Increased miR-708 expression in NSCLC and its association with poor survival in lung adenocarcinoma from Never Smokers
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Jang JS
PROVIDER: S-ECPF-GEOD-36681 | biostudies-other | 2012 Jul
REPOSITORIES: biostudies-other
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Project description:miRNA plays an important role in human disease and cancer. We seek to investigate the expression status, clinical relevance, and functional role of miRNA in non-small cell lung cancer.We conducted miRNA expression profiling in matched lung adenocarcinoma and uninvolved lung using 56 pairs of fresh-frozen (FF) and 47 pairs of formalin-fixed, paraffin-embedded (FFPE) samples from never smokers. The most differentially expressed miRNA genes were evaluated by Cox analysis and log-rank test. Among the best candidate, miR-708 was further examined for differential expression in two independent cohorts. Functional significance of miR-708 expression in lung cancer was examined by identifying its candidate mRNA target and through manipulating its expression levels in cultured cells.Among the 20 miRNAs most differentially expressed between tested tumor and normal samples, high expression level of miR-708 in the tumors was most strongly associated with an increased risk of death after adjustments for all clinically significant factors including age, sex, and tumor stage (FF cohort: HR, 1.90; 95% CI, 1.08-3.35; P = 0.025 and FFPE cohort: HR, 1.93; 95% CI, 1.02-3.63; P = 0.042). The transcript for TMEM88 gene has a miR-708 binding site in its 3' UTR and was significantly reduced in tumors high of miR-708. Forced miR-708 expression reduced TMEM88 transcript levels and increased the rate of cell proliferation, invasion, and migration in culture.miRNA-708 acts as an oncogene contributing to tumor growth and disease progression by directly downregulating TMEM88, a negative regulator of the Wnt signaling pathway in lung cancer.
| S-EPMC3616503 | biostudies-literature
Project description:We demonstrate that miR-708 is one of the most highly overexpressed miRNAs in non-small cell lung cancer. High level of miR-708 in tumor is also associated with a reduced overall survival in lung adenocarcinomas from never smokers. Functionally, miR-708 overexpression increases the proliferation, migration, and invasion in cultured cells and down regulates TMEM88, a negative regulator of Wnt signaling. Jointly, our results support an oncogenic role of miR-708 by activating Wnt signaling pathway to promote lung cancer progression.
2012-08-03 | GSE36681 | GEO
Project description:We demonstrate that miR-708 is one of the most highly overexpressed miRNAs in non-small cell lung cancer. High level of miR-708 in tumor is also associated with a reduced overall survival in lung adenocarcinomas from never smokers. Functionally, miR-708 overexpression increases the proliferation, migration, and invasion in cultured cells and down regulates TMEM88, a negative regulator of Wnt signaling. Jointly, our results support an oncogenic role of miR-708 by activating Wnt signaling pathway to promote lung cancer progression. We performed miRNA expression profiling in matched lung adenocarcinoma and uninvolved lung using 47 pairs from formalin-fixed, paraffin-embedded [FFPE] tissues from never smokers. We performed miRNA expression profiling in matched lung adenocarcinoma and uninvolved lung using 56 pairs of fresh-frozen [FF] samples from never smokers.
2012-08-02 | E-GEOD-36681 | biostudies-arrayexpress
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.
| S-EPMC3931519 | biostudies-literature
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.
| S-EPMC10313938 | biostudies-literature
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: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.
| S-EPMC4110480 | biostudies-literature
Project description:IntroductionLung cancer in never-smokers ranks among the 10 most common causes of death due to cancer worldwide and in the United States. However, it is unknown whether never-smokers at elevated risk for developing lung cancer may benefit from lung cancer screening.MethodsThe MIcrosimulation SCreening ANalysis (MISCAN)-Lung microsimulation model was used to assess the effects of lung cancer screening for simulated cohorts of never-smokers at different levels of relative risk (RR) for lung cancer compared with never-smokers at average risk. The benefits and harms of screening were estimated for each cohort and compared with those of a cohort of ever-smokers eligible for lung cancer screening according to the United States Preventive Services Task Force (USPSTF) criteria.ResultsThe relative lung cancer mortality reduction in never-smokers was higher than the USPSTF eligible cohort (37% compared with 32%). However, the number of life-years gained per lung cancer death averted was lower (10.4 compared with 11.9) and the proportion of overdiagnosed cancers was higher (9.6% compared with 8.4%) for never-smokers compared with the USPSTF eligible cohort, as never-smokers are diagnosed at a later age. The estimated number of screens per lung cancer death averted ranged from 6162 for never-smokers at average risk to 151 for never-smokers with an RR of 35 compared with 353 for the USPSTF eligible cohort.ConclusionsNever-smokers with RRs of 15 to 35 have similar to better trade-offs between benefits and harms compared with ever-smokers recommended for lung cancer screening by the USPSTF guidelines. For most never-smokers, lung cancer screening is not beneficial.
| S-EPMC4549205 | biostudies-literature
Project description:OBJECTIVES:Lung adenocarcinoma in never-smokers accounts for 15-20% of all lung cancer. Although targetable mutations are more prevalent in these tumors, the biological and clinical importance of coexisting and/or mutually exclusive abnormalities is just emerging. This study evaluates the relationships between common genetic and epigenetic aberrations in these tumors. MATERIALS AND METHODS:Next-generation sequencing was employed to screen 20 commonly mutated cancer-driver genes in 112 lung adenocarcinomas from never-smokers. The relationship of these mutations with cancer-related methylation of 59 genes, and geographical/ethnic differences in the prevalence for mutations compared to multiple East Asian never-smoker lung adenocarcinoma cohorts was studied. RESULTS:The most common driver mutation detected in 40% (45/112) of the tumors was EGFR, followed by TP53 (18%), SETD2 (11%), and SMARCA4 (11%). Over 72% (81/112) of the cases have mutation of at least one driver gene. While 30% (34/112) of the tumors have co-mutations of two or more genes, 42% (47/112) have only one driver gene mutation. Differences in the prevalence for some of these mutations were seen between adenocarcinomas in East Asian versus US (mainly Caucasian) never-smokers including a significantly lower rate of EGFR mutation among the US patients. Interestingly, aberrant methylation of multiple cancer-related genes was significantly associated with EGFR wildtype tumors. Among 15 differentially methylated genes by EGFR mutation, 14 were more commonly methylated in EGFR wildtype compared to mutant tumors. These findings were independently validated using publicly available data. CONCLUSION:Most lung adenocarcinomas from never-smokers harbor targetable mutation/co-mutations. In the absence of EGFR mutation that drives 40% of these tumors, EGFR wildtype tumors appear to develop by acquiring aberrant promoter methylation that silences tumor-suppressor genes.
| S-EPMC6331003 | biostudies-literature