COPD-dependent effects of genetic variation in key inflammation pathway genes on lung cancer risk

Genome-wide association studies (GWAS) have identified several loci contributing to lung cancer and COPD risk independently; however, inflammation-related pathways likely harbor additional lung cancer risk-associated variants in biologically relevant immune genes that differ dependent on COPD. We selected single nucleotide polymorphisms (SNPs) proximal to 2,069 genes within 48 immune pathways. We modeled the contribution of these variants to lung cancer risk in a discovery sample of 1,932 lung cancer cases and controls stratified by COPD status and validation sample of 953 cases and controls also stratified by COPD. There were 43 validated SNPs in those with COPD and 60 SNPs in those without COPD associated with lung cancer risk. Furthermore, 29 of 43 and 28 of 60 SNPs demonstrated a statistically significant interaction with COPD in the pooled sample. These variants demonstrated tissue-dependent effects on proximal gene expression, enhanced network connectivity and resided together in specific immune pathways. These results reveal that key inflammatory related genes and pathways, not found in prior GWAS, impact lung cancer risk in a COPD-dependent manner. Genetic variation identified in our study supplements prior lung cancer GWAS and serves as a foundation to further interrogate risk relationships in smoking and COPD populations.     

Germline variation in NCF4, an innate immunity gene,is associated with an increased risk of colorectal cancer

Chronic inflammation has been implicated in the etiology of colorectal adenoma and cancer; however, few key inflammatory genes mediating this relationship have been identified. In this study, we investigated the association of germline variation in innate immunity genes in relation to the risk of colorectal neoplasia. Our study was based on the analysis of samples collected from the prostate, lung, colorectal and ovarian (PLCO) Cancer Screening Trial. We investigated the association between 196 tag single nucleotide polymorphisms (SNPs) in 20 key innate immunity genes with risk of advanced colorectal adenoma and cancer in 719 adenoma cases, 481 cancer cases and 719 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). After Bonferroni correction, the AG/GG genotype of rs5995355, which is upstream of NCF4, was associated with an increased risk of colorectal cancer (OR = 2.43, 95% CI = 1.73–3.39; p < 0.0001). NCF4 is part of the NAPDH complex, a key factor in biochemical pathways and the innate immune response. While not definitive, our analyses suggest that the variant allele does not affect expression of NCF4, but rather modulates activity of the NADPH complex. Additional studies on the functional consequences of rs5995355 in NCF4 may help to clarify the mechanistic link between inflammation and colorectal cancer.     

Variation in innate immunity genes and risk of multiple myeloma

Multiple myeloma (MM) is a B‐cell lymphoid malignancy suspected to be associated with immunologic factors. Given recent findings associating single‐nucleotide polymorphisms (SNPs) in innate immunity genes with non‐Hodgkin lymphoma, we conducted an investigation of innate immune gene variants using specimens from a population‐based case‐control study of MM conducted in Connecticut women. Tag SNPs (N = 1461) summarizing common variation in 149 gene regions were genotyped in non‐Hispanic Caucasian subjects (103 cases, 475 controls). Odds ratios (OR) and 95% confidence intervals (CI) relating SNP associations with MM were computed using unconditional logistic regression, while the MinP test was used to investigate associations with MM at the gene level. We calculated permutation‐adjusted P‐values and false discovery rates (FDR) to account for the number of comparisons performed in SNP‐level and gene‐level tests, respectively. Three genes were associated with MM when controlling for a FDR of ≤10%: SERPINE1 (P_MinP < 0.0001; FDR = 0.02), CCR7 (P_MinP = 0.0006; FDR = 0.06) and HGF (P_MinP = 0.001; FDR = 0.08). Two SNPs demonstrated robust associations: SERPINE1 rs2227667 (P = 2.1 × 10^?5, P_permutation = 0.03) and HGF rs17501108 (P = 5.0 × 10^?5, P_permutation = 0.07). Our findings suggest that genetic variants in SERPINE1 and HGF, and possibly CCR7, are associated with MM risk, and warrant further investigation in other studies. Copyright © 2010 John Wiley & Sons, Ltd.     

