Risk Of Small Cell Lung Cancer Research Articles

Abstract 784: Proteome-wide mendelian randomization identifies causal association between plasma proteins and lung cancer

Abstract Background: Lung cancer is one of the world's main health issues, and the exploration of novel protein markers can help to understand the mechanisms of lung cancer development and the discovery of therapeutic targets. Based on this, we used proteome-wide Mendelian Randomization to determine causal associations between plasma protein levels and the risk of developing lung cancer and subtypes. Methods: We performed a two-sample Mendelian Randomization analysis using genome-wide association data for 4907 proteins from the deCODE genetics study and five lung cancer and its subtypes from the FinnGen database. Causal effects were estimated using the Wald-ratio method or the inverse variance weighted (IVW) method, with additional analyses using the other four common methods when the number of SNPs was more than one. The Steiger filter method was used to test the correct direction of the causal effect. Multiple corrections were utilized by the Benjamini-Hochberg method. Results: After filtering, we finally analyzed 4645 proteins for the causal association with lung cancer, and the F-statistic of the instrumental variable for each protein was more than 10. After multiple tests, the levels of four genetically predictive proteins were found to be associated with the risk of lung cancer, and one protein was associated with the risk of small-cell lung cancer. In detail, elevated levels of three genetically predicted proteins were significantly associated with increased risk of lung cancer, namely, SYSC (OR:4.75, 95%CI: 2.47-9.16, FDR=0.007), TM11D (OR: 1.34, 95%CI: 1.17-1.53, FDR=0.02), and PDC6I (OR: 2.35, 95%CI: 1.58-3.49, FDR=0.03). Elevated levels of FASLG (OR: 0.87, 95%CI: 0.82-0.92, FDR=0.007) were associated with a reduced risk of lung cancer. In addition, genetically predicted elevated levels of GRP (OR: 0.05, 95%CI: 0.01-0.17, FDR=0.02) were associated with an increased risk of small-cell lung cancer. The Steiger filter test showed that all directions were from proteins to lung cancer. Conclusion: In this study, we found that five proteins may have effects on the risk of lung cancer, in which genetically predicted SYSC, TM11D, and PDC6I were significantly associated with an increased risk of lung cancer, whereas FASLG and GRP were associated with a decreased risk of lung cancer and small-cell lung cancer, respectively. The above may help to explore the pathogenesis of lung cancer, but further comprehensive studies are still needed. Citation Format: Guojin Si, Wenxuan Li, Yacong Zhang, Zhangyan Lyu, Fengju Song, Kexin Chen. Proteome-wide mendelian randomization identifies causal association between plasma proteins and lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 784.

Lipid-lowering drugs affect lung cancer risk via sphingolipid metabolism: a drug-target Mendelian randomization study.

