Histological Subtypes Of Lung Cancer Research Articles

A 10-year retrospective study of lung cancer in Uganda

BackgroundLung cancer is a leading cause of cancer-related deaths in Uganda. In this study, we aimed to describe the baseline characteristics and survival of patients with lung cancer at the Uganda Cancer Institute (UCI).MethodsWe retrospectively reviewed medical records of all patients with a histological diagnosis of lung cancer registered at UCI between January 2008 and August 2018. Data on demographic, clinical, and treatment characteristics, and vital status were abstracted and analyzed. Patients with undocumented vital status on the medical records were contacted through phone calls. We determined survival as time from histological diagnosis to death. The Kaplan-Meier survival analysis was performed to estimate the median survival time and the 5-year overall survival rate.ResultsOf the 207 patients enrolled, 56.5% (n = 117) were female, median age was 60 years (range: 20–94), 78.7% (n = 163) were never-smokers and 18 (8.7%) were living with HIV. Presumptive anti-tuberculosis treatment was given to 23.2% (n = 48). Majority had non-small cell lung cancer (96.6%, n = 200) with 74.5% (n = 149) adenocarcinoma and 19% (n = 38) squamous cell carcinoma. All had advanced (stage III or IV) disease with 96.1% (n = 199) in stage IV. Chemotherapy (44.9%, n = 93) and biological therapy (34.8%, n = 72) were the commonest treatments used. Overall survival at 6 months, 1-, 2- and 5-years was 41.7, 29.7, 11.8, and 1.7%, respectively. The median survival time of 4.4 months was not statistically significantly different between participants with NSCLC or SCLC (4.5 versus 3.9 months, p = .335).ConclusionIn Uganda, adenocarcinoma is the predominant histologic subtype of lung cancer and patients are predominantly females, and non-smokers. Patients present late with advanced disease and poor overall survival. Public awareness should be heightened to facilitate early detection and improve outcomes.

MYC/MAX-Activated LINC00958 Promotes Lung Adenocarcinoma by Oncogenic Transcriptional Reprogramming Through HOXA1 Activation.

BackgroundLung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer. The role of the long non-coding RNA (lncRNA) LINC00958, which regulates the malignant behavior of multiple tumors, in LUAD has not been elucidated.MethodsTissue microarray, FISH, and qRT-PCR were used to detect the expression of LINC00958. Plasmid and viral infections were used to manipulate gene expression. The role of LINC00958 in LUAD was studied by cell proliferation analysis, cell apoptosis analysis, cell migration and invasion analysis, and subcutaneous inoculation of animal models. At the same time, RNA-Seq, RNA pull-down, ChIRP, ChIP, and luciferase reporter gene assays were performed to clarify the mechanism.ResultsThe expression of LINC00958 in LUAD tissues was significantly upregulated when compared with that in adjacent tissues and could independently predict poor survival of patients with LUAD. LINC00958 knockdown significantly inhibited the growth and metastasis of lung cancer cells in vitro and in vivo. LINC00958 localized to the nucleus, regulated oncogenes and metabolism-related and immune response-related genes, and interacted with histones. The targets of LINC00958 were TRPV3, STAP2, and EDN2 promoters with motifs of HOXA1, NANOG, FOSL2, JUN, and ATF4. Moreover, HOXA1 overexpression mitigated the LINC00958 knockdown-induced oncogenic phenotype. MYC/MAX motif, which was detected at the cis-element of LINC00958, trans-activated the LINC00958 promoter.ConclusionsMYC/MAX-trans-activated LINC00958 promotes the malignant behavior of LUAD by recruiting HOXA1 and inducing oncogenic reprogramming.

Glucose-6-phosphate dehydrogenase promotes the proliferation and migration of lung adenocarcinoma cells via the STAT3 signaling pathway.

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, and the leading cause of cancer-related deaths worldwide. G6PD has been reported to enhance the progression of various tumors by regulating the intracellular redox state and mediating nucleic acid synthesis. However, the biological role and molecular mechanism of G6PD in LUAD remain largely unknown. In this study, we found that G6PD was significantly upregulated in LUAD specimens and cell lines, and that the high levels of G6PD expression were closely associated with a poor prognosis for LUAD patients. Moreover, we found that G6PD significantly promoted the proliferation and migration of LUAD cells in vitro, and overexpression of G6PD also play a role of facilitating tumorigenesis in in vivo experiments. Mechanistically, the STAT3 signaling pathway was significantly activated by G6PD-mediated LUAD progression. Overall, our results suggest that G6PD could serve as a novel prognostic marker and therapeutic target for treating LUAD.

