Molecular Epidemiology of Lung Cancer Driver Mutations

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Purpose: The molecular epidemiology of most EGFR and KRAS mutations in lung cancer remains unclear. Experimental Design: We genotyped 3026 lung adenocarcinomas for the major EGFR (exon 19 deletions and L858R) and KRAS (G12, G13) mutations and examined correlations with demographic, clinical and smoking history data. Results: EGFR mutations were found in 43% of never smokers (NS) and in 11% of smokers. KRAS mutations occurred in 34% of smokers and in 6% of NS. In patients with smoking histories up to 10 pack-years, EGFR predominated over KRAS. Among former smokers with lung cancer, multivariate analysis showed that, independent of pack-years, increasing smoking-free years raise the likelihood of EGFR mutation. NS were more likely than smokers to have KRAS G>A transition mutation (mostly G12D) (58% vs. 20%, p=0.0001). KRAS G12C, the most common G>T transversion mutation in smokers, was more frequent in women (p=0.007) and these women were younger than men with the same mutation (median 65 vs. 69, p=0.0008) and had smoked less. Conclusions: The distinct types of KRAS mutations in smokers vs. NS suggest that most KRAS-mutant lung cancers in NS are not due to secondhand smoke exposure. The higher frequency of KRAS G12C in women, their younger age, and lesser smoking history together support a heightened susceptibility to tobacco carcinogens. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. To clarify the molecular epidemiology of EGFR and KRAS mutations in lung adenocarcinoma, we examined tumor genotyping data in 3026 patients in relation to demographic, clinical and smoking history data. In addition to the expected reciprocal associations of EGFR and KRAS mutations with smoking history, this showed that 11% of smokers had EGFR-mutated tumors and 6% of never smokers had KRAS-mutated tumors. Pack-years of smoking were predictive for EGFR and KRAS mutations but even in the context of a nomogram, it is difficult to identify a significant subset of smokers with an EGFR mutation likelihood of <1%, and therefore our data do not support excluding any patient subset from EGFR testing. The distinct types of KRAS mutations in smokers vs. never smokers suggest that most KRAS-mutant lung cancers in never smokers are not due to secondhand smoke exposure. The higher frequency of KRAS G12C in women, their younger age, and lesser smoking history support a …