Association between Smoking History and Tumor Mutation Burden in Advanced Non-Small Cell Lung Cancer

Abstract

Lung carcinogenesis is a complex and stepwise process involving accumulation of genetic mutations in signaling and oncogenic pathways via interactions with environmental factors and host susceptibility. Tobacco exposure is the leading cause of lung cancer, but its relationship to clinically relevant mutations and the composite tumor mutation burden (TMB) has not been fully elucidated. In this study, we investigated the dose-response relationship in a retrospective observational study of 931 patients treated for advanced-stage non-small cell lung cancer (NSCLC) between April 2013 and February 2020 at the Dana Farber Cancer Institute and Brigham and Women's Hospital. Doubling smoking pack-years was associated with increased KRAS^G12C and less frequent EGFR^del19 and EGFR^L858R mutations, whereas doubling smoking-free months was associated with more frequent EGFR^L858R . In advanced lung adenocarcinoma, doubling smoking pack-years was associated with an increase in TMB, whereas doubling smoking-free months was associated with a decrease in TMB, after controlling for age, gender, and stage. There is a significant dose-response association of smoking history with genetic alterations in cancer-related pathways and TMB in advanced lung adenocarcinoma. SIGNIFICANCE: This study clarifies the relationship between smoking history and clinically relevant mutations in non-small cell lung cancer, revealing the potential of smoking history as a surrogate for tumor mutation burden.

Figure 1.. Mutation landscape in advanced NSCLC patients by smoking status

Mutation landscape in advanced NSCLC patients by smoking status. A. Oncoplot of the top 10 mutated genes in each smoking group in our cohort. Each row represents a gene and each column represents a sample. Genes are ordered by mutation frequency and are differentially colored based on different mutation types. B. Transition and transversion plot displays distribution of Single Nucleotide Variants (SNV) classified into six transition and transversion events. Stacked bar plot (bottom) shows distribution of mutation spectra for every sample. C. Mutational signatures identified in each smoking subgroup. The y-axes indicate exposure of 96 trinucleotide motifs to the overall signature. Each plot title indicates the best match against validated Catalogue of Somatic Mutations in Cancer (COSMIC) signatures and cosine similarity value along with the proposed etiology. D. Mutually exclusive and co-occurring gene pairs are displayed as a triangular matrix. Green indicates tendency toward co-occurrence, whereas pink indicates tendency toward exclusiveness.

Figure 2.. Mutation rates of EGFR and KRAS by smoking metrics

EGFR and KRAS mutation rates in different smoking subgroups based on smoking status, smoking pack-years and smoking-free months. (Upper) EGFR and KRAS mutation rates by various smoking metrics. (Middle) EGFR mutation rates by smoking metrics at the variant level. (Down) KRAS mutation rates by smoking metrics at the variant level.

Figure 3.. Effect of smoking metrics on mutations and TMB

A. Odds ratios of EGFR and KRAS variant-specific mutations for smoking pack-years. B. Odds ratios of EGFR and KRAS variant-specific mutations for smoking-free months. C. Odds ratios of somatic mutations in cancer related pathways for former and current smokers obtained from multivariable logistic regression controlling for age, gender, stage and histological subtypes. D. TMB is significantly associated with smoking status, with the highest median TMB observed in current smokers (12.1 mut/Mb), followed by former and never smokers (9.1 mut/Mb and 6.8 mut/Mb, respectively). E. All patients were divided into never smokers and ever smokers and smoking pack-years in ever smokers were divided into tertiles. Smoking pack-years are significantly associated with TMB. F. Ever smokers were divided based on quartiles of smoking-free months. Smoking-free months are significantly associated with TMB. Pairwise comparisons by Wilcoxon test were conducted and FDR adjusted p-values are labeled. P ≤ 0.05 is considered statistically significant.