Pre-diagnosis neutrophil-to-lymphocyte ratio and mortality in individuals who develop lung cancer.

PURPOSE: The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation that has been reported to be associated with survival after chronic disease diagnoses, including lung cancer. We hypothesized that the inflammatory profile reflected by pre-diagnosis NLR, rather than the well-studied pre-treatment NLR at diagnosis, may be associated with increased mortality after lung cancer is diagnosed in high-risk heavy smokers. METHODS: We examined associations between pre-diagnosis methylation-derived NLR (mdNLR) and lung cancer-specific and all-cause mortality in 279 non-small lung cancer (NSCLC) and 81 small cell lung cancer (SCLC) cases from the ß-Carotene and Retinol Efficacy Trial (CARET). Cox proportional hazards models were adjusted for age, sex, smoking status, pack years, and time between blood draw and diagnosis, and stratified by stage of disease. Models were run separately by histotype. RESULTS: Among SCLC cases, those with pre-diagnosis mdNLR in the highest quartile had 2.5-fold increased mortality compared to those in the lowest quartile. For each unit increase in pre-diagnosis mdNLR, we observed 22-23% increased mortality (SCLC-specific hazard ratio [HR] = 1.23, 95% confidence interval [CI]: 1.02, 1.48; all-cause HR = 1.22, 95% CI 1.01, 1.46). SCLC associations were strongest for current smokers at blood draw (Interaction Ps = 0.03). Increasing mdNLR was not associated with mortality among NSCLC overall, nor within adenocarcinoma (N = 148) or squamous cell carcinoma (N = 115) case groups. CONCLUSION: Our findings suggest that increased mdNLR, representing a systemic inflammatory profile on average 4.5 years before a SCLC diagnosis, may be associated with mortality in heavy smokers who go on to develop SCLC but not NSCLC.

AHRR methylation in heavy smokers: associations with smoking, lung cancer risk, and lung cancer mortality.

BACKGROUND: A low level of methylation at cg05575921 in the aryl-hydrocarbon receptor repressor (AHRR) gene is robustly associated with smoking, and some studies have observed associations between cg05575921 methylation and increased lung cancer risk and mortality. To prospectively examine whether decreased methylation at cg05575921 may identify high risk subpopulations for lung cancer screening among heavy smokers, and mortality in cases, we evaluated associations between cg05575921 methylation and lung cancer risk and mortality, by histotype, in heavy smokers. METHODS: The ß-Carotene and Retinol Efficacy Trial (CARET) included enrollees ages 45-69 with ≥ 20 pack-year smoking histories and/or occupational asbestos exposure. A subset of CARET participants had cg05575921 methylation available from HumanMethylationEPIC assays of blood collected on average 4.3 years prior to lung cancer diagnosis in cases. Cg05575921 methylation ß-values were treated continuously for a 10% methylation decrease and as quintiles, where quintile 1 (Q1, referent) represents high methylation and Q5, low methylation. We used conditional logistic regression models to examine lung cancer risk overall and by histotype in a nested case-control study including 316 lung cancer cases (diagnosed through 2005) and 316 lung cancer-free controls matched on age (±5 years), sex, race/ethnicity, enrollment year, current/former smoking, asbestos exposure, and follow-up time. Mortality analyses included 372 lung cancer cases diagnosed between 1985 and 2013 with available methylation data. We used Cox proportional hazards models to examine mortality overall and by histotype. RESULTS: Decreased cg05575921 methylation was strongly associated with smoking, even in our population of heavy smokers. We did not observe associations between decreased pre-diagnosis cg05575921 methylation and increased lung cancer risk, overall or by histotype. We observed linear increasing trends for lung cancer-specific mortality across decreasing cg05575921 methylation quintiles for adenocarcinoma and small cell carcinoma (P-trends = 0.01 and 0.04, respectively). CONCLUSIONS: In our study of heavy smokers, decreased cg05575921 methylation was strongly associated with smoking but not increased lung cancer risk. The observed association between cg05575921 methylation and increased mortality in adenocarcinoma and small cell histotypes requires further examination. Our results do not support using decreased cg05575921 methylation as a biomarker for lung cancer screening risk stratification.