Tuberculosis and subsequent risk of lung cancer in Xuanwei,China

Tobacco and indoor air pollution from smoky coal are major causes of lung cancer in rural Xuanwei County, China. Tuberculosis has been suggested to increase lung cancer risk, but data from prior studies are limited. We conducted an analysis of data from a retrospective cohort study of 42,422 farmers in Xuanwei. In 1992, interviewers administered a standardized questionnaire that included lifetime medical history, including tuberculosis. Subjects were followed from 1976, with deaths from lung cancer ascertained through 1996. We used proportional hazards regression to assess the association between tuberculosis and subsequent lung cancer mortality. Tuberculosis was reported by 246 subjects (0.6%), and 2,459 (5.8%) died from lung cancer during follow‐up. Lung cancer mortality was substantially higher in subjects with tuberculosis than in those without (25 vs. 3.1 per 1,000 person‐years). The association was especially pronounced in the first 5 years after tuberculosis diagnosis (hazard ratios [HRs] ranging 6.7–13) but remained strong 5–9.9 years (HR 3.4, 95% CI 1.3–9.1) and 10+ years (HR 3.0, 95% CI 1.3–7.3) after tuberculosis. These associations were similar among men and women and among smoky coal users (70.5% of subjects). Adjustment for demographic characteristics, lung disease and tobacco use did not affect results. In Xuanwei, China, tuberculosis is an important risk factor for lung cancer. The increased lung cancer risk, persisting years after a tuberculosis diagnosis, could reflect the effects of chronic pulmonary inflammation and scarring arising from tuberculosis. Published 2008 Wiley‐Liss, Inc.     

Polymorphisms of the interleukin-1 beta gene are associated with increased risk of non-small cell lung cancer

Lung cancer is one of the leading causes of cancer death worldwide. Tobacco smoking is the main risk factor for lung cancer. Less than 20% of smokers develop lung cancer in their lifetime, however, indicating individual variations in lung cancer risk. Pro-inflammatory cytokines produced by inflammatory cells have been associated with inflammatory diseases and cancer. The IL1B gene, encoding IL-1beta cytokine, contains several single nucleotide polymorphisms (SNPs). Two of these are in the promoter region, at positions -511 (C-T) and -31 (T-C). These polymorphisms have been associated with increased risk of developing a number of inflammatory diseases and gastric carcinoma. We genotyped the 2 polymorphisms in 251 non-small cell lung cancer patients from Norway and 272 healthy controls chosen from the general Norwegian population. The T allele at the -31 SNP (p = 0.01) and C allele at -511 SNP (p < 0.01) were over represented in lung cancer cases. The homozygote subjects were particularly at higher risk of lung cancer with odds ratio of 2.39 (95% CI = 1.29-4.44) for -31T/T and 2.51 (95% CI = 1.47-4.58) for -511C/C genotypes. In view of the significance of the p53 gene in lung carcinogenesis, we also analyzed the IL1B genotypes in relation to p53 mutations in the tumors. The results indicated that subjects having homozygote genotypes were more likely to have a mutation in the p53 gene (p = 0.05). This is the first study to provide evidence for an association of 1L1B gene polymorphisms with lung cancer risk.     

Interleukin-10 promoter polymorphism is associated with decreased breast cancer risk

Interleukin-10 (IL-10) is an immunosuppressive cytokine which may facilitate development of cancer by supporting tumor escape from the immune response. A [TCATA] haplotype formed by polymorphisms at positions –3575, –2763, –1082, –819 and –592 in the promoter of the IL-10 gene is a strong determinant for IL-10 expression. The presence of this haplotype can be determined by analysis of the –592C > A polymorphism. Aim of the present study was to analyze the role of the IL-10 [TCATA] haplotype for breast cancer. We performed a case–control study including 500 female patients with histologically confirmed breast cancer and 500 female, age-matched, healthy control subjects from population-based screening studies. The –592C > A polymorphism was determined by a 5-nuclease assay (TaqMan). Frequency of the homozygous –592 AA genotype, indicating homozygosity for the [TCATA] haplotype, was 4.2% among patients and 7.3% among controls (p=0.038; odds ratio 0.56; 95% confidence interval 0.32–0.97). IL-10 genotypes were not associated with tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. Therefore we conclude that the IL-10 –592C > A promoter polymorphism may be associated with a reduced breast cancer risk.     