Background: The causal relationship between lipid-lowering drug (LLD) use and lung cancer risk is controversial, and the role of sphingolipid metabolism in this effect remains unclear. Methods: Genome-wide association study data on low-density lipoprotein (LDL), apolipoprotein B (ApoB), and triglycerides (TG) were used to develop genetic instrumental variables (IVs) for LLDs. Two-step Mendelian randomization analyses were performed to examine the causal relationship between LLDs and lung cancer risk. The effects of ceramide, sphingosine-1-phosphate (S1P), and ceramidases on lung cancer risk were explored, and the proportions of the effects of LLDs on lung cancer risk mediated by sphingolipid metabolism were calculated. Results: APOB inhibition decreased the lung cancer risk in ever-smokers via ApoB (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.70-0.92, p = 0.010), LDL (OR 0.82, 95% CI 0.71-0.96, p = 0.040), and TG (OR 0.63, 95% CI 0.46-0.83, p = 0.015) reduction by 1 standard deviation (SD), decreased small-cell lung cancer (SCLC) risk via LDL reduction by 1 SD (OR 0.71, 95% CI 0.56-0.90, p = 0.016), and decreased the plasma ceramide level and increased the neutral ceramidase level. APOC3 inhibition decreased the lung adenocarcinoma (LUAD) risk (OR 0.60, 95% CI 0.43-0.84, p = 0.039) but increased SCLC risk (OR 2.18, 95% CI 1.17-4.09, p = 0.029) via ApoB reduction by 1 SD. HMGCR inhibition increased SCLC risk via ApoB reduction by 1 SD (OR 3.04, 95% CI 1.38-6.70, p = 0.014). The LPL agonist decreased SCLC risk via ApoB (OR 0.20, 95% CI 0.07-0.58, p = 0.012) and TG reduction (OR 0.58, 95% CI 0.43-0.77, p = 0.003) while increased the plasma S1P level. PCSK9 inhibition decreased the ceramide level. Neutral ceramidase mediated 8.1% and 9.5% of the reduced lung cancer risk in ever-smokers via ApoB and TG reduction by APOB inhibition, respectively, and mediated 8.7% of the reduced LUAD risk via ApoB reduction by APOC3 inhibition. Conclusion: We elucidated the intricate interplay between LLDs, sphingolipid metabolites, and lung cancer risk. Associations of APOB, APOC3, and HMGCR inhibition and LPL agonist with distinct lung cancer risks underscore the multifaceted nature of these relationships. The observed mediation effects highlight the considerable influence of neutral ceramidase on the lung cancer risk reduction achieved by APOB and APOC3 inhibition.

EP01.01-01 Adenocarcinoma and Small Cell Lung Cancer Risk Associated with Occupation in Women

EP01.01-01 Adenocarcinoma and Small Cell Lung Cancer Risk Associated with Occupation in Women

Exploration of potential novel drug targets and biomarkers for small cell lung cancer by plasma proteome screening.

Background: Small cell lung cancer (SCLC) is characterized by extreme invasiveness and lethality. There have been very few developments in its diagnosis and treatment over the past decades. It is urgently needed to explore potential novel biomarkers and drug targets for SCLC. Methods: Two-sample Mendelian Randomization (MR) was performed to investigate causal associations between SCLC and plasma proteins using genome-wide association studies (GWAS) summary statistics of SCLC from Transdisciplinary Research Into Cancer of the Lung Consortium (nCase = 2,791 vs. nControl = 20,580), and was validated in another cohort (nCase = 2,664 vs. nControl = 21,444). 734 plasma proteins and their genetic instruments of cis-acting protein quantitative trait loci (pQTL) were used, whereas external plasma proteome data was retrieved from deCODE database. Bidirectional MR, Steiger filtering and phenotype scanning were applied to further verify the associations. Results: Seven significant (p < 6.81 × 10-5) plasma protein-SCLC pairs were identified by MR analysis, including ACP5 (OR = 0.76, 95% CI: 0.67-0.86), CPB2 (OR = 0.90, 95% CI: 0.86-0.95), GSTM3 (OR = 0.45, 95% CI: 0.33-0.63), SHMT1 (OR = 0.74, 95% CI: 0.64-0.86), CTSB (OR = 0.79, 95% CI: 0.71-0.88), NTNG1 (OR = 0.81, 95% CI: 0.74-0.90) and FAM171B (OR = 1.40, 95% CI: 1.21-1.62). The external validation confirmed that CPB2, GSTM3 and NTNG1 had protective effects against SCLC, while FAM171B increased SCLC risk. However, the reverse causality analysis revealed that SCLC caused significant changes in plasma levels of most of these proteins, including decreases of ACP5, CPB2, GSTM3 and NTNG1, and the increase of FAM171B. Conclusion: This integrative analysis firstly suggested the causal associations between SCLC and plasma proteins, and the identified several proteins may be promising novel drug targets or biomarkers for SCLC.

Wood dust exposure and small cell lung cancer: a systematic review and meta-analysis.