Nested case-control study of telomere length and lung cancer risk among heavy smokers in the ß-Carotene and Retinol Efficacy Trial.

BACKGROUND: Telomeres protect cells from genomic instability. We examined telomere length and lung cancer risk prospectively in heavy smokers. METHODS: In a nested case-control study with 709 cases and 1313 controls, conditional logistic regression was used to evaluate associations between telomere length (global, chromosome 5p, and 13q) and lung cancer risk by histotype, controlling for detailed smoking history. RESULTS: Risks of overall lung cancer and adenocarcinoma were suggestively elevated among individuals with telomere length in the longest tertile. No clear patterns were observed for other histotypes, or for chromosome 5p or 13q telomere length. Associations with adenocarcinoma were strongest among (OR, 95% CI for longest versus shortest tertile): former smokers (2.26, 1.03-4.96), individuals <65 years (2.22, 1.13-4.35), and women (2.21, 0.99-4.93). CONCLUSIONS: Our large study of heavy smokers adds additional evidence that long telomere length prior to diagnosis is associated with risk of lung adenocarcinoma, but not other histotypes.

Body mass index and lung cancer risk: a pooled analysis based on nested case-control studies from four cohort studies.

BACKGROUND: Obesity has been proposed as a potential protective factor against lung cancer. We examined the association between BMI and lung cancer risk in a pooled analysis based on nested case-control studies from four cohort studies. METHODS: A case-control study was nested within four cohorts in USA, Europe, China and Singapore that included 4172 cases and 8471 control subjects. BMI at baseline was calculated as weight in kilograms divided by height in meters squared (kg/m2), and classified into 4 categories: underweight (BMI < 18.5), normal weight (18.5 ≤ BMI < 25), overweight (25 ≤ BMI < 30) and obese (≥30). Odds ratios (ORs) and 95% confidence intervals (CIs) for BMI-lung cancer associations were estimated using unconditional logistic regression, adjusting for potential confounders. RESULTS: Considering all participants, and using normal weight as the reference group, a decreased risk of lung cancer was observed for those who were overweight (OR 0.77, 95% CI: 0.68-0.86) and obese (OR 0.69, 95% CI: 0.59-0.82). In the stratified analysis by smoking status, the decreased risk for lung cancer was observed among current, former and never smokers (P for interaction 0.002). The adjusted ORs for overweight and obese groups were 0.79 (95% CI: 0.68-0.92) and 0.75 (95% CI: 0.60-0.93) for current smokers, 0.70 (95% CI: 0.53-0.93) and 0.55 (95% CI: 0.37-0.80) for former smokers, 0.77 (95% CI: 0.59-0.99), and 0.71 (95% CI: 0.44-1.14) for never smokers, respectively. While no statistically significant association was observed for underweight subjects who were current smokers (OR 1.24, 95% CI: 0.98-1.58), former smokers (OR 0.27, 95% CI: 0.12-0.61) and never smokers (OR 0.83, 95% CI: 0.5.-1.28). CONCLUSION: The results of this study provide additional evidence that obesity is associated with a decreased risk of lung cancer. Further biological studies are needed to address this association.

Prior human polyomavirus and papillomavirus infection and incident lung cancer: a nested case-control study.

PURPOSE: To test whether infection with select human polyomaviruses (HPyV) and human papillomaviruses (HPV) is associated with incident lung cancer. METHODS: We performed a nested case-control study, testing serum from the carotene and retinol efficacy trial, conducted 1985-2005, for antibodies to Merkel cell (MCV), KI (KIV), and WU (WUV) HPyVs as well as to six high-risk and two low-risk HPV types. Incident lung cancer cases (n = 200) were frequency-matched with controls (n = 200) on age, enrollment and blood draw dates, intervention arm assignment, and the number of serum freeze/thaw cycles. Sera were tested using multiplex liquid bead microarray antibody assays. We used logistic regression to assess the association between HPyV and HPV antibodies and lung cancer. RESULTS: There was no evidence of a positive association between levels of MCV, KIV, or WUV antibodies and incident lung cancer (p corrected >0.10 for all trend tests; odds ratio (OR) range 0.72-1.09, p corrected >0.10 for all). There was also no evidence for a positive association between HPV 16 or 18 infection and incident lung cancer (p corrected ≥0.10 for all trend tests; OR range 0.25-2.54, p > 0.05 for all OR > 1), but the number of persons with serologic evidence of these infections was small. CONCLUSIONS: Prior infection with any of several types of HPyV or HPV was not associated with subsequent diagnosis of lung cancer. Infection with these viruses likely does not influence a person's risk of lung cancer in Western smoking populations.

