Transcription profiling by array of human lung adenocarcinoma tissue from smokers, ex-smokers and people who have never smoked
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Ding L
PROVIDER: S-ECPF-GEOD-12667 | biostudies-other | 2008 Oct
REPOSITORIES: biostudies-other
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Project description:BACKGROUND: Lung cancer in never smokers would rank as the seventh most common cause of cancer death worldwide. METHODS AND FINDINGS: We performed high-resolution array comparative genomic hybridization analysis of lung adenocarcinoma in sixty never smokers and identified fourteen new minimal common regions (MCR) of gain or loss, of which five contained a single gene (MOCS2, NSUN3, KHDRBS2, SNTG1 and ST18). One larger MCR of gain contained NSD1. One focal amplification and nine gains contained FUS. NSD1 and FUS are oncogenes hitherto not known to be associated with lung cancer. FISH showed that the amplicon containing FUS was joined to the next telomeric amplicon at 16p11.2. FUS was over-expressed in 10 tumors with gain of 16p11.2 compared to 30 tumors without that gain. Other cancer genes present in aberrations included ARNT, BCL9, CDK4, CDKN2B, EGFR, ERBB2, MDM2, MDM4, MET, MYC and KRAS. Unsupervised hierarchical clustering with adjustment for false-discovery rate revealed clusters differing by the level and pattern of aberrations and displaying particular tumor characteristics. One cluster was strongly associated with gain of MYC. Another cluster was characterized by extensive losses containing tumor suppressor genes of which RB1 and WRN. Tumors in that cluster frequently harbored a central scar-like fibrosis. A third cluster was associated with gains on 7p and 7q, containing ETV1 and BRAF, and displayed the highest rate of EGFR mutations. SNP array analysis validated copy-number aberrations and revealed that RB1 and WRN were altered by recurrent copy-neutral loss of heterozygosity. CONCLUSIONS: The present study has uncovered new aberrations containing cancer genes. The oncogene FUS is a candidate gene in the 16p region that is frequently gained in never smokers. Multiple genetic pathways defined by gains of MYC, deletions of RB1 and WRN or gains on 7p and 7q are involved in lung adenocarcinoma in never smokers.
| S-EPMC2997777 | biostudies-literature
Project description:Lung cancer in never-smokers (LCINS) presents clinicopathological and molecular features distinct from that in smokers. Tumor microenvironment (TME) plays important roles in cancer progression and therapeutic response. To decipher the difference in TME between never-smoker and smoker lung cancers, we conduct single-cell RNA sequencing on 165,753 cells from 22 treatment-naive lung adenocarcinoma (LUAD) patients. We find that the dysfunction of alveolar cells induced by cigarette smoking contributes more to the aggressiveness of smoker LUADs, while the immunosuppressive microenvironment exerts more effects on never-smoker LUADs' aggressiveness. Moreover, the SPP1hi pro macrophage is identified to be another independent source of monocyte-derived macrophage. Importantly, higher expression of immune checkpoint CD47 and lower expression of major histocompatibility complex (MHC)-I in cancer cells of never-smoker LUADs imply that CD47 may be a better immunotherapy target for LCINS. Therefore, this study reveals the difference of tumorigenesis between never-smoker and smoker LUADs and provides a potential immunotherapy strategy for LCINS.
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Project description:The EML4-anaplastic lymphoma kinase (ALK) translocation is a recognized oncogenic driver in non-small cell lung cancer. We investigated immunohistochemistry (IHC) screening with fluorescence in situ hybridization (FISH) confirmation for ALK detection and estimated the prevalence of ALK positivity in our patient cohort of never-smokers, together with differences in clinical outcomes and prognostic factors for patients with ALK-positive and ALK-negative tumors.We designed a three-phase study (training, validation, and testing) in 300 never-smokers with lung adenocarcinoma from the observational Mayo Clinic Lung Cancer Cohort. Tumor samples were tested using IHC and FISH, and concordance between the methods was assessed. Clinical outcomes were assessed via 5-year progression- or recurrence-free survival from diagnosis. Prognostic factors for ALK-positive tumors and metastases were also investigated.ALK-positive patients were significantly (p < 0.05) younger and had higher grade tumors than ALK-negative patients. ALK positivity was 12.2% by IHC and confirmed at 8.2% of tumors by FISH, with complete concordance between IHC 3+/0 and FISH+/- assessments, respectively. Five-year risk of progression or recurrence was doubled for patients with ALK-positive compared with ALK-negative tumors; ALK-positive tumors also appeared to be associated with a higher risk of brain and liver metastases.Our findings suggest that ALK positivity is associated with a significantly poor outcome in nonsmoking-related adenocarcinoma and that ALK-positive tumors may be associated with an increased risk of brain and liver metastases compared with ALK-negative disease. Consequently, an unmet medical need exists in ALK-positive lung cancer patients, and effective ALK-specific therapies are needed.
