Lung Cancer
ICD-11: 2C25
Disease Overview
Lung cancer encompasses carcinomas of the lung, predominantly non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Tobacco smoking is the principal environmental cause, accounting for ~85% of cases; the smoking–genetics interaction is among the best-characterized gene–environment relationships in oncology. Genetic susceptibility modifies both smoking initiation (nicotine dependence) and lung cancer risk among smokers. Key loci include CHRNA5/CHRNA3 (nicotinic acetylcholine receptors influencing smoking behavior and carcinogen susceptibility), TP53, and EGFR (driver mutations in adenocarcinoma). SNP heritability for lung cancer is modest (~0.05) but increases when considering smoking-adjusted models. Adolescent relevance is significant: smoking initiation typically occurs before age 24; genetic variants in CHRNA5 influence both nicotine dependence and lung cancer risk, creating a dual pathway. Never-smoker lung cancer has distinct genetics (stronger EGFR, weaker smoking loci) and rising incidence in some populations.
Smoking initiation peaks in adolescence; CHRNA5 variants influence both uptake and persistence. Genetic susceptibility established early may inform prevention messaging. Never-smoker lung cancer in young adults has distinct etiology; EGFR-driven cases may present earlier.
Genetic Architecture Summary
| Gene | Variant | GWAS p | Evidence | Strength |
|---|---|---|---|---|
| CHRNA5 | rs16969968 | 1.0e-25 | Nicotinic acetylcholine receptor α5; influences nicotine dependence, smoking heaviness, and lung cancer risk; smoking × genetics interaction | 0.92 |
| EGFR | — | — | Epidermal growth factor receptor; driver mutations in adenocarcinoma; stronger in never-smokers; treatment target | 0.88 |
| TP53 | rs1042522 | 3.0e-7 | Tumor suppressor; somatic mutations common; germline variants may modify susceptibility to tobacco carcinogens | 0.78 |
PRS notes: Lung cancer PRS perform better in smokers; CHRNA5 dominates. Never-smoker PRS distinct. Smoking-G×E critical for interpretation. European ancestry-dominated; limited transferability.
Exposure Modifier Panel
| Exposure | Direction | Strength | Confidence | Mechanism hypothesis |
|---|---|---|---|---|
| tobacco | amplify | 0.95 | HIGH | Tobacco carcinogens (PAHs, nitrosamines) cause DNA damage; CHRNA5 genotype amplifies both smoking heaviness and cancer risk; smoking × genetics multiplicative |
| air-pollution | amplify | 0.62 | MEDIUM | PM2.5 and diesel exhaust increase lung cancer; oxidative stress and inflammation; may amplify risk in never-smokers |
| diet-quality | buffer | 0.45 | LOW | Fruit/vegetable intake may modestly buffer risk; antioxidants; evidence less strong than tobacco |
Population Equity Notes
GWAS ancestry breakdown: Lung cancer GWAS predominantly European and East Asian; African ancestry underrepresented; smoking patterns vary by population
Transferability notes: CHRNA5 association replicates across ancestry; EGFR mutation prevalence higher in East Asian never-smokers; PRS transferability limited
Data gaps: Multi-ancestry lung cancer GWAS; never-smoker specific genetics; G×E for air pollution and tobacco across populations
Tissue Context
Mechanism Brief Links
Visualizations
Risk Shift by Exposure Stratum
Population-level data only — does not predict individual risk
Tissue Relevance
References
- 1.Amos CI, et al. (2008). A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature. doi:10.1038/nature06885
- 2.McKay JD, et al. (2017). Genome-wide association study identifies multiple loci associated with lung cancer. Nature Genetics. doi:10.1038/ng.3892
- 3.Paez JG, et al. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. doi:10.1126/science.1099314
- 4.Olivier M, et al. (2010). TP53 mutations and lung cancer. Human Mutation. doi:10.1002/humu.21275
- 5.Hung RJ, et al. (2013). Gene-environment interaction in lung cancer. Carcinogenesis. doi:10.1093/carcin/bgt040