Estimated intake of vitamin D and its interaction with vitamin A on lung cancer risk among smokers.

Data are very limited on vitamin D and lung cancer prevention in high-risk populations. The authors investigated whether estimated vitamin D intake was associated with lung cancer risk and whether effect modification by vitamin A existed among current/former heavy smokers and workers with occupational exposure to asbestos. A case-cohort study selected 749 incident lung cancers and 679 noncases from the Carotene and Retinol Efficacy Trial (CARET), 1988-2005. The active intervention was supplementation of 30 mg ß-carotene + 25,000 IU retinyl palmitate/day. Baseline total intake including both diet (from food frequency questionnaire) and personal supplements (from brand names linked to the labeled potencies) was assessed. Hazard ratios (HRs) were estimated by Cox proportional hazard models. No significant association of total vitamin D intake with lung cancer was observed overall. However, total vitamin D intake ≥600 versus <200 IU/day was associated with a lower risk of non-small cell lung cancer among former smokers [HR = 0.36, 95% confidence interval (CI) = 0.13-0.96]. Total vitamin D intake ≥400 versus <400 IU/day was associated with a lower risk of total lung cancer among participants who received the CARET active intervention (HR = 0.56, 95% CI = 0.32-0.99) and among those who had total vitamin A intake ≥1,500 µg/day retinol activity equivalent (RAE; HR = 0.46, 95% CI = 0.23-0.91). The beneficial associations were attenuated among those who did not receive the CARET active intervention or who had total vitamin A intake <1,500 µg/day RAE (p-interaction = 0.02 for current smokers). Our observation suggests that vitamin A may assist vitamin D in preventing lung cancer among smokers.

Serum phospholipid fatty acids, genetic variation in myeloperoxidase, and prostate cancer risk in heavy smokers: a gene-nutrient interaction in the carotene and retinol efficacy trial.

The authors investigated associations of serum phospholipid n-3 and n-6 polyunsaturated fatty acids (PUFAs) and trans-fatty acids with prostate cancer risk, and whether myeloperoxidase G-463A (rs2333227) modified the associations in the Carotene and Retinol Efficacy Trial (CARET) (Seattle, Washington; Irvine, California; New Haven, Connecticut; San Francisco, California; Baltimore, Maryland; and Portland, Oregon, 1985-2003). Prerandomization sera were assayed for fatty acids among 641 men with incident prostate cancer (368 nonaggressive and 273 aggressive (stage III/IV or Gleason score ≥7)) and 1,398 controls. Overall, dihomo-γ-linolenic (quartiles 4 vs. 1: odds ratio (OR) = 0.66, 95% confidence interval (CI): 0.49, 0.95; P(trend) = 0.024) and docosatetraenoic (OR = 0.69, 95% CI: 0.46, 1.02; P(trend) = 0.011) acids were inversely associated with nonaggressive and aggressive prostate cancer risks, respectively. Among men with MPO GG, the genotype upregulating oxidative stress, quartiles 4 versus 1 eicosapentaenoic plus docosahexaenoic acids were suggestively associated with an increased risk of aggressive prostate cancer (OR = 1.66, 95% CI: 0.95, 2.92; P(trend) = 0.07). However, the association was the inverse among men with MPO GA/AA genotypes (P(interaction) = 0.011). Interactions were also observed for docosapentaenoic acid, total n-3 PUFAs, and arachidonic acid. MPO GA/AA vs. GG was associated with a 2-fold increase in aggressive prostate cancer risk among men with low (quartile 1) n-3 PUFAs. This study adds important evidence linking oxidative stress with prostate carcinogenesis.

Contributions of Circulating microRNAs for Early Detection of Lung Cancer.

