Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.
Sources: Non-Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version (National Cancer Institute, 2025); Non–Small Cell Lung Cancer (StatPearls (NCBI Bookshelf), 2025).
Spotted a mistake?We are always improving for the community. Tell us what is wrong and our team will review it.Report a mistake
Representative model, for educational purposes only.