Occupational exposure role on small cell lung cancer (SCLC) onset has been little studied. Wood dust has been recognized as a human carcinogen, and many occupations have high wood-dust exposure. The aim of this study was therefore to perform a systematic review and meta-analysis of the scientific literature to summarize and analyse the risks of wood dust-related occupations on development of SCLC, taking tobacco use into account. We conducted a literature search of PubMed, EMBASE, Web of Science and Cochrane using a predefined strategy and including case-control and cohort studies assessing occupational exposure to wood dust or wood dust-related occupations. To perform the meta-analysis, the odds ratio (OR) and 95% confidence interval (CI) of each of the studies were extracted. A random-effects model was fitted using the DerSimonian Laird method. Sensitivity and subgroup analyses were performed. Quality was assessed using the Office and Health Assessment and Translation (OHAT) for human and animal studies instrument. Eleven studies with a total of 2,368 SCLC cases and 357,179 controls were included. Overall, exposure to wood dust significantly increases risk of SCLC (RR = 1.41, 95% CI 1.11-1.80), with low heterogeneity between studies (I2 = 40%). The association was maintained in studies conducted on males (RR = 1.41, 95% CI 1.12-1.78) but not in those conducted on females/both sexes (RR = 1.37, 95% CI 0.35-3.44). Sensitivity analysis showed that none of the studies significantly modified the results. Our results support that exposure to wood-dust can increase the risk of SCLC. Although the level of evidence is low, there are strong arguments to recommend the implementation of effective control measures to reduce exposure in occupational settings, as a means of preventing SCLC. The results of this study support that exposure to wood-dust can increase the risk of developing small cell lung cancer. Determining the impact of occupational exposure on workers is essential to improve their individual protection and prevention. There is a strong case for recommending the implementation of control measures to reduce occupational exposure to wood dust, specifically for highly exposed occupations such as carpenters and sawmills, in order to prevent small cell lung cancer.

Occupation as a risk factor of small cell lung cancer

Small cell lung cancer (SCLC) comprises approximately 10% of all lung cancer cases. Tobacco is its main risk factor; however, occupation might play a role in this specific lung cancer subtype. The effect of occupation on SCLC risk has been hardly studied and therefore we aim to assess the role of occupation on the risk of SCLC. To do this, we designed a multicentric, hospital-based, case–control study. Cases consisted exclusively in SCLC patients and controls were recruited from patients having minor surgery at the participating hospitals. Face to face interviews emphasizing occupation and tobacco consumption were held and residential radon was also measured. Logistic regression models were adjusted with odds ratios with 95%CI as estimations of the effect. 423 cases and 905 controls were included. Smoking prevalence was higher in cases compared to controls. Those who worked in known-risk occupations for lung cancer showed an OR of 2.17 (95%CI 1.33; 3.52), with a similar risk when men were analysed separately. The results were adjusted by age, sex, smoking and indoor radon exposure. Those who worked in known-risk occupations and were moderate or heavy smokers had a SCLC risk of 12.19 (95%CI 5.68–26.38) compared with never or moderate smokers who had not worked in such occupations. Occupation is a relevant risk factor of SCLC, and it seems that its effect is boosted when tobacco smoking is present.

TLR4 regulatory region variants reduce the susceptibility of small-cell lung cancer in Chinese population.

