Molecular epidemiological studies on the relationship between indoor coal burning and lung cancer in Xuan Wei, China

doi:10.1016/j.tox.2004.02.006

Toxicology

Volume 198, Issues 1–3, 20 May 2004, Pages 301-305

https://doi.org/10.1016/j.tox.2004.02.006 Get rights and content

Abstract

The lung cancer mortality rate in Xuan Wei County, China is among the highest in the country and has been associated with exposure to indoor smoky coal emissions that contain high levels of polycylic aromatic hydro carbons. In a case-control study, it was found that the individual susceptibility to lung cancer risk may be increased by GSTM1 null genotype as well as overexpression of the p53 protein. It is likely that the lung cancer excess in Xuan Wei County results from the complex interaction of genetic and environmental factors that will require further research to be understood.

Introduction

The lung cancer mortality rate in Xuan Wei County, China is among the highest in the country (27.7and 25.3 per 100,000 for males and females, respectively) and has been associated with exposure to indoor smoky coal emissions that contain high levels of polycyclic aromatic hydrocarbons (PAHs) (Lan and Robert, 2002). Further, a previous study showed a clear dose-response relationship between benzo(a)pyrene, a carcinogenic and representative member of the PAH family, and lung cancer. As such, the lung cancer experience in Xuan Wei County is both well characterized and relatively unique in that it is caused primarily by a clearly documented environmental exposure (Mumford and He, 1987, He et al., 1991, He et al., 1995).

Advances in molecular biology in the early 1990s made possible the incorporation of molecular methods into epidemiology studies. We were able to take advantage of these approaches to learn more about the pathogenesis of smoky coal-induced lung cancer in Xuan Wei County. The primary goals of the project were as follows:

1.
To determine if the GSTM1 null genotype, a common genetic polymorphism that results in decreased ability to detoxify PAHs, modifies the smoky coal lung cancer relationship; and
2.
to determine if exposure to smoky coal is more strongly associated with lung cancer among cases whose tumor cells abnormally overexpress the p53 protein, which is caused by certain types of mutations in the p53 gene that previously have been linked to PAH exposure.

Section snippets

Methods and materials

In 1994, we designed a population based molecular epidemiology case control study of incident of lung cancer in Xuan Wei County. Between March 1995 and 1996, a total of 122 lung cancer cases that met the study inclusion criteria and 122 individually matched controls were enrolled. A questionnaire was administered by trained interviewers to obtain demographic information, smoking history, and family and personal medical history. In addition, a series of questions were asked to estimate each

Results

Table 1 shows the general characteristics of the cases and controls in the GST study. There were no significant differences in sex, age, fuel type and cigarette smoking.

Table 2 shows the ORs and 95% CIs for lung cancer according to various factors. It was found that the GSTM1 null genotype was associated with a 2.3-fold (95% CI=1.3–4.2) increased risk of lung cancer. When smoky coal exposure was analyzed as a continuous variable and risk per unit dose estimated from the regression equation, the

Discussion

This is the first study to provide evidence that the GSTM1 null genotype is associated with increased risk of lung cancer in Xuan Wei County and that it interacts with smoky coal emissions. Also, it is one of the only examples in the literature of an interaction between a true environmental exposure and genetic susceptibility for cancer risk. Given that GSTM1 plays an important role in detoxifying PAHs such as benzo(a)pyrene, our finding lends weight to the hypothesis that PAHs contribute to

