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Many single nucleotide polymorphisms (SNPs) have been associated with lung cancer but lack confirmation and functional characterization. We retested the association of 56 candidate SNPs with lung adenocarcinoma risk and overall survival in a cohort of 823 Italian patients and 779 healthy controls, and assessed their function as expression quantitative trait loci (eQTLs). In the replication study, eight SNPs (rs401681, rs3019885, rs732765, rs2568494, rs16969968, rs6495309, rs11634351, and rs4105144) associated with lung adenocarcinoma risk and three (rs9557635, rs4105144, and rs735482) associated with survival. Five of these SNPs acted as cis-eQTLs, being associated with the transcription of IREB2 (rs2568494, rs16969968, rs11634351, rs6495309), PSMA4 (rs6495309) and ERCC1 (rs735482), out of 10,821 genes analyzed in lung. For these three genes, we obtained experimental evidence of differential allelic expression in lung tissue, pointing to the existence of in-cis genomic variants that regulate their transcription. These results suggest that these SNPs exert their effects on cancer risk/outcome through the modulation of mRNA levels of their target genes., Competing Interests: The authors declare no competing financial interests.

Read-through transcripts result from the continuous transcription of adjacent, similarly oriented genes, with the splicing out of the intergenic region. They have been found in several neoplastic and normal tissues, but their pathophysiological significance is unclear. We used high-throughput sequencing of cDNA fragments (RNA-Seq) to identify read-through transcripts in the non-involved lung tissue of 64 surgically treated lung adenocarcinoma patients. A total of 52 distinct read-through species was identified, with 24 patients having at least one read-through event, up to a maximum of 17 such transcripts in one patient. Sanger sequencing validated 28 of these transcripts and identified an additional 15, for a total of 43 distinct read-through events involving 35 gene pairs. Expression levels of 10 validated read-through transcripts were measured by quantitative PCR in pairs of matched non-involved lung tissue and lung adenocarcinoma tissue from 45 patients. Higher expression levels were observed in normal lung tissue than in the tumor counterpart, with median relative quantification ratios between normal and tumor varying from 1.90 to 7.78; the difference was statistically significant (P < 0.001, Wilcoxon's signed-rank test for paired samples) for eight transcripts: ELAVL1-TIMM44, FAM162B-ZUFSP, IFNAR2-IL10RB, INMT-FAM188B, KIAA1841-C2orf74, NFATC3-PLA2G15, SIRPB1-SIRPD, and SHANK3-ACR. This report documents the presence of read-through transcripts in apparently normal lung tissue, with inter-individual differences in patterns and abundance. It also shows their down-regulation in tumors, suggesting that these chimeric transcripts may function as tumor suppressors in lung tissue., Competing Interests: The authors declare no conflicts of interest.

Purpose: The main prognostic factor of lung cancer patient outcome is clinical stage, a parameter of tumor aggressiveness. Our study was conducted to test whether germ line variations modulate individual differences in clinical stage., Experimental Design: We conducted a case-only genome-wide association study (GWAS) using a 620,901 single-nucleotide polymorphism (SNP) array in a first series of 600 lung adenocarcinoma (ADCA) patients and in a replication series of 317 lung ADCA patients., Results: GWAS identified 54 putatively associated SNPs, 3 of which were confirmed in the replication series. Joint analysis of the two series pointed to 22 statistically associated (P < 0.01) genetic variants that together explained about 20% of the phenotypic variation in clinical staging (P < 2 × 10(-16)) and showed a statistically significant difference in overall survival (P = 8.0 × 10(-8)). The strongest statistical association was observed at rs10278557 (P = 1.1 × 10(-5)), located in the mesenchyme homeobox 2 (MEOX2) gene., Conclusion: These data point to the role of germ line variations involving multiple loci in modulating clinical stage and, therefore, prognosis in lung ADCA patients., (©2011 AACR.)

