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

Abstract

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.

A systematic review of genetic ancestry as a risk factor for incidence of non-small cell lung cancer in the US

“…Genetic ancestry level analyses conducted in Genome-Wide Association Studies (GWAS) have successfully identified differences in NSCLC risk, incidence, and survival across ancestral groups ( Zanetti et al, 2016 ; Jones et al, 2019 ; Schenk et al, 2020 ; Sinha et al, 2020 ; Adib et al, 2022 ). Sinha et al (2020) compared the frequency of copy number mutations and homologous recombination.…”

“…There was no evidence of associations between any of these novel gene variants and prognosis/overall survival outcome in NSCLC. Overall, findings suggest that genetic ancestry alone is not a significant predictor of lung cancer risk, incidence, nor survival (Araujo et al, 2015b;Zanetti et al, 2016;Jones et al, 2018;Jones et al, 2019;Mitchell et al, 2019;Schenk et al, 2020;Adib et al, 2022).…”

A novel epithelial-mesenchymal transition (EMT)-related gene signature of predictive value for the survival outcomes in lung adenocarcinoma

“…LUAD is the accepted common classification of lung cancer, accompanied by high prevalence and fatality ( 2 , 56 ). In cancer patients, metastasis is primary cause of shorten survival and high mortality, and often has already occurred at the time of diagnosis ( 57 , 58 ).…”

Integrative analysis of a large real-world cohort of small cell lung cancer identifies distinct genetic subtypes and insights into histological transformation

“…The challenges associated with capturing and analyzing self-reported race in the clinical trial setting has been well-described in the literature (72). The use of genomic ancestry in this real-world population offers a model for describing genomic differences across ancestral populations and contributes to a growing number of similar studies in other cancer types (73)(74)(75).…”