Small cell lung cancer: an overview of the targets

Lung cancer is the leading cause of cancer deaths worldwide. Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases. Despite a frequently good response to first-line treatment with chemotherapy and/or radiotherapy, early relapse occurs in the majority of patients and 5-year survival is only about 5%. This histological subtype of lung cancer is strongly associated with tobacco smoking. The behavior of SCLC is unique within solid tumors. Initially, it positively responds to chemotherapy or radiotherapy. However, at relapse, which occurs early in the majority of cases, the tumor is resistant to available therapy and eventually will cause the death of the patient. These results in an overall 5-year survival of approximately 5% for the entire population of patients diagnosed with SCLC. This dismal prognosis has not significantly changed in past years. There is an urgent need for discovery targets to select patients more prone to having a proper response to the treatment, avoiding to reduce their resistance and resulting the increase of overall and progression-free survivals.

CT-Guided Percutaneous Core Needle Biopsy in Typing and Subtyping Lung Cancer: A Comparison to Surgery

Background: Lung cancer histologic types and subtypes are closely associated with treatment selection and prognosis prediction. In this study, we aim to evaluate the suitability of computed tomography-guided percutaneous core needle biopsy (CT-guided PCNB) in typing and subtyping lung cancer. Methods: From August 2007 to December 2015, the patients who underwent CT-guided PCNB and lung lesion resection were retrospectively collected and analyzed. All pathological sections were reassessed in consensus by 2 junior pathologists (group A) and 2 senior pathologists (group B), respectively. All cases were diagnosed on 3 levels: first, malignant and benign diagnosis; second, histologic types diagnosis; and third, histologic subtypes diagnosis and compared with surgery results. Pearson chi-square test was used to compare the differences of diagnostic accuracy between pathologists in group A and group B. Results: A cohort of 160 patients was included in this study. On the first level, the diagnostic accuracy was 90.63% (group A) and 94.38% (group B), (P = .20). On the second level, the diagnostic accuracy for malignant lesions, adenocarcinoma (ADC), and squamous cell carcinoma (SQC) were, respectively, 72.66%, 84.72%, and 69.05% (group A) and 76.98%, 90.28%, and 71.43% (group B) (P > .05). On the third level, the diagnostic accuracy for ADC subtypes were 26.39% (group A) and 55.56% (group B) (P < 0.01); for SQC subtypes were 28.57% (group A) and 38.10% (group B) (P = 0.36). Conclusion: Small specimens obtained by CT-guided PCNB were suitable for the diagnosis of lung cancer histologic types, which may contribute to the selection of a suitable treatment strategy for the unresectable lung cancers. While for the diagnosis of subtypes, discussion with experienced pathologists was recommended.

Radiomic Signature as a Diagnostic Factor for Classification of Histologic Subtypes of Lung Cancer

&lt;sec&gt; &lt;title&gt;Objectives:&lt;/title&gt; To discuss the application of radiomics using Computerized Tomography (CT) analysis, for improving its diagnostic efficacy in lung, specifically in distinguishing Squamous Cell Carcinoma (SCC), lung Adenocarcinoma (ADC), and Small Cell Lung Cancer (SCLC). &lt;/sec&gt; &lt;sec&gt; &lt;title&gt;Methods:&lt;/title&gt; The pathology of 189 identified cases of lung cancer was analyzed, retrospectively (60 patients with SCC, 69 patients with lung ADC and 60 patients with SCLC). A neural network was used to determine whether the pulmonary or mediastinal window was selected to extract effective radiomic features. The key features of radiomic signature were retrieved by a Least Absolute Shrinkage and Selection Operator (LASSO) multiple logistic regression model. Next, receiver operating characteristic curve and Area Under the Curve (AUC) analysis were used to evaluate the performance of the radiomic signature in both, training(129 patients) and validation cohorts (60 patients). &lt;/sec&gt; &lt;sec&gt; &lt;title&gt;Results:&lt;/title&gt; About 295 features were extracted from a manually outlined tumor region. Features extracted from mediastinal window CT scans had a better prognostic ability than pulmonary window scans. The average accuracy for mediastinal window scans was 0.933. Our analysis revealed that the radiomic features extracted from mediastinal window scans had the potential to build a prediction model for distinguishing between SCC, lung ADC, and SCLC. The performance of the radiomic signature to diagnose SCC and SCLC in validation cohorts proved effective, with AUC values of 0.869 and 0.859, respectively. &lt;/sec&gt; &lt;sec&gt; &lt;title&gt;Conclusions:&lt;/title&gt; A unique radiomic signature was constructed as a diagnostic factor for different histologic subtypes of lung cancer. Patients with lung cancer may benefit from this proposed radiomic signature. &lt;/sec&gt;

Non-Small Cell Lung Cancer Histologic Subtypes Correlate with Unique Distant Site Metastatic Patterns and Have Significantly Distinct Overall Survival

Non-Small Cell Lung Cancer Histologic Subtypes Correlate with Unique Distant Site Metastatic Patterns and Have Significantly Distinct Overall Survival

MiR-1293 acts as a tumor promotor in lung adenocarcinoma via targeting phosphoglucomutase 5.