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Sub-multiplicative interaction between polygenic risk score and household coal use in relation to lung adenocarcinoma among never-smoking women in Asia
2021, Environment International
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There was a sub-multiplicative interaction between coal use and PRS, in which the genetic effect estimates were stronger among never coal users compared to ever coal users. We observed similar findings with coal users from Xuanwei, a region of particular scientific interest as it has among the highest lung cancer rates in China (Lan and He, 2004). Similarly, the effect of coal was stronger among those with low genetic susceptibility to lung adenocarcinoma compared to those with high genetic susceptibility.
We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10⁻²⁶). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10⁻³). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.
Quartz in ash, and air in a high lung cancer incidence area in China
2017, Environmental Pollution
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This finding indicates that exposure to quartz is unlikely to be the primary explanatory factor for the lung cancer rates in the area. High exposures to PAHs have previously been reported in the area, in addition to genetic studies which have identified higher lung cancer rates among individuals with variant PAH metabolism genes which together, may provide a better explanation for the high lung cancer rates (Downward et al., 2014a; Lan et al., 2000; Lan and He, 2004). The finding of fibre-like materials in household air samples has not previously been reported in this area, raising the possibility of another exposure metric of interest, however the clinical relevance (if any) of these materials has yet to be determined.
Exposure to crystalline silica (quartz) has been implicated as a potential cause of the high lung cancer rates in the neighbouring counties of Xuanwei and Fuyuan, China, where the domestic combustion of locally sourced “smoky” coal (a bituminous coal) is responsible for some of the highest lung cancer rates in the nation, irrespective of gender or smoking status. Previous studies have shown that smoky coal contains approximately twice as much quartz when compared to alternative fuels in the area, although it is unclear how the quartz in coal relates to household air pollution.
Samples of ash and fine particulate matter (PM_2.5) were collected from 163 households and analysed for quartz content by Fourier transformed infrared spectroscopy (FT-IR). Additionally, air samples from 12 further households, were analysed by scanning electron microscopy (SEM) to evaluate particle structure and silica content.
The majority (89%) of household air samples had undetectable quartz levels (<0.2 μg/m³) with no clear differences by fuel-type. SEM analyses indicated that there were higher amounts of silica in the smoke of smoky coal than smokeless coal (0.27 μg/m³ vs. 0.03 μg/m³). We also identified fibre-like particles in a higher concentration within the smoke of smoky coal than smokeless coal (5800 fibres/m³ vs. 550 fibres/m³). Ash analysis suggested that the bulk of the quartz in smoky coal went on to form part of the ash.
These findings indicate that the quartz within smoky coal does not become adequately airborne during the combustion process to cause significant lung cancer risk, instead going on to form part of the ash. The identification of fibre-like particles in air samples is an interesting finding, although the clinical relevance of this finding remains unclear.
Driver mutations among never smoking female lung cancer tissues in China identify unique EGFR and KRAS mutation pattern associated with household coal burning
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These rates have been partially attributed to known environmental risk factors such as fuel combustion byproducts from indoor heating and cooking and environmental tobacco smoke [5,7]. Xuanwei, China is a unique region in which to study these environmental exposures as it has the highest female prevalence of lung cancer in China and a majority of women are never smokers [6,8,9]. Nearly all Xuanwei women have substantial exposure to indoor air pollution from domestic fuel combustion for heating and cooking [10,11], an established risk factor for lung cancer [12].
Lung cancer in never smokers, which has been partially attributed to household solid fuel use (i.e., coal), is etiologically and clinically different from lung cancer attributed to tobacco smoking. To explore the spectrum of driver mutations among lung cancer tissues from never smokers, specifically in a population where high lung cancer rates have been attributed to indoor air pollution from domestic coal use, multiplexed assays were used to detect >40 point mutations, insertions, and deletions (EGFR, KRAS, BRAF, HER2, NRAS, PIK3CA, MEK1, AKT1, and PTEN) among the lung tumors of confirmed never smoking females from Xuanwei, China [32 adenocarcinomas (ADCs), 7 squamous cell carcinomas (SCCs), 1 adenosquamous carcinoma (ADSC)]. EGFR mutations were detected in 35% of tumors. 46% of these involved EGFR exon 18 G719X, while 14% were exon 21 L858R mutations. KRAS mutations, all of which were G12C_34G>T, were observed in 15% of tumors. EGFR and KRAS mutations were mutually exclusive, and no mutations were observed in the other tested genes. Most point mutations were transversions and were also found in tumors from patients who used coal in their homes. Our high mutation frequencies in EGFR exon 18 and KRAS and low mutation frequency in EGFR exon 21 are strikingly divergent from those in other smoking and never smoking populations from Asia. Given that our subjects live in a region where coal is typically burned indoors, our findings provide new insights into the pathogenesis of lung cancer among never smoking females exposed to indoor air pollution from coal.
Particle-induced oxidative damage of indoor PM<inf>10</inf> from coal burning homes in the lung cancer area of Xuan Wei, China
2013, Atmospheric Environment
Citation Excerpt :