Toll-like receptors (TLRs) participate in the induction and regulation of immune responses and are closely related to the occurrence and development of small-cell lung cancer (SCLC). This study aimed to investigate the impact of polymorphisms in the regulatory regions of TLRs on the susceptibility of SCLC. The case-control study included 304 SCLC patients and 304 healthy controls. TLRs gene polymorphisms were genotyped by PCR-restrictive fragment length polymorphism analysis and TaqMan assay. Unconditional logistic regression was used to estimate odds ratio (OR) and its 95% confidence interval (95% CI). Our results showed that TLR4 rs1927914 GG genotype and TLR4 rs7869402 TT genotype reduced the risk of SCLC with OR (95% CI) of 0.54 (0.32-0.90) and 0.47 (0.28-0.80), respectively. Stratified analysis suggested that TLR4 rs1927914 GG genotypes significantly reduced the risk of SCLC among male (OR = 0.35; 95% CI, 0.18-0.69; P < 0.01), the younger patients (OR = 0.49; 95% CI, 0.26-0.94; P = 0.03) and non-drinkers (OR = 0.47; 95% CI, 0.24-0.89; P = 0.02). TLR4 rs7869402 CT or TT genotype significantly reduced the susceptibility to SCLC among male patients (OR = 0.37; 95% CI, 0.19-0.71, P < 0.01), the younger patients (OR = 0.41; 95% CI, 0.22-0.79; P < 0.01), smokers (OR = 0.25; 95% CI, 0.10-0.60; P < 0.01) and drinkers (OR = 0.31; 95% CI, 0.11-0.88; P = 0.03). TLR3 rs5743303, TLR4 rs11536891, TLR5 rs1640816 and TLR7 rs3853839 had no significant correlation with the risk of SCLC. These findings emphasized the important role of TLR4 in the development of SCLC.

Clinical characteristics and prognostic model for extensive-stage small cell lung cancer: A retrospective study over an 8-year period.

BackgroundSmall cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with a short replication time and a rapid growth rate. Prognostic factors for SCLC in clinical practice are scarce. Retrospective analysis of 8‐year extensive‐stage SCLC data from the Department Respiratory and Intensive Care Unit, Peking Union Medical College Hospital (Beijing, China) was performed to develop a risk prediction model that can facilitate the identification of extensive‐stage SCLC with differing prognosis in clinical practice.MethodsA retrospective analysis of data from patients with extensive‐stage SCLC at a single‐center from January 2013 to January 2021, including age, sex, ECOG physical score, immunohistochemistry (CgA, Syn, CD56, TTF1, and Ki67), staging, treatment regimen, laboratory examinations, and survival period, was performed. Clinical variables with potential prognostic significance were screened by univariate Cox analysis. Next, multifactor Cox risk prediction regression analysis was performed to establish an extensive‐stage SCLC risk prognostic model. Survival curves and ROC curves for high and low risk groups were plotted according to risk scores. Nomogram and calibration curves were developed to assess the accuracy of the risk prediction model.ResultsThis study included 300 patients who were diagnosed with extensive‐stage SCLC at our center from January 2013 to January 2021. The most common first presentation was respiratory symptoms, especially cough (162, 54%). The most common extra‐thoracic metastatic organs were bone (36.3%), liver (24.7%), brain (15.7%), and adrenal glands (15.7%). A total of 99% of patients received first‐line systemic therapy, with 86.3% of patients treated with platinum‐etoposide and 10.7% of patients treated with immune checkpoint inhibitor combined with platinum‐etoposide backbone. First‐line progression‐free survival was up to 198 days, and the median OS was 439 days. After Cox regression screening and backward stepwise selection, “time from initial therapy to relapse or progression (PFS1), liver metastases, adrenal metastases, M stage and first‐line treatment pattern” were retained to establish a prognostic model with an AUC value of 0.763. The prognostic model was shown as a nomogram with good agreement between predicted and observed outcomes.ConclusionsThe first‐line treatment of SCLC patients admitted to our hospital in the past 8 years was relatively standardized, and the progression‐free survival and OS were slightly longer than those reported in the literature. We developed a prognostic risk score model for extensive‐stage SCLC to calculate individual survival in clinical practice.

