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

Genome Med. 2022 Apr 15;14(1):39. doi: 10.1186/s13073-022-01041-x.


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 KRASG12C, 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 KRASG12C 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.

Keywords: Genetic ancestry; Non-small cell lung cancer; Smoking; Targetable genomic alterations; Targeted therapies.

MeSH terms

  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • ErbB Receptors / genetics
  • Humans
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Mutation
  • Protein-Tyrosine Kinases / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Smoking / genetics


  • Proto-Oncogene Proteins
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins p21(ras)