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PDF file - 132K, Affymetrix Probesets Differentially Expressed in Stage I Lung Adenocarcinoma Cases Compared to Controls in Current Smokers and All Subjects Combined, Italy, 2002-2005.

Affordable early screening in subjects with high risk of lung cancer has great potential to improve survival from this deadly disease. We measured gene expression from lung tissue and peripheral whole blood (PWB) from adenocarcinoma cases and controls to identify dysregulated lung cancer genes that could be tested in blood to improve identification of at-risk patients in the future. Genome-wide mRNA expression analysis was conducted in 153 subjects (73 adenocarcinoma cases, 80 controls) from the Environment And Genetics in Lung cancer Etiology study using PWB and paired snap-frozen tumor and noninvolved lung tissue samples. Analyses were conducted using unpaired t tests, linear mixed effects, and ANOVA models. The area under the receiver operating characteristic curve (AUC) was computed to assess the predictive accuracy of the identified biomarkers. We identified 50 dysregulated genes in stage I adenocarcinoma versus control PWB samples (false discovery rate ≤0.1, fold change ≥1.5 or ≤0.66). Among them, eight (TGFBR3, RUNX3, TRGC2, TRGV9, TARP, ACP1, VCAN, and TSTA3) differentiated paired tumor versus noninvolved lung tissue samples in stage I cases, suggesting a similar pattern of lung cancer–related changes in PWB and lung tissue. These results were confirmed in two independent gene expression analyses in a blood-based case–control study (n = 212) and a tumor–nontumor paired tissue study (n = 54). The eight genes discriminated patients with lung cancer from healthy controls with high accuracy (AUC = 0.81, 95% CI = 0.74–0.87). Our finding suggests the use of gene expression from PWB for the identification of early detection markers of lung cancer in the future. Cancer Prev Res; 4(10); 1599–608. ©2011 AACR.

PDF file - 222K, Affymetrix Quality Assessment for the Gene Expression Data from Peripheral Whole Blood in Cases and Controls, Italy, 2002-2005.

PDF file - 386K

Background: Epidemiologic studies have reported that frequent consumption of quercetin-rich foods is inversely associated with lung cancer incidence. A quercetin-rich diet might modulate microRNA (miR) expression; however, this mechanism has not been fully examined.Methods: miR expression data were measured by a custom-made array in formalin-fixed paraffin-embedded tissue samples from 264 lung cancer cases (144 adenocarcinomas and 120 squamous cell carcinomas). Intake of quercetin-rich foods was derived from a food-frequency questionnaire. In individual-miR–based analyses, we compared the expression of miRs (n = 198) between lung cancer cases consuming high versus low quercetin-rich food intake using multivariate ANOVA tests. In family-miR–based analyses, we used Functional Class Scoring (FCS) to assess differential effect on biologically functional miR families. We accounted for multiple testing using 10,000 global permutations (significance at Pglobal < 0.10). All multivariate analyses were conducted separately by histology and by smoking status (former and current smokers).Results: Family-based analyses showed that a quercetin-rich diet differentiated miR expression profiles of the tumor suppressor let-7 family among adenocarcinomas (PFCS < 0.001). Other significantly differentiated miR families included carcinogenesis-related miR-146, miR-26, and miR-17 (PFCS < 0.05). In individual-based analyses, we found that among former and current smokers with adenocarcinoma, 33 miRs were observed to be differentiated between highest and lowest quercetin-rich food consumers (23 expected by chance; Pglobal = 0.047).Conclusions: We observed differential expression of key biologically functional miRs between high versus low consumers of quercetin-rich foods in adenocarcinoma cases.Impact: Our findings provide preliminary evidence on the mechanism underlying quercetin-related lung carcinogenesis. Cancer Epidemiol Biomarkers Prev; 21(12); 2176–84. ©2012 AACR.

Odds ratios and Hazard ratios (95% Confidence Intervals) for lung cancer and nut consumption in EAGLE and AARP, by smoking intensity

Odds ratios and Hazard ratios (95% Confidence Intervals) for lung cancer and nut consumption in EAGLE and AARP, by histology subtypes

PDF file - 80K, List of miRs (N=198) retained from chip array analysis

PDF file - 54K, All identified miR groups based on "seed" sequence (2-7nt)

PDF file - 47K, Food groups and individual food items

PDF file - 5418K, Hierarchical clustering heat map of miR expression levels for 25 miRs that displayed significant differential expression among former smokers with adenocarcinoma in the individual miR-based analysis. Average linkage was used to cluster miRs and samples with a distance metric of 1 minus centered correlation using BRB-ArrayTools version 4.2. Tertiles define subjects with low (Tertile 1) and high (Tertile 3) consumption of quercetin-rich food.

