Skip to content

The mutagenic forces shaping lung cancer genomes in never-smokers

One-paragraph summary

Sherlock-Lung analyzed treatment-naive lung cancers from 871 never-smokers across 28 geographic locations. The study identified geographic differences in drivers and mutational processes: KRAS mutations were 3.8-fold more frequent in North American/European than East Asian never-smoker adenocarcinomas, while EGFR and TP53 mutations were more prevalent in East Asia; exposure-associated signatures varied geographically (PMID 40604281).

Key findings

  • 871 never-smoker cancers across 28 locations.
  • Treatment-naive tumors reduced therapy-induced signature confounding.
  • KRAS frequency differed 3.8-fold between broad geographic groups.
  • EGFR and TP53 prevalence was higher in East Asian tumors.
  • Mutational signatures supported multiple environmental and endogenous forces.
  • “Never-smoker lung cancer” is not one molecular entity.

Limitations

  • Research cohort sampling is not population incidence sampling.
  • Geography is not a direct exposure measurement.
  • Signature attribution carries model uncertainty.
  • Individual causation cannot be inferred from a tumor signature.

Why it matters

The study connects molecular epidemiology with prevention questions and undermines the use of smoking status or ancestry as a substitute for tumor testing. It also sharpens the screening gap: never-smoker risk is heterogeneous, but current eligibility remains dominated by smoking history.

Cited by wiki pages

  • Overview
  • Epidemiology and risk factors
  • Molecular landscape
  • Screening and early detection