BackgroundLung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer. Studies have found that miR-1293 is related to the survival of LUAD patients. Unfortunately, its role in LUAD remains not fully clarified.MethodsmiR-1293 expression and its association with LUAD patients’ clinical characteristics were analyzed in TCGA database. Also, miR-1293 expression was detected in LUAD cell lines. Cell viability, migration, invasion and expression of MMP2 and MMP9 were measured in LUAD cells following transfection with miR-1293 mimic or antagomir. Phosphoglucomutase (PGM) 5 was identified to be negatively related to miR-1293 in LUAD patients in TCGA database, and their association was predicated by Targetscan software. Hence, we further verified the relationship between miR-1293 and PGM5. Additionally, the effect and mechanism of miR-1293 were validated in a xenograft mouse model.ResultsWe found miR-1293 expression was elevated, but PGM5 was decreased, in LUAD patients and cell lines. Higher miR-1293 expression was positively related to LUAD patients’ pathologic stage and poor overall survival. miR-1293 mimic significantly promoted, whereas miR-1293 antagomir suppressed the viability, migration, invasion, and expression of MMP2 and MMP9 in LUAD cells. PGM5 was a target of miR-1293. Overexpression of PGM5 abrogated the effects of miR-1293 on the malignant phenotypes of LUAD cells. Administration of miR-1293 antagomir reduced tumor volume and staining of Ki-67 and MMP9, but elevated PGM5 expression in vivo.ConclusionsmiR-1293 promoted the proliferation, migration and invasion of LUAD cells via targeting PGM5, which indicated that miR-1293 might serve as a potential therapeutic target for LUAD patients.

Lung cancer and interstitial lung diseases: the lack of prognostic impact of lung cancer in IPF

Lung Cancer (LC) is the first cause of death worldwide. Recently increased interest in interstitial lung diseases (ILD) has highlighted an association with lung cancer, offering interesting insights into the pathogenesis of the latter. Describe the association between lung cancer and ILD and evaluate the impact of LC on survival in these populations. We collected clinical, radiological, histologic data of 53 cases of advanced pulmonary fibrosis with lung cancer: 17 with UIP pattern (usual interstitial pneumonia, UIP/IPF-LC) and 36 with non-UIP pattern (ILD-LC). Adenocarcinoma was the most frequent histological subtype of lung cancer in all three groups and in UIP/IPF-LC developed in the lung periphery and in an advanced fibrosis context. Patients with DLCO% < 38% showed survival < 10 months, irrespective of group and development of carcinoma in UIP/IPF does not necessarily affect survival, unlike in SR-ILD. Our results confirm that the oncogenic mechanism is closely linked to fibrotic and inflammatory processes and that the development of carcinoma affects survival in SR-ILD but not in IPF.

Prognostic nutritional index as a prognostic factor in lung cancer patients receiving chemotherapy: a systematic review and meta-analysis.

Lung cancer is one of the leading causes of morbidity and mortality in the world. In the past decade, numerous studies focus on the prognostic nutritional index (i.e., a measure of serum albumin and lymphocyte in peripheral circulation) as a possible biomarker to predict the survival outcomes in cancer patients undergoing chemotherapy. Prognostic nutritional index can reliably predict the survivability outcomes by effectively quantifying the nutritional and immunological status of cancer patients. To date, only one review has attempted to evaluate the impact of the prognostic nutritional index on the survival outcomes in lung cancer patients with certain limitations. The goal of the present systematic review and meta-analysis is to bridge the gap in the literature and evaluate the capacity of the prognostic nutritional index for predicting the survivability outcomes in lung cancer patients undergoing chemotherapy. The aim of the study is to evaluate the impact of prognostic nutritional index scoring on survival outcomes in lung cancer patients undergoing chemotherapy. A systematic academic literature search was performed based on the PRISMA guidelines across Web of Science, EMBASE, CENTRAL, Scopus, and MEDLINE databases. A random-effect meta-analysis was performed to evaluate the impact of prognostic nutritional index scoring (i.e., high/low) on survival outcomes (i.e., progression-free survival, overall survival) in lung cancer patients undergoing chemotherapy. From 963 studies, 16 eligible studies with 4250 lung cancer patients (62.32 ± 5.08 years) undergoing chemotherapy were included. Our meta-analysis revealed worse mortality outcomes in terms of progression-free survival (HR: 1.31) and overall survival (1.21) for the group with a low prognostic nutritional index score as compared to the group with a high prognostic nutritional index score in lung cancer patients undergoing chemotherapy. Subsequent subgroup analyses further demonstrated markedly worse outcomes for progression-free survival (1.32) and overall survival (1.52) in non-small lung cancer patients with lower prognostic nutritional index scores. We provide preliminary evidence suggesting that lower prognostic nutrition index scores are associated with worse survivability outcomes (progression-free survival and overall survival) in lung cancer patients undergoing chemotherapy. We also show that lower prognostic nutrition index scores correlate with even worse survival outcomes in patients with non-small lung cancer histological subtype of lung cancer. These findings should help clinicians to stratify the risks associated with the chemotherapeutic management of lung cancer patients.