There is unmet need to develop circulating biomarkers that would enable earlier interception of lung cancer when more effective treatment options are available. Here, a set of 30 miRNAs, selected from a review of the published literature were assessed for their predictive performance in identifying lung cancer cases in the pre-diagnostic setting. The 30 miRNAs were assayed using sera collected from 102 individuals diagnosed with lung cancer within one year following blood draw and 212 controls matched for age, sex, and smoking status. The additive performance of top-performing miRNA candidates in combination with a previously validated four-protein marker panel (4MP) consisting of the precursor form of surfactant protein B (Pro-SFTPB), cancer antigen 125 (CA125), carcinoembryonic antigen (CEA) and cytokeratin-19 fragment (CYFRA21-1) was additionally assessed. Of the 30 miRNAs evaluated, five (miR-320a-3p, miR-210-3p, miR-92a-3p, miR-21-5p, and miR-140-3p) were statistically significantly (Wilcoxon rank sum test p < 0.05) elevated in case sera compared to controls, with individual AUCs ranging from 0.57−0.62. Compared to the 4MP alone, the combination of 3-miRNAs + 4MP improved sensitivity at 95% specificity by 19.1% ((95% CI of difference 0.0−28.6); two-sided p: 0.006). Our findings demonstrate utility for miRNAs for early detection of lung cancer in combination with a four-protein marker panel.

Chromosome 15q24-25.1 variants, diet, and lung cancer susceptibility in cigarette smokers.

BACKGROUND: Studying gene-environment interactions may provide insight about mechanisms underpinning the reported association between chromosome 15q24-25.1 variation and lung cancer susceptibility. METHODS: In a nested case-control study comparing 746 lung cancer cases to 1,477 controls, all of whom were non-Hispanic white smokers in the ß-Carotene and Retinol Efficacy Trial, we examined whether lung cancer risk is associated with single nucleotide polymorphisms (SNPs) tagging the AGPHD1, CHRNA5, CHRNA3, and CHRNB4 genes and whether such risk is modified by diet and other characteristics. Intake of fruits and vegetables, their botanical groups, and specific nutrients were ascertained generally at baseline by food-frequency questionnaire. RESULTS: Several sets of SNPs in high linkage disequilibrium were found: one set associated with a 27-34% increase and two sets associated with a 13-19% decrease in risk per minor allele. Associations were most prominent for the set including the non-synonymous SNP rs16969968. The rs16969968-lung cancer association did not differ by intake level of most dietary factors examined, but was stronger for individuals diagnosed at < 70 years of age or having a baseline smoking history of <40 cigarette pack-years. CONCLUSIONS: Our data suggests that diet has little influence on the relation between chromosome 15q24-25.1 variation and lung cancer risk.

Genetic variation in myeloperoxidase modifies the association of serum α-tocopherol with aggressive prostate cancer among current smokers.

We investigated associations of serum α- and γ-tocopherols and their effect modification by polymorphisms in oxidative stress regulatory enzymes in relation to prostate cancer risk. In a nested case-control study in the Carotene and Retinol Efficacy Trial, prerandomized serum α- and γ-tocopherol were assayed among 684 men with incident prostate cancer [375 nonaggressive and 284 aggressive cancer (stage III/IV or Gleason score ≥7)] and 1441 controls. Manganese superoxide dismutase Ala-16Val (rs4880), glutathione peroxidase 1 Pro200Leu (rs1050450), catalase -262 C > T (rs1001179), and myeloperoxidase (MPO) G-463A (rs2333227) were genotyped. A multivariate-adjusted inverse association of serum α-tocopherol with total prostate cancer risk was observed in current smokers (OR = 0.62, 95% CI = 0.40-0.96, 4th vs. 1st quartiles). High (≥median) compared to low serum concentrations of α- and γ-tocopherol were inversely associated with aggressive prostate cancer in current smokers (OR = 0.50, 95% CI = 0.32-0.78 and OR = 0.64, 95% CI = 0.43-0.95, respectively). The association was stronger among those with MPO G/A+A/A genotypes. Among current smokers with low serum α-tocopherol concentrations, MPO G/A+A/A, the genotypes downregulating oxidative stress, were associated with an increased risk for aggressive prostate cancer (OR = 2.06, 95% CI = 1.22-3.46). Conversely, current smokers with these genotypes who had high α-tocopherol concentrations had a reduced risk for aggressive prostate cancer (OR = 0.34, 95% CI = 0.15-0.80; P-interaction = 0.001). In conclusion, among current smokers, both high serum α- and γ-tocopherol concentrations were associated with reduced risks of aggressive prostate cancer. The α-tocopherol-associated risks are modified by polymorphism in MPO G-463A.

