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Background Genomic alterations in 8 genes are now the targets of FDA-approved therapeutics in non-small cell lung cancer (NSCLC), but their distribution according to genetic ancestry, sex, histology, and smoking is not well established. Methods Using multi-institutional genetic testing data from GENIE, we characterize the distribution of targetable genomic alterations in 8 genes among 8675 patients with NSCLC (discovery cohort: DFCI,  N  = 3115; validation cohort: Duke, Memorial Sloan Kettering Cancer Center, Vanderbilt,  N  = 5560). For the discovery cohort, we impute genetic ancestry from tumor-only sequencing and identify differences in the frequency of targetable alterations across ancestral groups, smoking pack-years, and histologic subtypes. Results We identified variation in the prevalence of  KRAS   G12C  , sensitizing  EGFR  mutations,  MET  alterations,  ALK , and  ROS1  fusions according to the number of smoking pack-years. A novel method for computing continental (African, Asian, European) and Ashkenazi Jewish ancestries from panel sequencing enables quantitative analysis of the correlation between ancestry and mutation rates. This analysis identifies a correlation between Asian ancestry and  EGFR  mutations and an anti-correlation between Asian ancestry and  KRAS   G12C   mutation. It uncovers 2.7-fold enrichment for  MET  exon 14 skipping mutations and amplifications in patients of Ashkenazi Jewish ancestry. Among never/light smokers, targetable alterations in LUAD are significantly enriched in those with Asian (80%) versus African (49%) and European (55%) ancestry. Finally, we show that 5% of patients with squamous cell carcinoma (LUSC) and 17% of patients with large cell carcinoma (LCLC) harbor targetable alterations. Conclusions Among patients with NSCLC, there was significant variability in the prevalence of targetable genomic alterations according to genetic ancestry, histology, and smoking. Patients with LUSC and LCLC have 5% rates of targetable alterations supporting consideration for sequencing in those subtypes.

Variation in targetable genomic alterations in non-small cell lung cancer by genetic ancestry, sex, smoking history, and histology