Systematically integrative analysis identifies diagnostic and prognostic candidates and small-molecule drugs for lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer (LC). However, the early-stage diagnostic rate is still low, and the 5-year overall survival (OS) rate remains poor. The present study aimed to identify critical genes as diagnostic and prognostic markers and small-molecule drugs for combating LUAD using a systematic bioinformatics analysis.MethodsFive gene expression profiling datasets were systematically integrated and analyzed. First, gene coexpression modules were identified, and differentially expressed genes (DEGs) were screened. Second, the functional changes of these DEGs were systematically investigated. Third, the protein-protein interaction network, high correlation module and key genes were identified. Fourth, prognosis and diagnostic analyses were performed. Fifth, small-molecule drugs were predicted for guiding LUAD therapy.ResultsFinally, 12-gene and 2-gene signatures were identified as diagnostic and prognostic markers. The areas under the curves (AUCs) of two signatures associated with 3-year survival were 0.686 and 0.603, respectively. The AUCs of two signatures were over 95% and 94% in diagnostic model, separately. Eleven small-molecule drugs were found and irinotecan was simultaneously predicted in three drug databases.ConclusionsThe present study identified some key dysregulated genes involved in LUAD and potential drugs by a comprehensive analysis, which provides novel insights into the pathological mechanism involved in LUAD and may shed light on the diagnosis, prognosis and treatment of LUAD patients.

CSNK1A1, KDM2A, and LTB4R2 Are New Druggable Vulnerabilities in Lung Cancer.

Simple SummaryThe main histological subtypes of lung cancer are small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). NSCLC is further subdivided into squamous-cell carcinoma (SCC) and adenocarcinoma (AD). Despite the recent introduction of innovative therapies, lung cancer is still the first cause of cancer-related human death, indicating that the discovery of new therapeutic targets is still a compelling need for this disease. In the present work, we performed a functional genomics analysis on different lung cancer histotypes, combining data derived from different omics resources with in vitro validation. Through this approach, we identified and validated CSNK1A1, KDMA2, and LTB4R2 as new druggable vulnerabilities in lung cancer. These results open new possibilities for the development of innovative therapies for lung cancer patients.Lung cancer is the leading cause of cancer-related human death. It is a heterogeneous disease, classified in two main histotypes, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), which is further subdivided into squamous-cell carcinoma (SCC) and adenocarcinoma (AD) subtypes. Despite the introduction of innovative therapeutics, mainly designed to specifically treat AD patients, the prognosis of lung cancer remains poor. In particular, available treatments for SCLC and SCC patients are currently limited to platinum-based chemotherapy and immune checkpoint inhibitors. In this work, we used an integrative approach to identify novel vulnerabilities in lung cancer. First, we compared the data from a CRISPR/Cas9 dependency screening performed in our laboratory with Cancer Dependency Map Project data, essentiality comprising information on 73 lung cancer cell lines. Next, to identify relevant therapeutic targets, we integrated dependency data with pharmacological data and TCGA gene expression information. Through this analysis, we identified CSNK1A1, KDM2A, and LTB4R2 as relevant druggable essentiality genes in lung cancer. We validated the antiproliferative effect of genetic or pharmacological inhibition of these genes in two lung cancer cell lines. Overall, our results identified new vulnerabilities associated with different lung cancer histotypes, laying the basis for the development of new therapeutic strategies.