Residential Radon and Small Cell Lung Cancer. Final Results of the Small Cell Study

IntroductionResidential radon is considered the second cause of lung cancer and the first in never smokers. Nevertheless, there is little information regarding the association between elevated radon levels and small cell lung cancer (SCLC). We aimed to assess the effect of residential radon exposure on the risk of SCLC in general population through a multicentric case–control study. MethodsA multicentric hospital-based case–control study was designed including 9 hospitals from Spain and Portugal, mostly including radon-prone areas. Indoor radon was measured using Solid State Nuclear Track Detectors at the Galician Radon Laboratory. ResultsA total of 375 cases and 902 controls were included, with 24.5% of cases being women. The median number of years living in the measured dwelling was higher than 25 years for both cases and controls. There was a statistically significant association for those exposed to concentrations higher than the EPA action level of 148Bq/m3, with an Odds Ratio of 2.08 (95%CI: 1.03–4.39) compared to those exposed to concentrations lower than 50Bq/m3. When using a dose-response model with 100Bq/m3 as a reference, it can be observed a linear effect for small cell lung cancer risk. Smokers exposed to higher radon concentrations pose a much higher risk of SCLC compared to smokers exposed to lower indoor radon concentrations. ConclusionsRadon exposure seems to increase the risk of small cell lung cancer with a linear dose-response pattern. Tobacco consumption may also produce an important effect modification for radon exposure.

Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer: A Mendelian Randomization Analysis.

Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non-small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.

Racial and Ethnic Differences in the Relationship between Aspirin Use and Non–Small Cell Lung Cancer Risk and Survival

African Americans (AA) experience higher incidence and mortality of lung cancer as compared with European Americans (EA). Inflammation is associated with lung cancer, many aspects of which differ between AA and EA. We investigated whether use, frequency, and duration of the anti-inflammatory drug aspirin were associated with lung cancer risk and survival, separately among AA and EA populations. Using data from the Maryland Non-Small Cell Lung Cancer (NSCLC) Case-Control Study (1,220 cases [404 AA and 816 EA] and 1,634 controls [1,004 EA and 630 AA]), we estimated the adjusted odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI) of the associations between aspirin use and NSCLC risk and survival, respectively. Any aspirin use (OR: 0.66; 95% CI, 0.49-0.89), daily use of ≥ 1 tablet (OR: 0.68; 95% CI, 0.50-0.90), and use for ≥ 3 years (OR: 0.61; 95% CI, 0.44-0.85) was associated with lower NSCLC risk only among men, even after adjustment for covariates including body mass index and global genetic ancestry. These variables were also associated with improved survival, but only among AA (HR: 0.64; 95% CI, 0.46-0.91; HR: 0.61; 95% CI, 0.42-0.90; and HR: 0.60; 95% CI, 0.39-0.92, respectively). Tylenol and other NSAIDs were either associated with elevated or no NSCLC risk. Aspirin use is associated with lower risk of NSCLC among men and improved survival among AA. Preventive regular aspirin use could be considered among men and AA.

Methylation-derived Neutrophil-to-Lymphocyte Ratio and Lung Cancer Risk in Heavy Smokers.

The neutrophil-to-lymphocyte ratio (NLR) is a biomarker that indicates systemic inflammation and can be estimated using array-based DNA methylation data as methylation-derived NLR (mdNLR). We assessed the relationship between prediagnosis mdNLR and lung cancer risk in a nested case-control study in the β-Carotene and Retinol Efficacy Trial (CARET) of individuals at high risk for lung cancer due to heavy smoking or substantial occupational asbestos exposure. We matched 319 incident lung cancer cases to controls based on age at blood draw, smoking, sex, race, asbestos, enrollment year, and time at risk. We computed mdNLR using the ratio of predicted granulocyte and lymphocyte proportions derived from DNA methylation signatures in whole blood collected prior to diagnosis (median 4.4 years in cases). Mean mdNLR was higher in cases than controls (2.06 vs. 1.86, P = 0.03). Conditional logistic regression models adjusted for potential confounders revealed a 21% increased risk of lung cancer per unit increase in mdNLR [OR 1.21; 95% confidence interval (CI) 1.01-1.45]. A 30% increased risk of non-small cell lung cancer (NSCLC) was observed for each unit increase in mdNLR (n = 240 pairs; OR 1.30, 95% CI, 1.03-1.63), and there was no statistically significant association between mdNLR and small-cell lung cancer risk. The mdNLR-NSCLC association was most pronounced in those with asbestos exposure (n = 42 male pairs; OR 3.39; 95% CI, 1.32-8.67). A better understanding of the role of mdNLR in lung cancer etiology may improve prevention and detection of lung cancer. Cancer Prev Res; 11(11); 727-34. ©2018 AACR.

