Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies

Area of Science:

• Genetics
• Epidemiology
• Cancer Research

Background:

• Clinical, molecular, and genetic epidemiology studies show significant differences between lung cancer in individuals who have ever smoked and those who have never smoked.
• Prior genetic association studies may have missed important variants due to a lack of stratification by smoking status.

Purpose of the Study:

• To identify novel genetic variants associated with lung cancer that were missed in previous non-stratified analyses by conducting a stratified multi-population association study.
• To investigate the functional roles of identified variants and their impact on lung cancer risk in relation to smoking quantity.

Main Methods:

• Conducted a stratified association study across European, East Asian, and African populations, analyzing data from 44,823 ever-smokers and 20,074 never-smokers.
• Performed functional analyses, including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, alongside annotation studies.
• Evaluated the impact of smoking quantity on lung cancer risk for variants associated with ever-smoking lung cancer.

Main Results:

• Identified five novel independent loci (GABRA4, 12q24.33, LRRC4C, LINC01088, LCNL1) associated with lung cancer in two or three populations.
• Functional analyses suggested variants influence lung cancer risk via DNA damage (GABRA4) or gene expression regulation (LCNL1).
• Observed distinct risk patterns for variants across different smoking groups (never, light, moderate-to-heavy smokers).

Conclusions:

• Identified novel genetic variants specifically associated with lung cancer in either ever-smokers or never-smokers, which were previously undetected.
• Highlighted the genetic heterogeneity between lung cancer in ever-smokers and never-smokers.
• Provided etiological insights into the complex genetic architecture of lung cancer.