Abstract

Although the connection between cancer and cigarette smoke is well established, nicotine is not characterized as a carcinogen. Here, we used exome sequencing to identify nicotine and oxidative stress-induced somatic mutations in normal human epithelial cells and its correlation with cancer. We identified over 6,400 SNVs, indels and microsatellites in each of the stress exposed cells relative to the control, of which, 2,159 were consistently observed at all nicotine doses. These included 429 nsSNVs including 158 novel and 79 cancer-associated. Over 80% of consistently nicotine induced variants overlap with variations detected in oxidative stressed cells, indicating that nicotine induced genomic alterations could be mediated through oxidative stress. Nicotine induced mutations were distributed across 1,585 genes, of which 49% were associated with cancer. MUC family genes were among the top mutated genes. Analysis of 591 lung carcinoma tumor exomes from The Cancer Genome Atlas (TCGA) revealed that 20% of non-small-cell lung cancer tumors in smokers have mutations in at least one of the MUC4, MUC6 or MUC12 genes in contrast to only 6% in non-smokers. These results indicate that nicotine induces genomic variations, promotes instability potentially mediated by oxidative stress, implicating nicotine in carcinogenesis, and establishes MUC genes as potential targets.

Highlights

  • The increased incidence of cancer in the last 50-60 years may be largely attributed to two factors: the aging of the population, and the increased exposure to disease promoting agents present in general and occupational environments [1]

  • By performing the initial experimental scans using this global microsatellite array that quantitates overall genomewide microsatellite content changes it was possible to www.impactjournals.com/oncotarget confirm biological and technical reproducibility. These experiments identified and confirmed overall comparable genomic changes in multiple independent experiments with nicotine and oxidative stress (Supplementary Fig. S1 and S2), providing confidence that the detailed sequencing experiment was being conducted on highly reproducible alterations induced by stress exposure

  • The genome-wide view of nicotine-induced somatic mutations, gene expression changes and mutated cancer associated genes is concisely presented in the Circos plot (Fig. 3)

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Summary

Introduction

The increased incidence of cancer in the last 50-60 years may be largely attributed to two factors: the aging of the population, and the increased exposure to disease promoting agents present in general and occupational environments [1]. The first considers that environmental pollutants and chemicals can only make minor contributions to the overall cancer incidence and increases in the size and aging of the population, and lifestyle influences such as smoking, alcohol consumption and diet can explain most of the increased cancer incidence [2]. The second interpretation, citing that these arguments are not sufficient, estimates that in addition to these factors, there are contributions from the environment such as exposure to diverse chemical and biological agents, which may play a major role in the occurrence of the disease [3]. Nicotine is considered as an addictive substance in cigarette smoke, but not as a carcinogen.

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