Second-hand smoke and human lung cancer

Abstract

Since the early 1980s, there has been growing concern about potential health consequences of exposure to second-hand smoke (SHS). Despite SHS being established as a risk factor for lung cancer development, the estimated risk has remained small yet somehow debatable. Human exposure to SHS is complicated because of temporal variabilities in source, composition, and concentration of SHS. The temporality of exposure to SHS is important for human lung carcinogenesis with a latency of many years. To explore the causal effect of SHS in lung carcinogenesis, exposure assessments should estimate chronic exposure to SHS on an individual basis. However, conventional exposure assessment for SHS relies on one-off or short-term measurements of SHS indices. A more reliable approach would be to use biological markers that are specific for SHS exposure and pertinent to lung cancer. This approach requires an understanding of the underlying mechanisms through which SHS could contribute to lung carcinogenesis. This Review is a synopsis of research on SHS and lung cancer, with special focus on hypothetical modes of action of SHS for carcinogenesis, including genotoxic and epigenetic effects.

Figure 1. Causal role of SHS in human lung cancer development

Mechanistic research into SHS-induced lung carcinogenesis may help identify unique biological markers that could be used for early detection and prognosis of lung cancer as well as for treatment of this lethal disease.

Figure 2. Schematic model of SHS-induced lung carcinogenesis

This hypothetical model simplistically shows two distinct pathways of genotoxic and epigenetic effects, which might contribute to human lung cancer development, including formation of persistent DNA damage at key cancer-related genes, and aberrant DNA methylation (global hypomethylation or locus-specific CpG island hypermethylation), respectively.

Figure 3. Codon distribution of the TP53 tumor suppressor gene in tobacco smoke-associated lung cancer (n = 2340)

Data were obtained from the TP53 mutation database of the International Agency for Research on Cancer (http://www-p53.iarc.fr/p53DataBase.htm; R12 version). Entries with confounding exposure to asbestos, mustard gas or radon were excluded. Codons containing methylated CpG sequences are indicated by asterisks (*).

Figure 4. Mutation spectrum of the TP53 tumor suppressor gene in tobacco smoke-associated lung cancer (n = 2340)

Data were obtained from the TP53 mutation database of the International Agency for Research on Cancer (http://www-p53.iarc.fr/p53DataBase.htm; R12 version). Entries with confounding exposure to asbestos, mustard gas or radon were excluded.

Figure 5. Schematic model of the mechanism of PAH-related DNA-damage leading to TP53 mutation

The proposed model demonstrates the targeting of methylated CpG dinucleotides by a PAH compound (benzo[a]pyrene diol epoxide) leading to G→T transversions at mutational hotspots.