Purpose: The molecular drivers that determine histology in lung cancer are largely unknown. We investigated whether microRNA (miR) expression profiles can differentiate histologic subtypes and predict survival for non–small cell lung cancer.Experimental Design: We analyzed miR expression in 165 adenocarcinoma and 125 squamous cell carcinoma (SQ) tissue samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study using a custom oligo array with 440 human mature antisense miRs. We compared miR expression profiles using t tests and F tests and accounted for multiple testing using global permutation tests. We assessed the association of miR expression with tobacco smoking using Spearman correlation coefficients and linear regression models, and with clinical outcome using log-rank tests, Cox proportional hazards, and survival risk prediction models, accounting for demographic and tumor characteristics.Results: MiR expression profiles strongly differed between adenocarcinoma and SQ (Pglobal < 0.0001), particularly in the early stages, and included miRs located on chromosome loci most often altered in lung cancer (e.g., 3p21-22). Most miRs, including all members of the let-7 family, were downregulated in SQ. Major findings were confirmed by quantitative real time-polymerase chain reaction (qRT-PCR) in EAGLE samples and in an independent set of lung cancer cases. In SQ, the low expression of miRs that are downregulated in the histology comparison was associated with 1.2- to 3.6-fold increased mortality risk. A five-miR signature significantly predicted survival for SQ.Conclusions: We identified a miR expression profile that strongly differentiated adenocarcinoma from SQ and had prognostic implications. These findings may lead to histology-based therapeutic approaches. Clin Cancer Res; 16(2); 430–41

PDF file - 3580K, Hierarchical clustering heat map of miR expression levels for 10 miRs that displayed significant differential expression among former smokers with squamous cell carcinoma in the individual miR-based analysis. Average linkage was used to cluster miRs and samples with a distance metric of 1 minus centered correlation using BRB-ArrayTools version 4.2. Tertiles define subjects with low (Tertile 1) and high (Tertile 3) consumption of quercetin-rich food.

Odds ratios and Hazard ratios (95% Confidence Intervals) for lung cancer and nut consumption in EAGLE and AARP, by smoking status

Pearson's correlation and covariance between nuts consumption and nutrients and smoking variables in controls

PDF file - 51K, Selected characteristics of included and excluded EAGLE cases

Hazard ratios (95% Confidence Intervals) for the lag analyses by 5 years and 10 years for lung cancer and nut consumption in AARP, by smoking status

Supplementary Data from MicroRNA Expression Differentiates Histology and Predicts Survival of Lung Cancer

Hazard ratios (95% Confidence Intervals) for the lag analyses by 5 years and 10 years for lung cancer and nut consumption in AARP, by histologic subtypes

Supplementary Table 1 from Intakes of Red Meat, Processed Meat, and Meat Mutagens Increase Lung Cancer Risk

Supplementary Table 2 from Intakes of Red Meat, Processed Meat, and Meat Mutagens Increase Lung Cancer Risk

Red and processed meat intake may increase lung cancer risk. However, the epidemiologic evidence is inconsistent and few studies have evaluated the role of meat mutagens formed during high cooking temperatures. We investigated the association of red meat, processed meat, and meat mutagen intake with lung cancer risk in Environment And Genetics in Lung cancer Etiology, a population-based case-control study. Primary lung cancer cases (n = 2,101) were recruited from 13 hospitals within the Lombardy region of Italy examining ∼80% of the cases from the area. Noncancer population controls (n = 2,120), matched to cases on gender, residence, and age, were randomly selected from the same catchment area. Diet was assessed in 1,903 cases and 2,073 controls and used in conjunction with a meat mutagen database to estimate intake of heterocyclic amines (HCA) and benzo(a)pyrene (BaP). Multivariable odds ratios (OR) and 95% confidence intervals (95% CI) for sex-specific tertiles of intake were calculated using unconditional logistic regression. Red and processed meat were positively associated with lung cancer risk (highest-versus-lowest tertile: OR, 1.8; 95% CI, 1.5–2.2; P trend < 0.001 and OR, 1.7; 95% CI, 1.4–2.1; P trend < 0.001, respectively); the risks were strongest among never smokers (OR, 2.4; 95% CI, 1.4–4.0; P trend = 0.001 and OR, 2.5; 95% CI, 1.5–4.2; P trend = 0.001, respectively). HCAs and BaP were significantly associated with increased risk of lung cancer. When separated by histology, significant positive associations for both meat groups were restricted to adenocarcinoma and squamous cell carcinoma but not small cell carcinoma of the lung. In summary, red meat, processed meat, and meat mutagens were independently associated with increased risk of lung cancer. [Cancer Res 2009;69(3):932–9]