Choice of serum tumor markers in patients with small cell lung cancer: progastrin-releasing peptide, neuron-specific enolase, and carcinoembryonic antigen

Abstract Lung cancer is a leading cause of cancer-related deaths worldwide. It mainly consists of 2 histological types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC, including squamous cell carcinoma and adenocarcinoma). The present study aimed to assess the role of serum progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE), and carcinoembryonic antigen (CEA) and their combinations in the histological diagnosis of lung cancer (specially SCLC), which is of great importance for the initiation of treatment and prognostic implications. Serum ProGRP, NSE, and CEA were determined by the electrochemiluminescence immunoassay (ECLIA) in 66 patients with SCLC, 73 with adenocarcinoma, 44 with squamous cell carcinoma, 45 with non-malignant pulmonary diseases, and 50 healthy controls. Receiver operating characteristic curves were constructed to compare the predictive ability of each biochemical marker and their combined detection models to discriminate among the patients with lung cancers of different histological groups, benign pulmonary diseases and healthy individuals. In the ECLIA detection system, ProGRP showed the sensitivity and specificity for SCLC diagnosis were 71.2% and 91.1% to 93.2%, respectively. Among the markers, the largest area under the ROCs was for ProGRP in discriminating SCLC from benign pulmonary diseases, squamous cell carcinoma and adenocarcinoma (0.815, 0.859, and 0.835, respectively), which indicated that ProGRP was the most efficient marker for identifying SCLC. Besides, ProGRP and NSE exhibited almost equivalent diagnostic performance in discriminating SCLC from benign diseases. As for squamous cell carcinoma, we recommended proGRP, while for adenocarcinoma, the combination of proGRP and CEA was preferred. Remarkably, when ProGRP ≤ 66 pg/mL, CEA was of great value in diagnosing SCLC and adenocarcinoma. If CEA ≤ 5 ng/mL, the patient was at higher risk for SCLC, whereas the patient was more likely to be diagnosed with adenocarcinoma. Our study provided promising information about the diagnostic values of serum ProGRP, NSE, CEA in distinguishing SCLC from benign pulmonary diseases and NSCLC, which was of crucial clinical significance in the early diagnosis and therapy of SCLC.

Residential radon and small cell lung cancer. A systematic review

Residential radon exposure is considered the second cause of lung cancer and the first in never smokers. Nevertheless, the association between the different histological types of lung cancer and radon is not completely clear, and radon effect on small cell lung cancer is not completely understood. We aim to asses the effect of residential radon exposure on the risk of small cell lung cancer (SCLC) in general population and miners through a systematic review applying predefined inclusion and exclusion criteria. 16 studies were included. Most of them point to a relationship between indoor radon and SCLC, though some investigations show no association. When comparing the risk of SCLC due to radon exposure with NSCLC, it can be observed that an increased risk for SCLC is present. Small cell lung cancer seems to be the histological type of lung cancer most tightly related with residential radon.

NQO1C609T polymorphism and lung cancer susceptibility: Evidence from a comprehensive meta-analysis

A variety of case-control studies have been performed to assess the correlation between NQO1 C609T polymorphism and the risk of lung cancer, but an explicit consensus has not been reached. We conducted this updated meta-analysis to identify the function of NQO1 C609T polymorphism in lung cancer risk. All relevant literature was retrieved from the PubMed, EMBASE, CNKI, and WanFang databases before April 2017. A total of 37 studies (29 articles) with 8493 cases and 10,999 controls were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of relations. We found that the NQO1 C609T polymorphism did not correlate with the risk of lung cancer in the overall analysis. In addition, no statistical significance was observed in the analysis stratified based on ethnicity, control source, quality score, or smoking status. A significant association was found in the subgroup of small cell lung cancer risk. Despite some limitations, this meta-analysis indicates that the NQO1 C609T polymorphism may not be associated with lung cancer risk. However, more epidemiological studies of larger samples and more ethnicities are needed to confirm these results.

