Non-Small-Cell Lung Cancer Promotion by Air Pollutants

Abstract

Environmental carcinogenic exposures are major contributors to global disease burden yet how they promote cancer is unclear. Over 70 years ago, the concept of tumour promoting agents driving latent clones to expand was first proposed. In support of this model, recent evidence suggests that human tissue contains a patchwork of mutant clones, some of which harbour oncogenic mutations, and many environmental carcinogens lack a clear mutational signature. We hypothesised that the environmental carcinogen, <2.5μm particulate matter (PM2.5), might promote lung cancer promotion through non-mutagenic mechanisms by acting on pre-existing mutant clones within normal tissues in patients with lung cancer who have never smoked, a disease with a high frequency of EGFR activating mutations. We analysed PM2.5 levels and cancer incidence reported by UK Biobank, Public Health England, Taiwan Chang Gung Memorial Hospital (CGMH) and Korean Samsung Medical Centre (SMC) from a total of 463,679 individuals between 2006-2018. We report associations between PM2.5 levels and the incidence of several cancers, including EGFR mutant lung cancer. We find that pollution on a background of EGFR mutant lung epithelium promotes a progenitor-like cell state and demonstrate that PM accelerates lung cancer progression in EGFR and Kras mutant mouse lung cancer models. Through parallel exposure studies in mouse and human participants, we find evidence that inflammatory mediators, such as interleukin-1ꞵ, may act upon EGFR mutant clones to drive expansion of progenitor cells. Ultradeep mutational profiling of histologically normal lung tissue from 247 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 33% of normal tissue samples, respectively. These results support a tumour-promoting role for PM acting on latent mutant clones in normal lung tissue and add to evidence providing an urgent mandate to address air pollution in urban areas.

Germline mutations and developmental mosaicism underlyingEGFR-mutant lung cancer

“…In the absence of smoking-associated field cancerization or known familial predisposition, the presence of multiple synchronous EGFR -mutant tumors appears paradoxical, and several distinct models have been proposed. Deep sequencing of normal lung tissues has revealed rare oncogenic EGFR mutant alleles in 18% of samples 29 , consistent with the emerging appreciation that cancer-causing mutations may populate apparently healthy aging tissues 30–34 . Any tumors ultimately derived from such mutant EGFR -harboring cells would constitute independent genetic events.…”

“…Recent studies in barrier organs, including skin and esophagus, have indicated that as they age, histologically normal tissues may acquire canonically oncogenic mutations that give rise to small patches of clonal expansion, but without evidence of frank malignancy 30–34 . In the lung, deep sequencing reveals that up to 18% of normal samples have a detectable mutant EGFR allele, and even more cases harbor KRAS and other mutated oncogenes 29 . The high prevalence of normal lung specimens with rare detectable EGFR -mutant alleles due to field cancerization does not explain the occurrence of multiple EGFR -mutant primary tumors described here, since they would be genetically independent, lacking the multiple shared mutations that define the developmental mosaically-derived primaries.…”

“…Unlike mutant EGFR alleles in the context of field cancerization, which represent random independent genetic events, these EGFR mutations within normal tissues may result from early developmental mosaicism, ultimately giving rise to anatomically disparate tumors that also share multiple passenger mutations, consistent with their common clonal origin. The mechanism by which EGFR -mutant lung epithelial cells generate pre-malignant and ultimately invasive cancers is unknown, but recent epidemiological and mouse modeling studies indicate that inflammation associated with air pollution enhances the likelihood that an EGFR -mutant cell will give rise to a malignant tumor 29 . In this context, the high frequency of mutant EGFR allele detection in normal lung is in marked contrast to their virtual absence (<0.1%) in normal skin 29 , raising the possibility that EGF signaling mediates distinct proliferative effects in the lung, thereby contributing to the persistence of mosaically-derived progeny during early lung development.…”

If Smoking Were Eliminated, Which US Counties Would Still Have High Rates of Smoking-Related Cancers?

“…For example, very recent work by Swanton and colleagues has identified a potentially powerful mechanism through which PM 2.5 can contribute to non-small cell lung cancer (NSCLC) in non-smokers, a disease with a high frequency of EGFR mutations (EGFRm). The authors found that PM promotes precursor lung epithelial cells initiated by EGFRm [ 14 ].…”

Peto’s paradox revisited: black box vs mechanistic approaches to understanding the roles of mutations and promoting factors in cancer

“…It is possible that in the coming decades we may experience a new wave of lung cancers due to vaping, if indeed promotion is the rate limiting step for development of this disease. Recent data on links between air pollution and lung cancer in non-smokers support this possibility, as a combination of epidemiological, molecular, and mechanistic studies highlight the role of pollutants as promoters of lung cancers worldwide [52]. It would be regrettable if ignorance of these possible mechanisms results in dependence on future black box epidemiologists to identify a strong link between vaping and lung cancer.…”