CHICAGO – Clonal hematopoiesis of indeterminate potential (CHIP) exacerbates the negative impact of air pollution and spurs the pathogenic process leading to non-small cell lung cancer in non-smokers, researchers at the American Society of Clinical Oncology's annual meeting proposed on Saturday.
"CHIP is a key mediator of this relationship between air pollution and lung cancer, acting as a driving force behind tumor-promoting inflammation," Marco Buttigieg, a graduate student at the department of pathology and molecular medicine at Queen's University in Toronto, said in presenting data at the meeting from a study exploring the relationship between CHIP, air pollution, and NSCLC development in never-smokers using data from the UK Biobank.
Although smoking is a primary cause of lung cancer, up to 25 percent of patients worldwide have never smoked, and the interplay of environmental and biological factors in lung cancer development in never-smokers is not well understood. At this same meeting last year, researchers led by the Francis Crick Institute's Charles Swanton reported they had found a significant association between levels of small particulate matter air pollution 2.5 µm in diameter or smaller (PM2.5) and the incidence of lung cancer in never-smokers, based on an analysis of nearly 33,000 EGFR-driven NSCLC cases in the UK Biobank longitudinal cohort study.
As described in a subsequent Nature paper, Swanton and colleagues also exposed normal lung tissue in mice to diesel particulates in these experiments and found that this drew pro-inflammatory macrophages into the lungs, causing epithelial cells to mutate, proliferate, and eventually become cancerous.
High levels of PM2.5 are a sign of air pollution typically due to car exhaust and other fuels. While research has linked PM2.5 levels to lung cancer, lots of people exposed to air pollution don't develop it.
At this year's ASCO annual meeting, Buttigieg and colleagues sought to explore the interaction between air pollution and CHIP in NSCLC development. CHIP is a condition in which people's hematopoietic stem cells acquire somatic mutations as they age. CHIP is pretty common in the general population and occurs in 20 percent of elderly individuals, Buttigieg estimated, adding that while most of these mutations in hematopoietic stem cells tend to be benign, "occasionally, they will be pathogenic and provide some sort of proliferative advantage to the cells, allowing the cells to expand and occupy blood cell production."
CHIP was initially found to be a precursor for certain blood cancers, and people with CHIP tend to have higher mortality compared to the general population. "This relationship stems from the fact that the mutations that drive CHIP rely on inflammation to spur their clonal expansion," Buttigieg explained. "This ultimately leads to heightened systemic inflammation and the production of hyper-inflammatory immune cells, and these wreak havoc across the body leading to a number of chronic and age-related conditions."
To explore the specific question of the role that CHIP plays in concert with PM2.5 in NSCLC, Buttigieg and colleagues drew on genomic data from approximately 450,000 participants in the UK Biobank; NSCLC incidence data from the UK cancer registry; and regional measures of PM2.5 exposure from 2010. Specifically, researchers gauged patients' CHIP status from whole-genome sequencing analysis performed on UK Biobank participants' peripheral blood samples.
They identified more than 15,000 participants in the biobank, or 3.4 percent, who had CHIP. And among nearly 2,000 NSCLC cases, approximately 300 were never-smokers.
Researchers found that PM2.5 levels were neither independently associated with NSCLC in non-smokers, nor were they associated with whether patients were more likely to have CHIP.
However, Buttigieg and colleagues did find after adjusting and stratifying for smoking status, that CHIP status was associated with a significant increase in lung cancer risk, and that it doubled the risk of lung cancer in non-smokers. "This effect was even more pronounced for what we call large CHIP clones, which are CHIP clones where the mutations are going to impact more than 20 percent of immune cells," Buttigieg said. Moreover, the interaction between PM2.5 and CHIP appeared to increase levels of C-reactive peptide and IL6, which are systemic proinflammatory markers.
"Small particulate matter air pollution seems to become relevant to the picture only when it's considered in the context of an interaction with CHIP," Buttigieg said. "What we see here is that the effect of CHIP is predominantly found within those higher exposures to PM2.5 air pollution, and there is a significant interaction between these two variables."
Based on their findings, Buttigieg and colleagues described PM2.5 and CHIP in their study abstract as a "novel gene-environment interaction pair" that play a role in the development of NSCLC in non-smokers. The study demonstrates "the importance of multi-faceted risk prediction in lung cancer," Buttigieg concluded at the meeting.
He further pointed out that the UK, where this study was conducted, has some of the lowest air pollution in the world, with median PM2.5 ambient levels at 9.93 µg/m3. But in other parts of the world, with five to seven times higher PM2.5 ambient levels and higher rates of NSCLC among non-smokers, the effects of CHIP might be greater than what was reported in the present study.
"We're hypothesizing that what's happening in the lungs here is that CHIP is exacerbating this process where the air pollution is drawing these [macrophage] cells in, and the cells create a very inflammatory environment [where] ultimately, the tumors are growing," Buttigieg said, adding that he and his colleagues expect that the interaction between CHIP and air pollution is likely to contribute "substantially to the global burden of lung cancer."