Identification of Small and Non-Small Cell Lung Cancer Markers in Peripheral Blood Using Cytokinesis-Blocked Micronucleus and Spectral Karyotyping Assays

Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer. There is an urgent need to develop tools to identify individuals at high risk of developing SCLC. We have previously reported that the cytokinesis-blocked micronucleus (CBMN) assay is a strong predictor of non-small cell lung cancer (NSCLC). Here, we investigate the sensitivity of the CBMN endpoints as predictors of SCLC risk. We conducted the CBMN assay on SCLC patients (n = 216), NSCLC patients (n = 173), and healthy controls (n = 204). Per sample, 1,000 binucleated cells (BN) were scored, and 3 endpoints, micronuclei (BN-MN), nucleoplasmic bridges (BN-NPB), and nuclear buds(BN-BUD), were recorded. Spectral karyotyping was also conducted on SCLC patients (n = 116) and NSCLC patients (n = 137) to identify genomic regions unique to each disease. Significantly higher levels of CBMN endpoints were observed in both cancer groups compared to controls. BN-NPBs were significantly higher among SCLC patients compared to NSCLC patients (p < 0.001). Chromosomes 5 and 17 were associated with BN-MN, and chromosomes 5, 18, 20, and 22 were associated with BN-NPBs in SCLC patients. Given the high frequency of chromosome aberrations observed in SCLC, events such as reinsertion of the micronucleus and chromothripsis may be potential mechanisms for the genetic instability in these patients.

Single nucleotide polymorphism rs3124599 in Notch1 is associated with the risk of lung cancer in northeast Chinese non-smoking females.

Lung cancer is one of the most common cancers and the main cause of cancer-related deaths. Notch1 might play a part in tumorigenesis of lung cancer. Here we explored the relationship of three SNPs (rs3124599, rs3124607 and rs3124594) in Notch1 with the risk and the survival of lung cancer in non-smoking females, including 556 cases and 395 controls. Chi-square tests, logistic regression analysis and crossover analysis were conducted to estimate the association between SNPs and the risk of lung cancer and the interaction between SNPs and environmental exposure. Survival analysis was conducted to explore the association between SNPs and survival of lung cancer. The results demonstrated that the polymorphism of rs3124599 was associated with the susceptibility of lung cancer in recessive model (AA+AG vs. GG). Compared to the those with AA or AG genotype, individuals with GG genotype had a 1.562-fold increased risk of lung cancer (P = 0.023, OR = 1.562, 95% CI = 1.062-2.297). In stratified analysis, the GG genotype of rs3124599 would increase the risk of small cell lung cancer (SCLC) (P = 0.011, OR = 2.167, 95% CI = 1.193-3.396). However, no significant interaction between rs3124599 and cooking oil fume exposure was observed either in addictive model or multiplicative model. The results of survival analysis showed there was no significant association between SNPs and prognosis of lung cancer (P = 0.949 for rs3124599, P = 0.508 for rs3124607, P = 0.884 for rs3124594). Our study might indicate that rs312599 in Notch1 may be a novel biomarker for SCLC risk in Chinese non-smoking females

Pretreatment Albumin/Globulin Ratio Predicts the Prognosis for Small-Cell Lung Cancer.