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Project description:Non-small-cell lung cancer (NSCLC) has been recognized as a highly heterogeneous disease with phenotypic and genotypic diversity in each subgroup. While never-smoker patients with NSCLC have been well studied through next generation sequencing, we have yet to recognize the potentially unique molecular features of young never-smoker patients with NSCLC. In this study, we conducted whole genome sequencing (WGS) to characterize the genomic alterations of 36 never-smoker Chinese patients, who were diagnosed with lung adenocarcinoma (LUAD) at 45 years or younger. Besides the well-known gene mutations (e.g., TP53 and EGFR), our study identified several potential lung cancer-associated gene mutations that were rarely reported (e.g., HOXA4 and MST1). The lung cancer-related copy number variations (e.g., EGFR and CDKN2A) were enriched in our cohort (41.7%, 15/36) and the lung cancer-related structural variations (e.g., EML4-ALK and KIF5B-RET) were commonly observed (22.2%, 8/36). Notably, new fusion partners of ALK (SMG6-ALK) and RET (JMJD1C-RET) were found. Furthermore, we observed a high prevalence (63.9%, 23/36) of potentially targetable genomic alterations in our cohort. Finally, we identified germline mutations in BPIFB1 (rs6141383, p.V284M), CHD4 (rs74790047, p.D140E), PARP1 (rs3219145, p.K940R), NUDT1 (rs4866, p.V83M), RAD52 (rs4987207, p.S346*), and MFI2 (rs17129219, p.A559T) were significantly enriched in the young never-smoker patients with LUAD when compared with the in-house noncancer database (p < 0.05). Our study provides a detailed mutational portrait of LUAD occurring in young never-smokers and gives insights into the molecular pathogenesis of this distinct subgroup of NSCLC.
| S-EPMC6175072 | biostudies-literature
Project description:Long intergenic non-coding RNA (lincRNA) is a family of gene transcripts, the functions of which are largely unknown. Although cigarette smoking is the main cause for lung cancer, lung cancer in non-smokers is a separate entity and its underlying cause is little known. Growing evidence suggests lincRNAs play a significant role in cancer development and progression; however, such data is lacking for lung cancer in non-smokers, or those who have never smoked. This study conducted comprehensive profiling of lincRNAs from RNA sequencing (RNA-seq) data of non-smoker patients with lung adenocarcinoma. Both known and novel lincRNAs distinctly segregated tumors from normal tissues. Approximately one third of lincRNAs were differentially expressed between tumors and normal samples and most of them were coordinated with their putative protein gene targets. More importantly, lincRNAs defined two clusters of tumors that were associated with tumor aggressiveness and patient survival. We identified a subset of lincRNAs that were differentially expressed and also associated with patient survival. Very high concordance (R² = 0.9) was observed for the differentially expressed lincRNAs in the Cancer Genome Atlas (TCGA) validation set of 85 transcriptomes and the lincRNAs associated with survival from the discovery set were similarly predictive in the validation set. These lincRNAs warrant further investigation as potential diagnostic and prognostic markers.