The relationship between body-mass index and overall survival in non-small cell lung cancer by sex, smoking status, and race: A pooled analysis of 20,937 International lung Cancer consortium (ILCCO) patients.

INTRODUCTION: The relationship between Body-Mass-Index (BMI) and lung cancer prognosis is heterogeneous. We evaluated the impact of sex, smoking and race on the relationship between BMI and overall survival (OS) in non-small-cell-lung-cancer (NSCLC). METHODS: Data from 16 individual ILCCO studies were pooled to assess interactions between BMI and the following factors on OS: self-reported race, smoking status and sex, using Cox models (adjusted hazard ratios; aHR) with interaction terms and adjusted penalized smoothing spline plots in stratified analyses. RESULTS: Among 20,937 NSCLC patients with BMI values, females = 47 %; never-smokers = 14 %; White-patients = 76 %. BMI showed differential survival according to race whereby compared to normal-BMI patients, being underweight was associated with poor survival among white patients (OS, aHR = 1.66) but not among black patients (aHR = 1.06; pinteraction = 0.02). Comparing overweight/obese to normal weight patients, Black NSCLC patients who were overweight/obese also had relatively better OS (pinteraction = 0.06) when compared to White-patients. BMI was least associated with survival in Asian-patients and never-smokers. The outcomes of female ever-smokers at the extremes of BMI were associated with worse outcomes in both the underweight (pinteraction<0.001) and obese categories (pinteraction = 0.004) relative to the normal-BMI category, when compared to male ever-smokers. CONCLUSION: Underweight and obese female ever-smokers were associated with worse outcomes in White-patients. These BMI associations were not observed in Asian-patients and never-smokers. Black-patients had more favorable outcomes in the extremes of BMI when compared to White-patients. Body composition in Black-patients, and NSCLC subtypes more commonly seen in Asian-patients and never-smokers, may account for differences in these BMI-OS relationships.

Body mass index and prostate cancer risk in the Carotene and Retinol Efficacy Trial.

The aim of this study was to investigate the association between BMI (kg/m) and prostate cancer risk. BMI is a modifiable lifestyle factor and may provide a unique opportunity for primary prevention of prostate cancer if a causal association exists. Data from 11 886 men from the Carotene and Retinol Efficacy Trial (CARET, 1985-1996 with active follow-up through 2005) comprising current and former heavy smokers were analyzed. CARET was a multicenter randomized, double-blind placebo-controlled chemoprevention trial testing daily supplementation of 30 mg ß-carotene+25 000 IU retinyl palmitate for primary prevention of lung cancer. Prostate cancer was a secondary outcome. Nonaggressive disease was defined as Gleason less than 7 and stage I/II. Aggressive disease was primarily defined as at least Gleason 7 or stage III/IV, and secondarily by excluding Gleason 3+4 from the first definition. BMI was calculated from measured weight and height. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for cancer incidence between BMI categories. During follow-up, 883 men were diagnosed with prostate cancer. In the analysis of aggressive disease when Gleason 3+4 was excluded, men with a BMI of at least 35 kg/m had an increased rate of prostate cancer (HR: 1.80, 95% CI: 1.04-3.11, Ptrend=0.04) compared with men with BMI 18-24.9 kg/m. No other differences were seen in risk estimates for overall, nonaggressive or aggressive prostate cancer including all Gleason 7 cases, between BMI categories. Our results show an association between having a BMI of at least 35 kg/m and an increased risk of aggressive prostate cancer (not including Gleason 3+4 tumors), but do not support an association between BMI and risk of overall, aggressive disease including all Gleason 7, or nonaggressive prostate cancer within a population of current and former heavy smokers.