Simple Summary: Since the factors influencing age at diagnosis of lung adenocarcinoma are unknown, in our study, we examined the relationships of age at diagnosis with smoking habit, clinical stage of disease, and sex in Italian and German patients with lung adenocarcinoma who underwent lung adenocarcinoma resection. Our results indicated that smoking habit, advanced clinical stage (more aggressive and larger tumour), and female sex were variables associated with younger age at diagnosis. This study provides new findings on the clinical variables influencing age at diagnosis of lung adenocarcinoma and paves the way for studies on the genetic and molecular mechanisms responsible for these associations. To date, the factors which affect the age at diagnosis of lung adenocarcinoma are not fully understood. In our study, we examined the relationships of age at diagnosis with smoking, pathological stage, sex, and year of diagnosis in a discovery (n = 1694) and validation (n = 1384) series of lung adenocarcinoma patients who had undergone pulmonary resection at hospitals in the Milan area and at Thoraxklinik (Heidelberg), respectively. In the discovery series, younger age at diagnosis was associated with ever-smoker status (OR = 1.5, p = 0.0035) and advanced stage (taking stage I as reference: stage III OR = 1.4, p = 0.0067; stage IV OR = 1.7, p = 0.0080), whereas older age at diagnosis was associated with male sex (OR = 0.57, p < 0.001). Analysis in the validation series confirmed the ever versus never smokers' association (OR = 2.9, p < 0.001), the association with highest stages (stage III versus stage I OR = 1.4, p = 0.0066; stage IV versus stage I OR = 2.0, p = 0.0022), and the male versus female sex association (OR = 0.78, p = 0.032). These data suggest the role of smoking in affecting the natural history of the disease. Moreover, aggressive tumours seem to have shorter latency from initiation to clinical detection. Finally, younger age at diagnosis is associated with the female sex, suggesting that hormonal status of young women confers risk to develop lung adenocarcinoma. Overall, this study provided novel findings on the mechanisms underlying age at diagnosis of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background: Sex and age strongly influence the pathophysiology of human lungs, but scarce information is available about their effects on pulmonary gene expression. Methods: We followed a discovery-validation strategy to identify sex- and age-related transcriptional differences in lung. Results: We identified transcriptional profiles significantly associated with sex (215 genes; FDR < 0.05) and age at surgery (217 genes) in non-involved lung tissue resected from 284 lung adenocarcinoma patients. When these profiles were tested in three independent series of non-tumor lung tissue from an additional 1,111 patients, we validated the association with sex and age for 25 and 22 genes, respectively. Among the 17 sex-biased genes mapping on chromosome X, 16 have been reported to escape X-chromosome inactivation in other tissues or cells, suggesting that this mechanism influences lung transcription too. Our 22 age-related genes partially overlap with genes modulated by age in other tissues, suggesting that the aging process has similar consequences on gene expression in different organs. Finally, seven genes whose expression was modulated by sex in non-tumor lung tissue, but no age-related gene, were also validated using publicly available data from 990 lung adenocarcinoma samples, suggesting that the physiological regulatory mechanisms are only partially active in neoplastic tissue. Conclusions: Gene expression in non-tumor lung tissue is modulated by both sex and age. These findings represent a validated starting point for research on the molecular mechanisms underlying the observed differences in the course of lung diseases among men and women of different ages. [ABSTRACT FROM AUTHOR]

Background: MFSD2A (major facilitator superfamily domain containing 2) gene maps on chromosome 1p34 within a linkage disequilibrium block containing genetic elements associated with progression of lung cancer. Results: Here we show that MFSD2A expression is strongly downregulated in non-small cell lung cancer cell lines of different histotypes and in primary lung adenocarcinomas. Experimental modulation of MFSD2A in lung cancer cells is associated with alteration of mRNA levels of genes involved in cell cycle control and interaction with the extracellular matrix. Exogenous expression of MFSD2A in lung cancer cells induced a G1 block, impaired adhesion and migration in vitro, and significantly reduced tumor colony number in vitro (4- to 27-fold, P < 0.0001) and tumor volume in vivo (∼3-fold, P < 0.0001). siRNA knockdown studies in normal human bronchial epithelial cells confirmed the role of MFSD2A in G1 regulation. Conclusion: Together these data suggest that MFSD2A is a novel lung cancer tumor suppressor gene that regulates cell cycle progression and matrix attachment. [ABSTRACT FROM AUTHOR]

Alterations in the gene expression of organs in contact with the environment may signal exposure to toxins. To identify genes in lung tissue whose expression levels are altered by cigarette smoking, we compared the transcriptomes of lung tissue between 118 ever smokers and 58 never smokers. In all cases, the tissue studied was non-involved lung tissue obtained at lobectomy from patients with lung adenocarcinoma. Of the 17,097 genes analyzed, 357 were differentially expressed between ever smokers and never smokers (FDR < 0.05), including 290 genes that were up-regulated and 67 down-regulated in ever smokers. For 85 genes, the absolute value of the fold change was ≥2. The gene with the smallest FDR was MYO1A (FDR = 6.9 × 10−4) while the gene with the largest difference between groups was FGG (fold change = 31.60). Overall, 100 of the genes identified in this study (38.6%) had previously been found to associate with smoking in at least one of four previously reported datasets of non-involved lung tissue. Seven genes (KMO, CD1A, SPINK5, TREM2, CYBB, DNASE2B, FGG) were differentially expressed between ever and never smokers in all five datasets, with concordant higher expression in ever smokers. Smoking-induced up-regulation of six of these genes was also observed in a transcription dataset from lung tissue of non-cancer patients. Among the three most significant gene networks, two are involved in immunity and inflammation and one in cell death. Overall, this study shows that the lung parenchyma transcriptome of smokers has altered gene expression and that these alterations are reproducible in different series of smokers across countries. Moreover, this study identified a seven-gene panel that reflects lung tissue exposure to cigarette smoke. [ABSTRACT FROM AUTHOR]