In a study reported in the Journal of Clinical Oncology, Devarakonda et al found that never-smokers with lung adenocarcinoma had a high frequency of RTK/RAS/RAF pathway driver alterations—similar to smokers with lung adenocarcinoma—but also harbored a significantly higher total frequency of clinically actionable driver alterations.
The study involved assessment of 88 never-smokers in an institutional cohort, as well as data from 76 never-smokers and 299 smokers from an external cohort from The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC).
Key Findings
A known RTK/RAS/RAF pathway driver alteration was identified in 65% of never-smoker samples in the institutional cohort. Overall, driver alterations were identified in 81% of samples in the institutional cohort. Clinically actionable driver alterations were identified in 78% of TCGA never-smokers and 92% of CPTAC never-smokers, compared with 49.5% of smokers (P < .0001).
In this comprehensive genomic and transcriptome analysis of never-smoker lung adenocarcinomas, we observed a potential role for germline variants in DNA repair genes and passive exposure to cigarette smoke in the pathogenesis of a subset of never-smoker lung adenocarcinomas.— Devarakonda et al
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Overall, significantly higher frequencies of alterations in EGFR, CTNNB1, SETD2, MET, and RB1 were observed in never-smokers, and significantly higher frequencies of alterations in KRAS, TP53, STK11, NF1, BRAF, and KEAP1 were observed in smokers, with EGFR (51%) vs KRAS (35%) being the most common driver alterations in the two groups.
A subgroup of never-smoker samples exhibited germline alterations in DNA repair genes. However, the frequency of samples with germline variants in cancer predisposition genes was comparable between smokers and never-smokers (6.4% vs 6.9%, P = .82). A subgroup of never-smoker samples (5.9%) exhibited mutation signatures suggestive of passive exposure to cigarette smoke.
RNA sequencing in the never-smoker institutional cohort showed three clusters of tumors based on presence of immune and stromal cell types and expression of immune markers. Compared with cluster 1 tumors, cluster 2 and 3 tumors exhibited relative depletion of various types of immune cells, and cluster 1 tumors exhibited higher levels of expression of immune markers such as PD-L1, PD-L2, TIM3, CTLA4, and SIGLEC15.
Cluster 3 tumors had the lowest proportion of immune cells and showed relative depletion in expression of immune checkpoint molecules. Cluster 2 tumors exhibited a mix of cluster 1 and 3 tumors, exhibiting a continuum of levels of expression of immune checkpoint molecules and percentages of immune cells.
As stated by the investigators, “Our analyses indicate that the genomic features of smoking-related and never-smoker lung adenocarcinomas are largely comparable with activation of RTK/RAS/RAF signaling as a hallmark feature of lung adenocarcinoma…. However, our results show that lung adenocarcinomas arising in never-smokers demonstrate a much higher prevalence of driver alterations in this pathway than those from smokers.”
They concluded, “In this comprehensive genomic and transcriptome analysis of never-smoker lung adenocarcinomas, we observed a potential role for germline variants in DNA repair genes and passive exposure to cigarette smoke in the pathogenesis of a subset of never-smoker lung adenocarcinomas. Our findings also show that clinically actionable driver alterations are highly prevalent in never-smoker lung adenocarcinomas, highlighting the need for obtaining biopsies with adequate cellularity for clinical genomic testing in these patients.”
Ramaswamy Govindan, MD, of Washington University School of Medicine in St. Louis, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Institutes of Health and National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.
