Journal
JOURNAL OF THORACIC ONCOLOGY
Volume 18, Issue 4, Pages 487-498Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jtho.2022.11.030
Keywords
Non-small cell lung cancer; Tobacco smoking; Whole genome sequencing; Mutational signature; Biomarker
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Next-generation sequencing allows for the reclassification of smoking-associated NSCLC based on individual genomic tumor characteristics, which can help reduce lung cancer stigma.
Introduction: Patient-reported smoking history is frequently used as a stratification factor in NSCLC-directed clinical research. Nevertheless, this classification does not fully reflect the mutational processes in a tumor. Next-generation sequencing can identify mutational signatures associated with tobacco smoking, such as single-base signature 4 and indel-based signature 3. This provides an opportunity to redefine the classification of smoking-and nonsmoking-associated NSCLC on the basis of individual genomic tumor characteristics and could contribute to reducing the lung cancer stigma.Methods: Whole genome sequencing data and clinical re-cords were obtained from three prospective cohorts of metastatic NSCLC (N = 316). Relative contributions and absolute counts of single-base signature 4 and indel-based signature 3 were combined with relative contributions of age-related signatures to divide the cohort into smoking -associated (smoking high) and nonsmoking-associated (smoking low) clusters.Results: The smoking high (n = 169) and smoking low (n = 147) clusters differed considerably in tumor mutational burden, signature contribution, and mutational landscape. This signature-based classification overlapped considerably with smoking history. Yet, 26% of patients with an active smoking history were included in the smoking low cluster, of which 52% harbored an EGFR/ALK/RET/ROS1 alteration, and 4% of patients without smoking history were included in the smoking high cluster. These discordant samples had similar genomic contexts to the rest of their respective cluster.
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