Association of microsomal epoxide hydrolase polymorphisms and lung cancer risk

Microsomal epoxide hydrolase (mEH) plays a dual role in the detoxification and activation of tobacco procarcinogens. Two polymorphisms affecting enzyme activity have been described in the exons 3 and 4 of the mEH gene, which result in the substitution of amino acids histidine to tyrosine at residue 113, and arginine to histidine at residue 139, respectively. We performed a hospital-based case-control study consisting of 277 newly diagnosed lung cancer patients and 496 control subjects to investigate a possible association between these two polymorphisms and lung cancer risk. The polymorphisms were determined by polymerase chain reaction/restriction fragment length polymorphism and TaqMan assay using DNA from peripheral white blood cells. Logistic regression was performed to calculate odds ratios (ORs), confidence limits (CL) and to control for possible confounders. The exon 3 polymorphism of the mEH gene was associated with a significantly decreased risk of lung cancer. The adjusted OR, calculated relative to subjects with the Tyr113/Tyr113 wild type, for the His113/His113 genotype was 0.38 (95% CL 0.20-0.75). An analysis according to histological subtypes revealed a statistically significant association for adenocarcinomas; the adjusted OR for the His113/His113 genotype was 0.40 (95% CL 0.17-0.94). In contrast, no relationship between the exon 4 polymorphism and lung cancer risk was found. The adjusted OR, calculated relative to the His139/His139 wild type, was for the Arg139/Arg139 genotype 1.83 (0.76-4.44). Our results support the hypothesis that genetically reduced mEH activity may be protective against lung cancer.     

Dinucleotide polymorphism of p73 gene is associated with a reduced risk of lung cancer in a Chinese population

p73, a structural and functional homologue of p53, shares some p53-like tumor suppressor activity but also possesses oncogenic activity. Therefore, p73 plays an important role in modulating cell-cycle control and apoptosis. A potentially functional dinucleotide polymorphism, G4C14-to-A4T14, has been identified in the 5' untranslated region (UTR) of exon 2 of the p73 gene, which may theoretically form a stem-loop structure and affect gene expression. To test the hypothesis that these 2 common variants play a role in lung cancer susceptibility, we conducted a case-control study of 425 lung cancer patients and 588 cancer-free controls frequency-matched to the cases on age and sex in a Chinese population. The results showed that these 2 polymorphisms were in complete linkage disequilibrium and the frequencies of variant p73 AT haplotype (A4T14) were less common in the cases (0.225) than in the controls (0.287) (p = 0.0018), suggesting that this AT haplotype was protective against lung cancer. Compared to the p73 GC/GC homozygotes, both the AT/AT variant homozygotes and GC/AT heterozygotes were associated with a significantly decreased risk (adjusted OR: 0.45, 95% CI: 0.26-0.80 and OR: 0.70, 95% CI: 0.53-0.92, respectively). These results suggest that this p73 dinucleotide polymorphism may have a role in lung cancer susceptibility in our study population. Further studies are needed to elucidate potential functional relevance of the p73 AT variant allele.     

炎症因子与肺癌研究进展

目的：总结分析炎症因子在肺部肿瘤患者血清中的表达水平及其与肺部肿瘤临床病理特征间的关系及相关性。方法：应用PubMed及CNKl期刊全文数据库检索系统,以“炎症、肿瘤和肺”为关键词,检索年限为1996—01—2013—10。共检索到113篇文献,其中英文文献9l篇,中文文献22篇。纳入标准：1）炎症因子的增加或减少与肺部肿瘤的关系：2）炎症因子成为治疗炎症相关性肺部肿瘤的重要靶点。根据纳入标准分析其中40篇文献。结果：白细胞介素一6（inter—leukin-6,IL-6）、移动抑制因子相关蛋白和高迁移率族蛋白Bl均属于促炎因子,在肿瘤的发生和发展中具有重要作用。IL-10和IL-13属于抑炎因子．在恶性肿瘤生长和转移的过程中可以产生截然相反的结果。结论：炎症因子与肺部肿瘤的发生、发展具有相关性,可以促进恶性细胞的增殖和存活,削弱机体的获得性免疫反应,对患者的诊断、治疗及预后有重要意义。     

Elevated levels of the acute‐phase serum amyloid are associated with heightened lung cancer risk

BACKGROUND:

The authors investigated whether early stage lung cancer could be identified by proteomic analyses of plasma.

METHODS:

For the first case‐control study, plasma samples from 52 patients with lung cancer and from a group of 51 controls were analyzed by surface‐enhanced laser desorption/ionization time‐of‐flight mass spectrometry. In a second case‐control study, a classifier of 4 markers (mass‐to‐charge ratio, 11,681, 6843, 5607, and 8762) also was tested for validation on plasma from 16 consecutive patients with screen‐detected cancer versus 406 healthy individuals. The most relevant marker was identified, and an enzyme‐linked immunosorbent assay‐based analysis revealed that signal intensity was correlated with concentration.

RESULTS:

The classifier had a sensitivity of 94.23% and a specificity of 76.47% in the first study but lost predictive value in the second study. Nevertheless, the 11,681 cluster, which was identified as serum amyloid protein A (SAA), resulted in a multiple logistic regression model that indicated a strong association with lung cancer. When both studies were considered as a together, the odds ratio (OR) for an SAA intensity ≥0.5 was 10.27 (95% confidence interval [CI], 4.64‐22.74), whereas an analysis restricted to stage I cancers (TNM classification) revealed an OR of 8.45 (95% CI, 2.76‐25.83) for T1 lung cancer and 21.22 (95% CI, 5.62‐80.14) for T2 lung cancer.

