Study links air pollution to increased risk of colon cancer through DNA changes

Study links air pollution to increased risk of colon cancer through DNA changes

A recent oneeBioMedicineStudy examines the association between air pollution and colorectal cancer (CRC) risk based on epigenomic analysis.

The role of air pollution in CRC risk

CRC is one of the most common cancers worldwide, the etiology of which is related to a variety of lifestyle and environmental factors. In connection with environmental factors, air pollution is particularly important because it can lead to the development of cancer by influencing the inflammatory system.

A significant association has been documented between particulate matter (PM) and the risk of colorectal cancer, the incidence of gastrointestinal and liver cancer, and mortality. Therefore, it is imperative to understand the mechanism by which PM influences the incidence of CRC. The synergistic effect of PM with other air pollutants such as nitrogen oxides on the incidence of colorectal cancer also requires further investigation.

New epigenome-wide association studies (EWAS) have highlighted that exposure to air pollution leads to alteration of epigenetic markers, particularly DNA methylation (DNAm). This change triggers inflammation, which could increase the risk of disease development and progression.

The formation of 5-methylcytosine in cytosine-phosphate-guanine (CpG) dinucleotides, which reflect aberrant DNAm, has been identified as an important epigenetic mechanism in CRC carcinogenesis. Given this finding, it is crucial to understand the role of air pollution in the altered DNAm associated with CRC pathogenesis.

Mendelian randomization (MR) analysis is a powerful tool for identifying causal interference. It uses genetic variants as a proxy for DNAm exposure caused by air pollution to identify the causative factor. A major advantage of this method is the minimization of reverse causality and confounding factors.

About the study

The current prospective cohort study examined the association of individual and combined air pollution exposure with CRC risk and all-cause mortality. The pathological effects associated with air pollution-related DNAm and gene-environment interaction were also evaluated.

The association between air pollutants, including PM10, PM2.5 and nitrogen oxides (NOx and NO2), and colorectal cancer incidence and survival was assessed using relevant samples from the United Kingdom Biobank (UKB) cohort. Both genotypic and phenotypic health-related data were obtained from the UKB.

Epigenetic MR methylation quantitative trait loci (mQTL) analyzes were performed in two samples to identify the underlying mechanism of air pollution-related DNAm. Gene-environment interaction and genetic colocalization analyzes were performed to elucidate the potential carcinogenic effect of air pollutants on CRC manifestation.

Study results

A total of 428,632 UKB participants were included, 2,401 of whom were diagnosed with colorectal cancer and were eligible for the current study. Among these individuals, 533 all-cause deaths and 767 newly diagnosed CRC cases were identified. To determine all-cause mortality in patients with CRC, those with a previous CRC diagnosis were considered.

Consistent with previous studies, the current study also showed a positive correlation between PM2.5 exposure and increased risk of CRC. The newly developed Air Pollutants Exposure Score (APES) showed that exposure to different air pollutants, individually or together, reduced the overall CRC survival rate in a dose-dependent manner.

The adverse prognostic effects of air pollution were more common in men, smokers and those with insufficient physical activity, although not statistically significant. Therefore, changing certain lifestyle factors could reduce the risk of colon cancer.

A significant association between air pollution and CRC incidence/survival was observed. DNA methylation occurred within the protein-coding genes of transmembrane BAX inhibitor motif-containing 1 protein (TMBIM1)/paroxysmal nonkinesigenic dyskinesia (PNKD), CX-C motif chemokine receptor 5 (CXCR5), and transmembrane protein 110 (TMEM110), which mediate the adverse effects of air pollution on CRC. The experimental results strongly suggest that exposure to air pollution has an overall detrimental effect on the development and prognosis of colorectal cancer.

Air pollution mediates the development of CRC through the systemic inflammatory pathway, which is associated with increased messenger ribonucleic acid (mRNA) and protein levels of interferon-γ (IFN-γ), interleukin production, and pro-inflammatory activity in the blood.

The gene-environment interaction analyzes showed that PM2.5 exposure affects the CpG site rs876961 of the TMBIM1/PNKD gene, which influences CRC survival. Long-term PM2.5 exposure has also been linked to increased C-reactive protein levels and the induction of a systemic inflammatory state.

The PM2.5-related CpG site cg16235962 was associated with the CXCR5 gene, which encodes a vital inflammatory factor in the microenvironment. The PM2.5-related CpG site cg16947394 was associated with the TMBIM1 gene, whereas the presence of rs992157 in the intron of PNKD and TMBIM1s is significantly associated with CRC progression and susceptibility.

Conclusions

The current study confirmed the deleterious effect of air pollution on CRC risk and survival and the impact of epigenetic alterations of TMBIM1/PNKD, CXCR5 and TMEM110 on CRC pathogenesis. Future studies are needed to elucidate the underlying mechanism by which epigenetic changes cause colon cancer development. In particular, the current study identified some modifiable factors such as physical activity, smoking and air pollution that may contribute to the prevention of colorectal cancer.

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