Abstract 896: Comparison of tumor profiles of second cancers among breast cancer survivors to first cancers in the SEER registries: A nationwide study

Abstract Background: In the US, the number of breast cancer (BC) survivors is expected to increase to 5 million by 2030. Although it is well established that BC survivors are at increased risk of second primary cancer (SPC), little is known about the characteristics of these tumors. Methods: We conducted a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) 18 database to compare the tumor characteristics of first primary cancer (FPC) to SPC among women diagnosed with BC between 2000-2016. For this analysis, we focused on breast, lung, colorectal, uterine, and cervical cancer. Odds ratio (OR) and 95% confidence interval (CI) for tumor characteristics comparing SPC to FPC were estimated from logistic or multinomial logistic regression, adjusting for race/ethnicity, year of diagnosis, and age at diagnosis. Tumor characteristics included summary tumor stage, T stage, tumor grade, hormone receptor (HR) status of BC, molecular subtype of BC, Oncotype DX score of BC for a subset (N=48,826), and histologic subtype of lung cancer. Results: The study population included 14,392 second and 586,788 first BC, 5,202 second and 246,543 first lung cancers, 3,525 second and 190,640 first colorectal cancers, 2,517 second and 125,818 first uterine cancers, as well as 230 second and 42,601 first cervical cancers. Women with SPC were older than women with FPC. Compared to FPC, SPC were more likely to be diagnosed at local stage for breast (OR: 1.30, 95%CI: 1.25-1.34), lung (OR: 1.57, 95%CI: 1.47-1.68), colorectal (OR: 1.20, 95%CI: 1.12-1.28), and cervical cancer (OR: 1.59, 95%CI: 1.19-2.12), but not for uterine cancer (OR: 1.07, 95%CI: 0.98-1.17). Second breast (OR: 1.26, 95%CI: 1.21-1.31) and uterine (OR: 1.83, 95%CI: 1.65-2.03) cancers were more likely to present at poorly or undifferentiated tumor grade after adjusting for tumor stage. No difference in tumor grade was found for lung, colorectal, and cervical cancer. Second BC were more likely to be of hormone receptor (HR) negative (OR: 1.64, 95%CI: 1.57-1.71), human epidermal growth factor receptor 2 (HER2) enriched (OR:1.30, 95%CI: 1.16-1.45) and triple negative (OR: 1.66, 95%: 1.55-1.77) subtype, and having Oncotype DX score above 26 (OR: 1.73, 95%CI: 1.47-2.04). Second lung cancers were more likely to be of small cell histology compared to first lung cancers (OR =1.15, 95%CI: 1.06-1.25). Conclusion: Screen-detectable second cancers were diagnosed at an earlier stage compared with first cancers. Further, second breast, uterine, and lung cancer had a more aggressive tumor profile compared to women with a similar type of first cancer suggestive of underlying biological differences between the two groups. It is plausible that more intensive screening strategies akin to screening recommendations for women at high risk of BC may be needed for survivors at risk for certain second cancers. Citation Format: Zhengyi Deng, Miranda R. Jones, Kala Visvanathan. Comparison of tumor profiles of second cancers among breast cancer survivors to first cancers in the SEER registries: A nationwide study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 896.

Abstract 130: Resolving the spatial and cellular architecture of lung adenocarcinoma by multi-region single-cell sequencing

Abstract Lung adenocarcinoma (LUAD) is the most commonly diagnosed histological subtype of lung cancer. While earlier work has underscored genomic and immune alterations in LUAD, the roles of individual cell populations in early-stage human LUAD evolution in space remain unknown. Here, we provide a detailed cellular atlas of early-stage LUAD and its spatial ecosystem along the peripheral lung. We performed single-cell RNA sequencing of 186,916 cells including enriched epithelial fractions from five early-stage LUADs with fourteen multi-region normal lung tissues of defined spatial proximities from the primary LUADs. We show that major epithelial and immune cellular lineages, states, and transcriptomic features geospatially and progressively evolve across normal regions and with increasing LUAD proximity. Analysis of 70,030 lung epithelial cells unraveled diverse lineage trajectories, transcriptional lineage plasticity programs underlying KRAS-mutant cells, and intratumoral heterogeneity within single sites. T regulatory cell programs including multiple immune checkpoints increased in tissues with closer proximity to LUADs, in sharp contrast to signatures of CD8+ cytotoxic T cells, antigen presentation by macrophages, and inflammatory dendritic cells. We found that some spatial signatures (e.g. a B cell signature score) were increased along the pathologic spectrum of normal lung, preneoplastic lesions, and matched invasive LUADs. LUAD cell-cell communication networks were enriched with ligand-receptor interactions involving CD24, LGALS9 and TIM3 immune checkpoints, including crosstalk between CD24 antigen in LUAD epithelial cells and SIGLEC10 in myeloid subsets. CD24 was markedly increased in preneoplasias relative to normal lung and further in LUAD, and its expression was highly positively correlated with immunosuppressive phenotypes. These data provide an atlas of cellular states and phenotypes underlying early-stage LUAD evolution in space, and a scalable resource for identification of targets for early treatment. Citation Format: Ansam Sinjab, Guangchun Han, Warapen Treekitkarnmongkol, Kieko Hara, Patrick Brennan, Minghao Dang, Dapeng Hao, Ruiping Wang, Enyu Dai, Hitoshi Dejima, Jiexin Zhang, Elena Bogatenkova, Beatriz Sanchez-Espiridion, Kyle Chang, Danielle R. Little, Samer Bazzi, Linh Tran, Kostyantyn Krysan, Carmen Behrens, Dzifa Duose, Edwin R. Parra, Maria Gabriela Raso, Luisa M. Solis, Junya Fukuoka, Jianjun Zhang, Boris Sepesi, Tina Cascone, Lauren A. Byers, Don L. Gibbons, Jichao Chen, Seyed Javad Moghaddam, Edwin J. Ostrin, Daniel G. Rosen, John V. Heymach, Paul Scheet, Steven Dubinett, Ignacio I. Wistuba, Junya Fujimoto, Christopher S. Stevenson, Avrum E. Spira, Linghua Wang, Humam Kadara. Resolving the spatial and cellular architecture of lung adenocarcinoma by multi-region single-cell sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 130.

