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

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

Elio Adib #  1   2 , Amin H Nassar #  1   2 , Sarah Abou Alaiwi  1   2 , Stefan Groha  3   4 , Elie W Akl  1 , Lynette M Sholl  5 , Kesi S Michael  6 , Mark M Awad  6 , Pasi A Jӓnne  6 , Alexander Gusev  3   4 , David J Kwiatkowski  7
Affiliations

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

Elio Adib et al. Genome Med. .

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.

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

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Conflict of interest statement

Pasi A. Jänne reports support from Hanmi Pharmaceutical Company, Ltd; grants from Boehringer-Ingelheim, Eli Lilly, Daiichi Sankyo, and Takeda Oncolog; personal fees from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Ignyta, Loxo Oncology, Eli Lilly, SFJ Pharmaceuticals, Voronoi, Daiichi Sankyo, Biocartis, Novartis, Sanofi Oncology, Takeda Oncology, Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Astellas, PUMA, and Revolution Medicines, outside the submitted work; and postmarketing royalties from a Dana-Farber Cancer Center–owned patent (EGFR Mutations) licensed to Lab Corp.

Lynette M. Sholl reports consulting fees from EMD Serono, Foghorn Therapeutics, and AstraZeneca and research grants from Genentech.

Mark M. Awad reports receiving grants and personal fees from Genentech, AstraZeneca, and Bristol-Myers Squibb; grants from Eli Lilly; and personal fees from Merck, Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, and Gritstone, outside of the submitted work. David J. Kwiatkowski reports receiving grants from Genentech, Revolution Medicines, and AADI; and consulting fees from Guidepoint and BridgeBio Gene Therapy.

The remaining authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Histology-specific differences in genomic alterations in NSCLC in the discovery (A) and validation (B) cohorts. Frequency of eight targetable genomic alterations in five main NSCLC histologic subtypes
Fig. 2
Fig. 2
EGFR L858R/ex19del/ex20ins, ROS1 fusions, and KRASG12C in lung adenocarcinoma, grouped according to pack-years of smoking
Fig. 3
Fig. 3
Logistic regression plots showing the association between continuous ancestry scores and the presence (1) or absence (0) of targetable alterations. A EGFR L858R/ex19del/ex20ins and Asian ancestry (AA) score. B KRASG12C and Asian Ancestry (AA) score. C METamp/ex14skipping and Ashkenazi Jewish ancestry (AJ) score. Each dot represents an individual patient
Fig. 4
Fig. 4
Distribution of targetable alterations by inferred ancestral groups among light smokers (≤15 pack-year smoking history) with LUAD
See this image and copyright information in PMC

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