CONCLUSIONS:

SAA levels were predictive of an elevated risk of lung cancer, supporting the general view that inflammation is implicated in lung cancer development. Cancer 2010. © 2010 American Cancer Society.     

肺癌相关血清学肿瘤标志物研究进展

肿瘤生物标志物近年来一直是肿瘤基础和临床研究的一个十分活跃的领域.尽管迄今尚未找到肺癌特异性抗原,国内外研究人员已发现多种有潜力用于肺癌早期诊断、临床分型和分期、预后判断和疗效观察等的肿瘤生物标志.本文以癌胚抗原、神经元特异性烯醇化酶、细胞角蛋白19片段抗原、碳水化合物抗原242、粘蛋白1抗原、神经细胞粘附分子、组织多肽特异性抗原、干细胞因子、血管内皮生长因子、肝细胞生长因子、肺癌相关抗原和磷脂酰肌醇蛋白聚糖等为例,对肺癌相关血清学肿瘤生物标志物的研究进展作一综述.     

A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk

A common 936 C/T polymorphism in the gene for the vascular endothelial growth factor (VEGF) has been associated with VEGF plasma levels. In our case-control study, we investigated the role of this polymorphism for breast cancer risk. VEGF genotype was determined in 500 women with breast cancer and 500 sex- and age-matched healthy control subjects. Carriers of a 936T-allele were more frequent among controls (29.4%) than among patients (17.6%; p = 0.000014). The odds ratio for carriers of a 936T-allele for breast cancer was 0.51 (95% confidence interval 0.38-0.70). Additionally, VEGF plasma levels were determined in 21 nonsmoking post-menopausal controls; carriers of a 936T allele had significantly lower levels (median 23 pg/ml; range 6-50 pg/ml) than noncarriers (37; 21-387; p = 0.034). We conclude that carriers of a VEGF 936T-allele are at decreased risk for breast cancer, this, however, requiring further confirmation in a larger study.     

Prognosis in HIV-infected patients with non-small cell lung cancer

Background:

We conducted a population-based study to evaluate whether non-small cell lung cancer (NSCLC) prognosis was worse in HIV-infected compared with HIV-uninfected patients.

Methods:

Using the Surveillance, Epidemiology and End Results (SEER) registry linked to Medicare claims, we identified 267 HIV-infected patients and 1428 similar controls with no evidence of HIV diagnosed with NSCLC between 1996 and 2007. We used conditional probability function (CPF) analyses to compare survival by HIV status accounting for an increased risk of non-lung cancer death (competing risks) in HIV-infected patients. We used multivariable CPF regression to evaluate lung cancer prognosis by HIV status adjusted for confounders.

Results:

Stage at presentation and use of stage-appropriate lung cancer treatment did not differ by HIV status. Median survival was 6 months (95% confidence interval (CI): 5–8 months) among HIV-infected NSCLC patients compared with 20 months (95% CI: 17–23 months) in patients without evidence of HIV. Multivariable CPF regression showed that HIV was associated with a greater risk of lung cancer-specific death after controlling for confounders and competing risks.

Conclusion:

NSCLC patients with HIV have a poorer prognosis than patients without evidence of HIV. NSCLC may exhibit more aggressive behaviour in the setting of HIV.     

Signal-transducing innate receptors in tumor immunity

The signal-transducing innate receptors represent classes of pattern recognition receptors (PRRs) that play crucial roles in the first line of the host defense against infections by the recognition of pathogen-derived molecules. Because of their poorly discriminative nature compared with antigen receptors of the adaptive immune system, they also recognize endogenous molecules and evoke immune responses without infection, resulting in the regulation of tumor immunity. Therefore, PRRs may be promising targets for effective cancer immunotherapy, either by activating or inhibiting them. Here, we summarize our current knowledge of signal-transducing PRRs in the regulation of tumor immunity.     