Diagnosis-to-surgery interval and survival for different histologies of stage I-IIA lung cancer.

BackgroundGuidelines on timeliness of lung cancer surgery are inconsistent. Lung cancer histologic subtypes have different prognosis and treatment. It is important to understand the consequences of delayed surgery for each lung cancer histologic subtype. This study aimed to examine the association between diagnosis-to-surgery time interval and survival for early stage lung cancer and selected histologic subtypes.MethodsPatients diagnosed with stage I–IIA lung cancer between 2004 and 2015 receiving definitive surgery and being followed up until Dec. 31, 2018, were identified from Surveillance, Epidemiology, and End Results database. Histologic subtypes included adenocarcinoma, squamous or epidermoid carcinoma, bronchioloalveolar carcinoma, large cell carcinoma, adenosquamous carcinoma, carcinoid carcinoma, and small cell carcinoma. Diagnosis-to-surgery interval was treated as multi-categorical variables (<1, 1–2, 2–3, and ≥3 months) and binary variables (≥1 vs. <1 month, ≥2 vs. <2 months, and ≥3 vs. <3 months). Outcomes included cancer-specific and overall survival. Covariates included age at diagnosis, sex, race, marital status, tumor size, grade, surgery type, chemotherapy, radiotherapy, and study period. Kaplan-Meier survival curves and Cox proportional hazards regression models were applied to examine the survival differences.ResultsWith a median follow-up time of 51 months, a total of 40,612 patients were analyzed, including 40.1% adenocarcinoma and 24.5% squamous or epidermoid carcinoma. The proportion of patients receiving surgery <1, 1–2, 2–3, and ≥3 months from diagnosis were 34.2%, 33.9%, 19.8%, and 12.1%, respectively. Delayed surgery was associated with worse cancer-specific and overall survival for all lung cancers, adenocarcinoma, squamous or epidermoid, bronchioloalveolar, and large cell carcinoma (20–40% increased risk). Dose-dependent effects (longer delay, worse survival) were observed in all lung cancers, adenocarcinoma, and squamous and epidermoid carcinoma. No significant association between surgery delay and survival was observed in adenosquamous, carcinoid, and small cell carcinoma.ConclusionsOur findings support the guidelines of undertaking surgery within 1 month from diagnosis in patients with stage I–IIA lung cancer. The observed dose-dependent effects emphasize the clinical importance of early surgery. Future studies with larger sample size of less frequent histologic subtypes are warranted to provide more evidence for histology-specific lung cancer treatment guidelines.

Identification of significant genes as prognostic markers and potential tumor suppressors in lung adenocarcinoma via bioinformatical analysis