Body Mass Index (BMI), BMI Change, and Overall Survival in Patients With SCLC and NSCLC: A Pooled Analysis of the International Lung Cancer Consortium.

INTRODUCTION: The relationships between morbid obesity, changes in body mass index (BMI) before cancer diagnosis, and lung cancer outcomes by histology (SCLC and NSCLC) have not been well studied. METHODS: Individual level data analysis was performed on 25,430 patients with NSCLC and 2787 patients with SCLC from 16 studies of the International Lung Cancer Consortium evaluating the association between various BMI variables and lung cancer overall survival, reported as adjusted hazard ratios (aHRs) from Cox proportional hazards models and adjusted penalized smoothing spline plots. RESULTS: Overall survival of NSCLC had putative U-shaped hazard ratio relationships with BMI based on spline plots: being underweight (BMI < 18.5 kg/m2; aHR = 1.56; 95% confidence interval [CI]:1.43-1.70) or morbidly overweight (BMI > 40 kg/m2; aHR = 1.09; 95% CI: 0.95-1.26) at the time of diagnosis was associated with worse stage-specific prognosis, whereas being overweight (25 kg/m2 ≤ BMI < 30 kg/m2; aHR = 0.89; 95% CI: 0.85-0.95) or obese (30 kg/m2 ≤ BMI ≤ 40 kg/m2; aHR = 0.86; 95% CI: 0.82-0.91) was associated with improved survival. Although not significant, a similar pattern was seen with SCLC. Compared with an increased or stable BMI from the period between young adulthood until date of diagnosis, a decreased BMI was associated with worse outcomes in NSCLC (aHR = 1.24; 95% CI: 1.2-1.3) and SCLC patients (aHR=1.26 (95% CI: 1.0-1.6). Decreased BMI was consistently associated with worse outcome, across clinicodemographic subsets. CONCLUSIONS: Both being underweight or morbidly obese at time of diagnosis is associated with lower stage-specific survival in independent assessments of NSCLC and SCLC patients. In addition, a decrease in BMI at lung cancer diagnosis relative to early adulthood is a consistent marker of poor survival.

Iron intake, oxidative stress-related genes (MnSOD and MPO) and prostate cancer risk in CARET cohort.

Iron overload may increase prostate cancer risk through stimulation of oxidative stress, and endogenous pro- and antioxidant capabilities, i.e. manganese superoxide dismutase (MnSOD) and myeloperoxidase (MPO), may modify these associations. We investigated this hypothesis in the Carotene and Retinol Efficacy Trial cohort in a nested case-control study. Although there was no association between iron intake and risk overall, there was a suggestion of increased risk of clinically aggressive prostate cancer with higher iron intake [odds ratio (OR) = 1.4, 95% confidence interval (CI) = 0.9-2.0]. Associations were most notable for men with aggressive prostate cancer who were below the median consumption of total fruits and vegetables (OR = 1.8, 95% CI = 1.1-3.2). Associations between MPO -463 G to A genotype (rs2333227) and prostate cancer risk were only noted among men with aggressive cancer, with more than a 2-fold risk reduction among men with AA genotypes (OR = 0.4, 95% CI = 0.2-1.0); MnSOD was not associated with risk overall, but the MnSOD T to C (Val-9Ala, rs4880) polymorphism modified associations between risk of clinically aggressive prostate cancer and dietary iron intake (P for interaction = 0.02). Among aggressive cancer cases with the TT genotype, higher iron intake level was associated with >2-fold increase in risk (OR = 2.3, 95% CI = 1.0-4.9), whereas there was no association among men with CC genotypes (OR = 0.9, 95% CI = 0.4-2.3). Although interactions were not significant, there were similar patterns for MPO genotype, iron intake and risk. These findings suggest that higher iron intake may be associated with risk of clinically aggressive prostate cancer, and that endogenous antioxidant capabilities may modify these associations.

A mouse to human search for plasma proteome changes associated with pancreatic tumor development.