Increased risk of colorectal cancer among patients with biliary tract inflammation: A 5‐year follow‐up study

The purpose of the study was to investigate the risk of colorectal cancer among patients with biliary tract inflammation (BTI) compared to non‐BTI patients during a 5‐year follow‐up period. The study group comprised 1,613 patients with BTI, among which 32 cases (1.98%) developed colorectal cancer. The comparison group included 8,065 randomly selected subjects (5 for every patient with BTI), 74 of whom contracted colorectal cancer (0.92%). Stratified Cox proportional hazard regressions were calculated to estimate the adjusted hazard of colorectal cancer between the study group and comparison group. The adjusted hazard ratio for colorectal cancer for patients with BTI was 6.54 times (95% CI = 3.07–13.92) as high as for those without BTI within a 1‐year follow‐up period, 3.20 times (95% CI = 1.93–5.30) as high within a 3‐year follow‐up period, and 2.21 times (95% CI = 1.45–3.37) as high within a 5‐year follow‐up period. We also found that the adjusted hazard ratio for colorectal cancer for those with bile duct inflammation was 3.30 times (95% CI = 1.87–5.84) as high as for those without BTI within the 5‐year follow‐up period. However, no increased hazard of colorectal cancer was observed for patients with gallbladder inflammation. We concluded that patients with BTI had a significantly higher risk of colorectal cancer compared to patients without BTI.     

Occupational X-ray examinations and lung cancer risk

Occupational X-ray examination programs have been conducted in many countries to screen for occupational and nonoccupational respiratory diseases, resulting in widespread exposure to X-radiation. We conducted a multicentre case-control study of lung cancer in the Czech Republic, Hungary, Poland, Romania, Russia and Slovakia, including 2,589 cases and 2,859 controls enrolled during 1998-2002. We collected detailed information on occupational X-ray examinations, occupations and tobacco smoking. We calculated odds ratios of lung cancer via multiple logistic regression after adjustment for age, sex, center and tobacco smoking. Among controls 24.9% reported no X-ray examination, 62.9% reported 1-30 examinations and 12.2% reported more than 30 examinations. When we chose individuals with no examination as the reference group, the odds ratios of lung cancer were 1.21 (95% confidence interval [CI] 0.99-1.48), 1.33 (95% CI 1.08-1.64), 1.49 (95% CI 1.18-1.87), 1.52 (95% CI 1.17-1.99) and 2.15 (95% CI 1.50-3.08) for 1-10, 11-20, 21-30, 31-40 and more than 40 examinations, respectively (p-value of test for linear trend <0.0001). The association between X-ray examinations and lung cancer risk was strong in countries with low prevalence of exposure and absent in countries with high prevalence of exposure. Odds ratios for X-ray examinations were lower among smokers than among nonsmokers. The magnitude of the increased risk observed is higher than expected on the basis of other studies of radiation-exposed populations. Although the association we detected between X-ray examinations and lung cancer risk may reflect a carcinogenic effect of repeated exposure to low-level ionizing radiation, reporting bias and particularly uncontrolled confounding by occupational exposure to carcinogens are also likely explanations of the results.     

肺癌患者血清中21种细胞因子的表达水平及其临床意义

目的:检测肺癌患者血清中21种细胞因子[干扰素诱导的T细胞趋化因子(IFN-inducible T cellαchemoattractant,ITAC)、GM-CSF、Fractalkine、IFN-γ、IL-10、巨噬细胞炎性蛋白-3α(macrophage inflammatory protein-3α,MIP-3α)]、IL-12(p70)、IL-13、IL-17A、IL-1β、IL-2、IL-4、IL-21 、IL-23、IL-5、IL-6、IL-7、IL-8、MIP-1α、MIP-1β和TNF-α的表达情况并分析其意义.方法:收集2015年3月至6月的山西省肿瘤医院40例肺癌患者;采用液相芯片技术检测30名健康人和40例初诊肺癌患者治疗前血清中21种细胞因子的表达水平,分析其与肺癌临床特征之间的关系及表达存在明显差异细胞因子间的相关性.结果:肺癌患者血清中11种细胞因子[(GM-CSF、Fractalkine、IFN-γ、MIP-3α、IL-12 (p70)、IL-1β、IL-2、IL-6、IL-7、IL-8、TNF-α]的表达水平明显升高(P＜0.05或P＜0.01),肺癌患者非转移组与转移组血清中21种细胞因子的表达水平比较无明显差异(P＞0.05),肺腺癌(adenocarcinoma,AC)组血清IFN-γ与MIP-1β水平明显高于鳞癌(squamous cell carcinoma,SCC)组(均P＜0.05),肺SCC组血清ITAC表达水平明显高于小细胞肺癌(small cell lung cancer,SCLC)组(P＜0.05).高表达的11种细胞因子在两组间表达的相关性不同.结论:肺癌患者血清中IL-6、IL-8等11种细胞因子表达升高,可能参与了肺癌发生发展,这些高表达的细胞因子或许可用于肺癌的辅助诊断,并为肺癌治疗提供新的靶标.     

Molecular pathways and therapeutic targets in lung cancer

Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review.