In rural Xuan Wei County, Yunnan Province, the lung cancer mortality rate is among the highest in China, especially in women (27.95 and 24.49 per 100,000 for males and females, respectively) (Mumford et al., 1987). To understand the etiology of lung cancer revealed in this unusual pattern of Xuan Wei, multidisciplinary studies have been conducted since the late 1970s (He et al., 1995; He, 2001; Chuang et al., 1992a, 1992b; Lan et al., 1993; Lan and He, 2004; Zhang and Smith, 2007). Many important findings have shown that lung cancer mortality in Xuan Wei was highly associated with the domestic use of bituminous coals (Mumford et al., 1987; He and Yang, 1994; Lan et al., 2002).
The lung cancer mortality rate in the rural area of the Xuan Wei, Yunnan, is among the highest in China, especially in women. In this paper, the coal-burning indoor and corresponding outdoor PM₁₀ samples were collected at the Hutou village, representing the case of high lung cancer rate, and the Xize village, representing the case of low lung cancer rate. Plasmid scission assay was used to investigate the bioreactivity of the PM₁₀. The inductively coupled plasma-mass spectrometry (ICP-MS) was employed to investigate the trace element compositions of the PM₁₀. The results showed that the oxidative damage caused by both indoor and outdoor PM₁₀ at the Hutou village was obviously higher than that at the Xize village, with the indoor PM₁₀ having higher oxidative damage than corresponding outdoors. Among all analyzed samples, the indoor night PM₁₀ samples from the Hutou village have the highest oxidative capacity. The levels of total water-soluble elements had a higher level in the PM₁₀ of the Hutou village than that of the Xize village. It is interesting that the levels of water-soluble As, Cd, Cs, Pb, Sb, Tl and Zn in PM₁₀ had better positive correlation with DNA damage rates, implying that these elements in their water-soluble state should be one of the main factors responsible for the high oxidative capacity of PM_10, thus possibly the higher lung cancer rates, at the Hutou village.
Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibility
2009, Lung Cancer
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Xuanwei Province in China poses a unique opportunity to assess lung cancer susceptibility in a population with substantial in-home coal smoke exposure, a classified human carcinogen [13]. Xuanwei has the highest prevalence of lung cancer in China [14] and the age-adjusted lung cancer mortality rates for men and women are 27.7 and 25.3 per 100,000, respectively [15]. The similarity of lung cancer rates in Xuanwei men and women is interesting given that nearly all women and few men cook, while most men and nearly no women smoke tobacco [16].
Telomeres are responsible for the protection of the chromosome ends and shortened telomere length has been associated with risk of multiple cancers. Genetic variation in telomere-related genes may alter cancer risk associated with telomere length. Using lung cancer cases (n = 120) and population-based controls (n = 110) from Xuanwei, China, we analyzed telomere length separately and in conjunction with single nucleotide polymorphisms in the telomere maintenance genes POT1, TERT, and TERF2, which we have previously reported were associated with risk of lung cancer in this study. POT1 rs10244817, TERT rs2075786, and TERF2 rs251796 were significantly associated with lung cancer (p_trend ≤ 0.05). The shortest tertile of telomere length was not significantly associated with risk of lung cancer (OR = 1.58; 95% CI = 0.79–3.18) when compared to the longest tertile of telomere length. When stratified by genotype, there was a suggestion of a dose–response relationship between tertiles of telomere length and risk of lung cancer among the POT1 rs10244817 common variant carriers (OR (95% CI) = 1.33 (0.47–3.75), 3.30 (1.14–9.56), respectively) but not among variant genotype carriers (p_interaction = 0.05). Our findings provide evidence that telomere length and genetic variation in telomere maintenance genes may be associated with risk of lung cancer susceptibility and warrant replication in larger studies.
Age-related Effects of Smoking on Lung Cancer Mortality: A Nationwide Case-Control Comparison in 103 Population Centers in China
2008, Annals of Epidemiology
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Finally, our study did not take into account any other environmental exposures related to lung cancer. For example, elevated lung cancer risks from burning coal and biomass fuel have been documented by many studies (29, 30). Since coal and biomass have been commonly used as sources of heating and cooking fuel in the latter half of the last century in China, this increased background lung cancer rate among nonsmokers could lead to lower relative risk of lung cancer from smoking.
To examine age-related effects of smoking on lung cancer mortality in a large population-based case-control study that was incorporated into a nationwide retrospective survey of mortality in China.
Two data sets were pooled for this analysis: national mortality survey data and data from a nationwide case-control comparison. These pooled data were used to calculate age-specific lung cancer death rates by smoking status and expected years of lost life expectancy for each smoking-associated death.
There was a significant excess of deaths (54% of urban deaths, 51% of rural deaths) at 35 to 69 years of age among male smokers and the average loss of life expectancy per smoking-associated death at these ages was 18.3 years. For women ages 35 to 69 years of age, 29% and 11% excess lung cancer mortality was observed in urban and rural smokers, respectively, with an average loss of life expectancy per smoking-associated death of 21.3 years.
Tobacco smoking was associated with a large number of deaths from lung cancer. Utilizing information from a population-based retrospective mortality survey for conducting an analytic epidemiological study of main determinants of disease is feasible and can generate important results.

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Molecular epidemiological studies on the relationship between indoor coal burning and lung cancer in Xuan Wei, China

Abstract

Introduction

Section snippets

Methods and materials

Results

Discussion

Archival analysis of p 53 genetic and protein alterations in Chinese esophageal cancer

Oncogene

An epidemiological study of lung cancer in Xuan Wei County, China: Current progress. Casecontrol study on lung cancer and cooking fuel

Environ. Health Perspect.

An overview of studies on risk factors for lung cancer in Xuan Wei, China (1979–1993)

J. Hyg. Res.