BACKGROUND: The complexity and heterogeneity of the human plasma proteome have presented significant challenges in the identification of protein changes associated with tumor development. Refined genetically engineered mouse (GEM) models of human cancer have been shown to faithfully recapitulate the molecular, biological, and clinical features of human disease. Here, we sought to exploit the merits of a well-characterized GEM model of pancreatic cancer to determine whether proteomics technologies allow identification of protein changes associated with tumor development and whether such changes are relevant to human pancreatic cancer. METHODS AND FINDINGS: Plasma was sampled from mice at early and advanced stages of tumor development and from matched controls. Using a proteomic approach based on extensive protein fractionation, we confidently identified 1,442 proteins that were distributed across seven orders of magnitude of abundance in plasma. Analysis of proteins chosen on the basis of increased levels in plasma from tumor-bearing mice and corroborating protein or RNA expression in tissue documented concordance in the blood from 30 newly diagnosed patients with pancreatic cancer relative to 30 control specimens. A panel of five proteins selected on the basis of their increased level at an early stage of tumor development in the mouse was tested in a blinded study in 26 humans from the CARET (Carotene and Retinol Efficacy Trial) cohort. The panel discriminated pancreatic cancer cases from matched controls in blood specimens obtained between 7 and 13 mo prior to the development of symptoms and clinical diagnosis of pancreatic cancer. CONCLUSIONS: Our findings indicate that GEM models of cancer, in combination with in-depth proteomic analysis, provide a useful strategy to identify candidate markers applicable to human cancer with potential utility for early detection.

V89L polymorphism of the 5alpha-reductase Type II gene (SRD5A2), endogenous sex hormones, and prostate cancer risk.

We examined the combined effect of circulating sex hormones and SRD5A2 V89L polymorphism on prostate cancer risk in a case-control study (300 cases and 300 controls) nested within the Carotene and Retinol Efficacy Trial. A moderate increase in risk associated with above-median serum levels of androstenedione and dehydroepiandrosterone sulfate (DHEAS) was present irrespective of V89L genotype. However, in L/L or V/L men, above-median DHEAS levels were associated with an increased risk of aggressive tumors [odds ratios (OR), 3.12; 95% confidence interval (95% CI), 1.28-7.63] but not of nonaggressive ones (OR, 0.56; 95% CI, 0.25-1.25). Above-median serum levels of free estradiol were associated with a lower risk, especially for aggressive cancer. The association with aggressive disease was more pronounced in men with a V/V genotype (OR, 0.34; 95% CI, 0.14-0.81), than in men with an L/L or V/L genotype (OR, 0.77; 95% CI, 0.37-1.60). Above-median levels of 3alpha-diol G were associated with an increased risk, but only in men with the L/L or V/L genotype (OR, 2.16; 95% CI, 1.31-3.56). The increase in risk in L/L and V/L men was restricted to aggressive tumors. Our study observed that only in men with the L/L or V/L genotype were increased serum levels of DHEAS and 3alpha-diol G positively associated with a higher risk of aggressive prostate cancer. Free estradiol levels were negatively associated with risk of aggressive prostate cancer in men with the V/V genotype. However, the absence of an overall association between V89L genotype and aggressive prostate cancer argues for a cautious interpretation of these observations.

Inflammatory Gene Polymorphisms in Lung Cancer Susceptibility.

INTRODUCTION: Chronic inflammation has been implicated in carcinogenesis, with increasing evidence of its role in lung cancer. We aimed to evaluate the role of genetic polymorphisms in inflammation-related genes in the risk for development of lung cancer. METHODS: A nested case-control study design was used, and 625 cases and 625 well-matched controls were selected from participants in the ß-Carotene and Retinol Efficacy Trial, which is a large, prospective lung cancer chemoprevention trial. The association between lung cancer incidence and survival and 23 polymorphisms descriptive of 11 inflammation-related genes (interferon gamma gene [IFNG], interleukin 10 gene [IL10], interleukin 1 alpha gene [IL1A], interleukin 1 beta gene [IL1B], interleukin 2 gene [IL2], interleukin 4 receptor gene [IL4R], interleukin 4 gene [IL4], interleukin 6 gene [IL6], prostaglandin-endoperoxide synthase 2 gene [PTGS2] (also known as COX2), transforming growth factor beta 1 gene [TGFB1], and tumor necrosis factor alpha gene [TNFA]) was evaluated. RESULTS: Of the 23 polymorphisms, two were associated with risk for lung cancer. Compared with individuals with the wild-type (CC) variant, individuals carrying the minor allele variants of the IL-1ß-511C>T promoter polymorphism (rs16944) (CT and TT) had decreased odds of lung cancer (OR = 0.74, [95% confidence interval (CI): 0.58-0.94] and OR = 0.71 [95% CI: 0.50-1.01], respectively, p = 0.03). Similar results were observed for the IL-1ß-1464 C>G promoter polymorphism (rs1143623), with presence of the minor variants CG and CC having decreased odds of lung cancer (OR = 0.75 [95% CI: 0.59-0.95] and OR = 0.69 [95% CI: 0.46-1.03], respectively, p = 0.03). Survival was not influenced by genotype. CONCLUSIONS: This study provides further evidence that IL1B promoter polymorphisms may modulate the risk for development of lung cancer.