| S-EPMC5704234 | biostudies-literature
Project description:Lung cancer in never smokers (NS) shows striking demographic, clinicopathological and molecular distinctions from the disease in smokers (S). Studies on selected genetic and epigenetic alterations in lung cancer identified that the frequency and profile of some abnormalities significantly differ by smoking status. This study compared the transcriptome of lung adenocarcinoma cell lines derived from S (n = 3) and NS (n = 3) each treated with vehicle (control), histone deacetylation inhibitor (trichostatin A) or DNA methylation inhibitor (5-aza-2'-deoxycytidine). Among 122 genes reexpressed following 5-aza-2'-deoxycytidine but not trichostatin A treatment in two or more cell lines (including 32 genes in S-only and 12 NS-only), methylation was validated for 80% (98/122 genes). After methylation analysis of 20 normal tissue samples and 14 additional non-small cell lung cancer cell lines (total 20), 39 genes frequently methylated in normal (>20%, 4/20) and 21 genes rarely methylated in non-small cell lung cancer (?10%, 2/20) were excluded. The prevalence for methylation of the remaining 38 genes in lung adenocarcinomas from S (n = 97) and NS (n = 75) ranged from 8-89% and significantly differs between S and NS for CPEB1, CST6, EMILIN2, LAYN and MARVELD3 (P < 0.05). Furthermore, methylation of EMILIN2, ROBO3 and IGDCC4 was more prevalent in advanced (Stage II-IV, n = 61) than early (Stage I, n = 110) tumors. Knockdown of MARVELD3, one of the novel epigenetically silenced genes, by small interfering RNA significantly reduced anchorage-independent growth of lung cancer cells (P < 0.001). Collectively, this study has identified multiple, novel, epigenetically silenced genes in lung cancer and provides invaluable resources for the development of diagnostic and prognostic biomarkers.
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Project description:CGH array in Lung Adenocarcinoma in Never Smokers
2010-12-31 | E-TABM-926 | biostudies-arrayexpress
Project description:Lung cancer in never smokers (LCINS) has lately been recognized as a unique disease based on rapidly gained knowledge from genomic changes to treatment responses. The focus of this article is on current knowledge and challenges with regard to LCINS expanded from recent reviews highlighting five areas: (1) distribution of LCINS by temporal trends, geographic regions, and populations; (2) three well-recognized environmental risk factors; (3) other plausible environmental risk factors; (4) prior chronic lung diseases and infectious diseases as risk factors; and (5) lifestyles as risk or protective factors. This article will also bring attention to recently published literature in two pioneering areas: (1) histological characteristics, clinical features with emerging new effective therapies, and social and psychological stigma; and (2) searching for susceptibility genes using integrated genomic approaches.
| S-EPMC3404817 | biostudies-literature
Project description:Tobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure. We performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e.g., NEK2, TTK, PRC1). Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors and early stage tumor tissue from non-tumor tissue (p<0.001 and fold-change>1.5, for each comparison), consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p<0.001) and TTK (p=0.002) expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers. Our work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers. Experiment Overall Design: Overall, 180 adenocarcinoma and non-tumor tissue samples were selected for the analyses, including duplicate or triplicate samples from 14 subjects for quality control. From the original 180 samples, 148 provided sufficient quantity of high-quality RNA for microarray analyses; 13 additional samples were excluded because of problematic assays. Normalization was conducted on the remaining 135 microarrays. After normalization, 13 samples were excluded because of low percentage of tumor cells in the tumor tissues. This report is based on 122 samples, of which 15 duplicates were averaged, resulting in 107 final expression values from 58 tumor and 49 non-tumor tissues from 20 never smokers, 26 former smokers, and 28 current smokers.
| S-ECPF-GEOD-10072 | biostudies-other
Project description:BackgroundDeep sequencing techniques provide a remarkable opportunity for comprehensive understanding of tumorigenesis at the molecular level. As omics studies become popular, integrative approaches need to be developed to move from a simple cataloguing of mutations and changes in gene expression to dissecting the molecular nature of carcinogenesis at the systemic level and understanding the complex networks that lead to cancer development.ResultsHere, we describe a high-throughput, multi-dimensional sequencing study of primary lung adenocarcinoma tumors and adjacent normal tissues of six Korean female never-smoker patients. Our data encompass results from exome-seq, RNA-seq, small RNA-seq, and MeDIP-seq. We identified and validated novel genetic aberrations, including 47 somatic mutations and 19 fusion transcripts. One of the fusions involves the c-RET gene, which was recently reported to form fusion genes that may function as drivers of carcinogenesis in lung cancer patients. We also characterized gene expression profiles, which we integrated with genomic aberrations and gene regulations into functional networks. The most prominent gene network module that emerged indicates that disturbances in G2/M transition and mitotic progression are causally linked to tumorigenesis in these patients. Also, results from the analysis strongly suggest that several novel microRNA-target interactions represent key regulatory elements of the gene network.ConclusionsOur study not only provides an overview of the alterations occurring in lung adenocarcinoma at multiple levels from genome to transcriptome and epigenome, but also offers a model for integrative genomics analysis and proposes potential target pathways for the control of lung adenocarcinoma.
| S-EPMC3566005 | biostudies-literature