The pretreatment albumin/globulin ratio (AGR) has been used as a prognostic factor in various cancers. This study aimed to evaluate the predictive value of AGR in small-cell lung cancer (SCLC).We tested albumin and total proteins in plasma samples from 276 SCLC patients from our cancer center between January 2003 and December 2006. The AGR was defined by the formula: albumin/(total proteins–albumin). The correlation between AGR and overall survival (OS) was examined by Kaplan–Meier and Cox regression methods. For validation, AGR was used to evaluate the prognosis of SCLC in another independent group.Total 276 patients (testing) and 379 patients (validation) were finally enrolled. The median OS was 15.31 months for testing patients and 15.06 months for validation patients, respectively. We determined 1.29 as the cutoff value by using the biostatistical tool (Cutoff Finder), then the patients in the testing group were classified into 2 groups. Kaplan–Meier curves showed high AGR group had significantly longer OS than low AGR group (P = 0.026). According to multivariate analyses, AGR was an independent prognostic factor for OS of SCLC patients in the testing group (HR, 1.35, 95% CI: 1.01–1.81, P = 0.046). In the validation group, AGR was also verified as a predictive factor for OS (P < 0.001), and the risk of SCLC in the low AGR group was 1.43 times higher than that in the high AGR group (HR, 1.43, 95% CI: 1.05–1.94, P = 0.022).AGR is an independent prognostic marker in SCLC patients. Furthermore, it could be of great value in the management of SCLC patients.

Associated Links Among Smoking, Chronic Obstructive Pulmonary Disease, and Small Cell Lung Cancer: A Pooled Analysis in the International Lung Cancer Consortium

BackgroundThe high relapse and mortality rate of small-cell lung cancer (SCLC) fuels the need for epidemiologic study to aid in its prevention. MethodsWe included 24 studies from the ILCCO collaboration. Random-effects panel logistic regression and cubic spline regression were used to estimate the effects of smoking behaviors on SCLC risk and explore their non-linearity. Further, we explored whether the risk of smoking on SCLC was mediated through COPD. FindingsSignificant dose–response relationships of SCLC risk were observed for all quantitative smoking variables. Smoking pack-years were associated with a sharper increase of SCLC risk for pack-years ranged 0 to approximately 50. The former smokers with longer cessation showed a 43%quit_for_5–9years to 89%quit_for_≥20years declined SCLC risk vs. subjects who had quit smoking <5years. Compared with non-COPD subjects, smoking behaviors showed a significantly higher effect on SCLC risk among COPD subjects, and further, COPD patients showed a 1.86-fold higher risk of SCLC. Furthermore, smoking behaviors on SCLC risk were significantly mediated through COPD which accounted for 0.70% to 7.55% of total effects. InterpretationThis is the largest pooling study that provides improved understanding of smoking on SCLC, and further demonstrates a causal pathway through COPD that warrants further experimental study.

Association of the functional BCL-2 rs2279115 genetic variant and small cell lung cancer.

As a well-known oncogene, B cell lymphoma-2 (BCL-2) can promote cancer cell survival through preventing their apoptosis. Several functional BCL-2 single nucleotide polymorphisms (SNPs), such as rs2279115, rs1801018, and rs1564483, have been identified and might contribute to cancer susceptibility. However, the involvement of these SNPs in small cell lung cancer (SCLC) was still unclear. As a result, we investigated associations between these three genetic variants and SCLC risk in a case-control design. Genotypes were determined in two independent case-control sets consisted of 520 SCLC patients and 1040 controls from two medical centers. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated utilizing unconditional logistic regression. We found that only BCL-2 rs2279115 genetic variant significantly contributed to decreased SCLC risk in Chinese Han populations, with the rs2279115 A allele as the protective allele. Stratified analyses of association between BCL2 rs2279115 SNP and SCLC risk indicated that the functional polymorphism was only significantly associated with decreased risk of the limited stage SCLC but not the extensive stage disease. Our results indicate that the BCL-2 rs2279115 genetic variant was associated with SCLC risk in Chinese populations and support the hypothesis that SNPs in regulatory regions of oncogenes might contribute to cancer susceptibility.