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 ß-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.

Variations in lung cancer risk among smokers.

BACKGROUND: Although there is no proven benefit associated with screening for lung cancer, screening programs are attracting many individuals who perceive themselves to be at high risk due to smoking. We sought to determine whether the risk of lung cancer varies predictably among smokers. METHODS: We used data on 18 172 subjects enrolled in the Carotene and Retinol Efficacy Trial (CARET)-a large, randomized trial of lung cancer prevention-to derive a lung cancer risk prediction model. Model inputs included the subject's age, sex, asbestos exposure history, and smoking history. We assessed the model's calibration by comparing predicted and observed rates of lung cancer across risk deciles and validated it by assessing the extent to which a model estimated on data from five CARET study sites could predict events in the sixth study site. We then applied the model to evaluate the risk of lung cancer among smokers enrolled in a study of lung cancer screening with computed tomography (CT). RESULTS: The model was internally valid and well calibrated. Ten-year lung cancer risk varied greatly among participants in the CT study, from 15% for a 68-year-old man who has smoked two packs per day for 50 years and continues to smoke, to 0.8% for a 51-year-old woman who smoked one pack per day for 28 years before quitting 9 years earlier. Even among the subset of CT study participants who would be eligible for a clinical trial of cancer prevention, risk varied greatly. CONCLUSIONS: The risk of lung cancer varies widely among smokers. Accurate risk prediction may help individuals who are contemplating voluntary screening to balance the potential benefits and risks. Risk prediction may also be useful for researchers designing clinical trials of lung cancer prevention.

Selenium and Prostate Cancer: Analysis of Individual Participant Data From Fifteen Prospective Studies.

BACKGROUND: Some observational studies suggest that a higher selenium status is associated with a lower risk of prostate cancer but have been generally too small to provide precise estimates of associations, particularly by disease stage and grade. METHODS: Collaborating investigators from 15 prospective studies provided individual-participant records (from predominantly men of white European ancestry) on blood or toenail selenium concentrations and prostate cancer risk. Odds ratios of prostate cancer by selenium concentration were estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided. RESULTS: Blood selenium was not associated with the risk of total prostate cancer (multivariable-adjusted odds ratio [OR] per 80 percentile increase = 1.01, 95% confidence interval [CI] = 0.83 to 1.23, based on 4527 case patients and 6021 control subjects). However, there was heterogeneity by disease aggressiveness (ie, advanced stage and/or prostate cancer death, Pheterogeneity = .01), with high blood selenium associated with a lower risk of aggressive disease (OR = 0.43, 95% CI = 0.21 to 0.87) but not with nonaggressive disease. Nail selenium was inversely associated with total prostate cancer (OR = 0.29, 95% CI = 0.22 to 0.40, Ptrend < .001, based on 1970 case patients and 2086 control subjects), including both nonaggressive (OR = 0.33, 95% CI = 0.22 to 0.50) and aggressive disease (OR = 0.18, 95% CI = 0.11 to 0.31, Pheterogeneity = .08). CONCLUSIONS: Nail, but not blood, selenium concentration is inversely associated with risk of total prostate cancer, possibly because nails are a more reliable marker of long-term selenium exposure. Both blood and nail selenium concentrations are associated with a reduced risk of aggressive disease, which warrants further investigation.