This study represents the largest evaluation of innate immunity genes in a population with extremely high coal emission exposure and lung cancer incidence. We found that several SNPs in genes associated with innate immunity were associated with lung cancer risk in Xuanwei, suggesting that innate immunity plays a role in coal-emission related-lung carcinogenesis. Out of six pre-defined pathways (oxidative response; pattern recognition molecules and antimicrobials; integrins/receptors; complement; chemokines; and response genes and tissue factors), the two pathways with the most significant associations were the integrin/receptor and the complement pathways. Even though the most significant findings were based on variation in an untranslated region (5′ or 3′) or an intron, these variants may be markers of causal loci or may influence gene expression.
Chronic inflammation is an important risk factor in the pathogenesis of lung cancer [Coussens & Werb, 2002
; Schottenfeld & Beebe-Dimmer, 2006
; Ames et al., 1995
]. Recurrent and persistent inflammation may cause or facilitate malignant transformation, incite tissue reparative proliferation, and create a microenvironment to promote carcinogenesis and tumor progression. Host’s immunoinflammatory up-regulation may induce carcinogenesis, which was documented in smoking-induced lung cancer [Ballaz & Mulshine, 2003
]. The innate immunity is the first barrier to protect the host from invasion of exogenous chemicals or microbes. There is also some molecular crosstalk between components of the innate immunity and adaptive immunity pathways through pattern recognition receptors and cytokines [Kabelitz & Medzhitov, 2007
]. Coal smoke contains a variety of particulates and chemicals that can stimulate airways and induce acute and chronic inflammatory reaction. The innate immunity system is recruited and activated when individuals inhale the coal smoke. Excessive inflammation can increase the risk of malignant transformation through oxidative DNA damage, or facilitate the carcinogenesis of PAHs in coal smoke. In addition, local chronic inflammation can promote the development of cancer. Tumor-associated macrophages and mast cells are two documented innate immunity facilitators of lung cancer progression [Vella & Finn, 2006
Those genes whose SNPs showed very significant associations or gene-environmental interactions play an important role in innate immunity. FCER2
is known to code a key molecule for B-cell activation and growth. It is a receptor for IgE and is important in regulation of IgE levels. The expression of FCER2
is highly up-regulated in normal activated follicular B cells and in chronic lymphocytic leukemia B cells [Pathan et al., 2008
]. Atopy, defined by the presence of elevated levels of total and specific IgE antibodies, was associated with elevated risk of lung cancer in a meta-analysis [Wang & Diepgen, 2005
]. A few SNPs, including FCER2
rs7249320 (included in our study) and haplotypes of FCER2,
have been found to be associated with a higher level of serum IgE [Laitinen et al., 2000
; Tantisira et al., 2007
]. Our results support the hypothesis that altered IgE level due to genetic variation is involved in lung carcinogenesis. We found three significant tag SNPs, covering from intron 4 to the 3′ end, which overlaps the conserved domain of this gene (CD03590). More SNPs in this region should be investigated to explore the causal locus.
Kallikreins are a group of serine proteases and are implicated in carcinogenesis [Borgono & Diamandis, 2004
]. Expression and genetic polymorphisms of kallikreins have been used as biomarkers for diagnosis and prognosis for hormone-dependent cancers, including prostate cancer, breast cancer, and ovarian cancer [Yousef et al., 2001
; Yousef et al., 2002
; Yousef et al., 2003
]. Kallikreins have also been found to be dysregulated and differentially expressed in lung cancer [Bhattacharjee et al., 2001
; Planque et al., 2005
]. Kallikrein markers might be useful for lung cancer diagnosis and prognosis estimate [Planque et al., 2008
; Sher et al., 2006
]. The chromosome region 19q13.3–q13.4, where KLK15
are localized, is an area known to undergo rearrangements in various tumors [Obiezu & Diamandis, 2005
]. Such rearrangements may lead to dysregulation of expression of involved genes. Consistent with these findings, our results point to the promoter regions of KLK15
as promising functional regions. Epigenetic changes leading to up- or down-regulation of expression of these genes may participate in lung cancer pathogenesis.
Our study is limited by its small sample size and consequently low power to detect effects that may truly exist. Also, given the multiple comparisons carried out, there is a possibility that one or more findings are false positives. As such, our results need to be considered as preliminary. However, the findings derive from a unique population that provides a special model for non-smoking PAH-(particulates) carcinogenesis, and are biologically plausible. A substantially larger case-control study of lung cancer is currently being conducted in this region of China and will provide an opportunity to replicate and extend these findings.
In summary, we found genetic polymorphisms in a number of innate immunity genes that were associated with lung cancer risk in Xuanwei, China. This suggests that innate immunity, especially the regulation of IgE may play a role in the pathogenesis of lung cancer in populations exposed to high levels of PAHs and coal emissions.