BackgroundLung adenocarcinoma (LAC) is the predominant histologic subtype of lung cancer and has a complicated pathogenesis with high mortality. The purpose of this study was to identify differentially expressed genes (DEGs) with prognostic value and determine their underlying mechanisms.MethodsGene expression data of GSE27262 and GSE118370 were acquired from the Gene Expression Omnibus database, enrolling 31 LAC and 31 normal tissues. Common DEGs between LAC and normal tissues were identified using the GEO2R tool and Venn diagram software. Next, the Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to analyze the Gene Ontology and Kyoto Encyclopedia of Gene and Genome (KEGG) pathways. Then, protein-protein interaction (PPI) network of DEGs was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes and central genes were identified via Molecular Complex Detection. Furthermore, the expression and prognostic information of central genes were validated via Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier analysis, respectively. Finally, DAVID, real-time PCR and immunohistochemistry were applied to re-analyze the identified genes, which were also further validated in two additional datasets from ArrayExpress database.ResultsFirst, 189 common DEGs were identified among the two datasets, including 162 downregulated and 27 upregulated genes. Next, Gene Ontology and KEGG pathway analysis of the DEGs were conducted through DAVID. Then, PPI network of DEGs was constructed and 17 downregulated central genes were identified. Furthermore, the 17 downregulated central genes were validated via GEPIA and datasets from ArrayExpress, and 12 of them showed a significantly better prognosis. Finally, six genes were identified significantly enriched in neuroactive ligand-receptor interactions (EDNRB, RXFP1, P2RY1, CALCRL) and Rap1 signaling pathway (TEK, P2RY1, ANGPT1) via DAVID, which were further validated to be weakly expressed in LAC tissues via RNA quantification and immunohistochemistry analysis.ConclusionsThe low expression pattern and relation to prognosis indicated that the six genes were potential tumor suppressor genes in LAC. In conclusion, we identified six significantly downregulated DEGs as prognostic markers and potential tumor suppressor genes in LAC based on integrated bioinformatics methods, which could act as potential molecular markers and therapeutic targets for LAC patients.

KLF5-induced BBOX1-AS1 contributes to cell malignant phenotypes in non-small cell lung cancer via sponging miR-27a-5p to up-regulate MELK and activate FAK signaling pathway

BackgroundNon-small cell lung cancer (NSCLC) is a major histological subtype of lung cancer with high mortality and morbidity. A substantial amount of evidence demonstrates long non-coding RNAs (lncRNA) as critical regulators in tumorigeneis and malignant progression of human cancers. The oncogenic role of BBOX1 anti-sense RNA 1 (BBOX1-AS1) has been reported in several tumors. As yet, the potential functions and mechanisms of BBOX1-AS1 in NSCLC are obscure.MethodsThe gene and protein expression was detected by qRT-PCR and western blot. Cell function was determined by CCK-8, colony forming, would healing and transwell assays. Bioinformatics tools, ChIP assays, dual luciferase reporters system and RNA pull-down experiments were used to examine the interaction between molecules. Subcutaneous tumor models in nude mice were established to investigate in vivo NSCLC cell behavior.ResultsBBOX1-AS1 was highly expressed in NSCLC tissues and cells. High BBOX1-AS1 expression was associated with worse clinical parameters and poor prognosis. BBOX1-AS1 up-regulation was induced by transcription factor KLF5. BBOX1-AS1 deficiency resulted in an inhibition of cell proliferation, migration, invasion and EMT in vitro. Also, knockdown of BBOX1-AS1 suppressed NSCLC xenograft tumor growth in mice in vivo. Mechanistically, BBOX1-AS1 acted act as a competetive “sponge” of miR-27a-5p to promote maternal embryonic leucine zipper kinase (MELK) expression and activate FAK signaling. miR-27a-5p was confirmed as a tumor suppressor in NSCLC. Moreover, BBOX1-AS1-induced increase of cell proliferation, migration, invasion and EMT was greatly reversed due to the overexpression of miR-27a-5p. In addition, the suppressive effect of NSCLC progression owing to BBOX1-AS1 depletion was abated by the up-regulation of MELK. Consistently, BBOX1-AS1-mediated carcinogenicity was attenuated in NSCLC after treatment with a specific MELK inhibitor OTSSP167.ConclusionsKLF5-induced BBOX1-AS1 exerts tumor-promotive roles in NSCLC via sponging miR-27a-5p to activate MELK/FAK signaling, providing the possibility of employing BBOX1-AS1 as a therapeutic target for NSCLC patients.

Identification of transcriptional subtypes in lung adenocarcinoma and squamous cell carcinoma through integrative analysis of microarray and RNA sequencing data

Classification of tumors into subtypes can inform personalized approaches to treatment including the choice of targeted therapies. The two most common lung cancer histological subtypes, lung adenocarcinoma and lung squamous cell carcinoma, have been previously divided into transcriptional subtypes using microarray data, and corresponding signatures were subsequently used to classify RNA-seq data. Cross-platform unsupervised classification facilitates the identification of robust transcriptional subtypes by combining vast amounts of publicly available microarray and RNA-seq data. However, cross-platform classification is challenging because of intrinsic differences in data generated using the two gene expression profiling technologies. In this report, we show that robust gene expression subtypes can be identified in integrated data representing over 3500 normal and tumor lung samples profiled using two widely used platforms, Affymetrix HG-U133 Plus 2.0 Array and Illumina HiSeq RNA sequencing. We tested and analyzed consensus clustering for 384 combinations of data processing methods. The agreement between subtypes identified in single-platform and cross-platform normalized data was then evaluated using a variety of statistics. Results show that unsupervised learning can be achieved with combined microarray and RNA-seq data using selected preprocessing, cross-platform normalization, and unsupervised feature selection methods. Our analysis confirmed three lung adenocarcinoma transcriptional subtypes, but only two consistent subtypes in squamous cell carcinoma, as opposed to four subtypes previously identified. Further analysis showed that tumor subtypes were associated with distinct patterns of genomic alterations in genes coding for therapeutic targets. Importantly, by integrating quantitative proteomics data, we were able to identify tumor subtype biomarkers that effectively classify samples on the basis of both gene and protein expression. This study provides the basis for further integrative data analysis across gene and protein expression profiling platforms.

A comprehensive pan-cancer analysis of CD274 gene amplification, tumor mutation burden, microsatellite instability, and PD-L1 expression in Chinese cancer patients.

BackgroundImmune checkpoint inhibitors blocking programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) have emerged as effective treatment options for cancer. However, immunotherapy is only effective in a subset of patients. Identifying effective biomarkers to predict the treatment response to PD-1/PD-L1 inhibitors remains an unmet clinical need.MethodsThis study retrospectively analyzed clinical information and genetic profiling results of 16,013 samples from Chinese patients with various cancer types in order to investigate the prevalence of CD274 (also known as PD-L1) amplification in various cancer types and its association with existing PD-1/PD-L1 biomarkers, including tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 expression.ResultsAmplification of CD274 was identified in 174 samples with an overall prevalence of 1.09% among all cancer types in the cohort. The prevalence of CD274 amplification in different cancer types and histological subtypes of lung cancer was varied, with cervical cancer having the highest prevalence. Distinct distributions of TMB, MSI, and PD-L1 expression between CD274-amplified and wild-type samples were observed in several cancer types as well as among different histological subtypes of lung cancer.ConclusionsAlthough CD274 amplification was only observed in a small proportion of patients, it demonstrated an association with TMB, MSI, and PD-L1 expression in several common cancer types. The molecular features of CD274 in different cancer types are heterogeneous. The role of CD274 amplification as a novel biomarker of PD-1/PD-L1 inhibitors remains to be characterized in future prospective clinical studies.

Age at first birth and lung cancer: a two-sample Mendelian randomization study.

BackgroundGrowing evidence suggests that female reproductive factors, like age at first birth (AFB), may play a potential role in the progression of lung cancer (LC). However, previous studies are susceptible to confounding factors, inadequate attention to variation by histology or reverse causality. Few studies have comprehensively evaluated their association and the causal effect remains unclear.MethodsWe aimed to determine whether AFB is causally correlated with the risk of LC, by means of utilizing aggregated data from the large genome-wide association studies conducted on AFB (251,151 individuals) and data of LC from International Lung and Cancer Consortium (ILCCO, 11,348 cases and 15,861 controls). We used 10 AFB-related single nucleotide polymorphisms as instrument variables and applied several two-sample Mendelian randomization (MR) methods. Secondary results according to different histological subtypes of lung cancer were also implemented.ResultsConventional inverse-variance weighted method indicated that genetic predisposition towards number unit (1 year) increase of AFB was associated with a 18% lower risk of LC [odds ratio (OR) =0.82, 95% confidence interval (CI): 0.69–0.97; P=0.029]. When results were examined by histotypes, an inverse association was observed between genetically predisposed number unit (1 year) increase of AFB and lung adenocarcinoma (OR =0.75, 95% CI: 0.59–0.97, P=0.017) but not with squamous cell lung cancer (OR =0.77, 95% CI: 0.57–1.05, P=0.103). The results demonstrated no association between number unit decrease of AFB and LC. Pleiotropy was not presented through sensitivity analyses including MR pleiotropy residual sum and outlier test (P=0.412). Genetic predisposition towards older AFB was additionally associated with longer years of schooling (OR =1.12, 95% CI: 1.08–1.16, P<0.001), lower body mass index (OR =0.93, 95% CI: 0.88–0.98, P=0.004) and less alcohol consumption (OR =0.99, 95% CI: 0.99–1.00, P=0.004).ConclusionsOur study suggested that older AFB was a causal protective factor in the progression of LC. Further studies elucidating the potential mechanisms are needed.