scholarly journals Up-regulated tumor intrinsic growth potential and decreased immune function orchestrate the evolution of lung adenocarcinoma

2022 ◽  
Author(s):  
Yue Zhao ◽  
Jun Shang ◽  
Jian Gao ◽  
Han Han ◽  
Zhendong Gao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Adenocarcinoma ◽  
Immune Function ◽  
Expression Patterns ◽  
Growth Potential ◽  
Adenocarcinoma In Situ ◽  
Invasive Adenocarcinoma ◽  
Genetic Changes ◽  
Normal Tissues ◽  
Pathological Subtype

Introduction Lung adenocarcinoma is the most common pathological subtype of lung cancer. Precursors of lung adenocarcinoma, namely adenocarcinoma in situ and minimally invasive adenocarcinoma, have a superb 5-year survival rate after surgical resection. A deeper understanding of the key genetic changes driving the progression of lung adenocarcinoma is needed. Methods In this study, we performed whole-exome sequencing and RNA-sequencing on surgically resected 24 AIS, 74 MIA, 99 LUAD specimens and their adjacent paired normal tissues. Radiological, clinical, and pathological characteristics were recorded. Gene expression patterns were identified to find key pathways driving the progression of lung adenocarcinoma. Furthermore, genomic alterations and differential expression analyses were performed to compare tumors with different radiological manifestations. Finally, a progressive index was developed to quantitatively measure the level of imbalance between tumor intrinsic growth potential and immune microenvironment. Results 12 patterns of gene expression were identified. Pathways associated with tumor growth and metastasis were found to be up-regulated as tumors progressed, while pathways associated with immune function were found to be down-regulated. Deconvolution of RNA-seq data also showed a decrease of CD8+ T cells and an increase of Tregs as the tumors progressed. Furthermore, tumors with more solid components on CT scan had a higher mutation frequency of tumor suppressor genes, higher tumor mutation burden and higher frequency of somatic copy number alterations. Finally, tumor progressive index demonstrated an increasing trend with the progression of lung adenocarcinoma. Discussion Imbalance of tumor intrinsic growth potential and immune function orchestrate the evolution of lung adenocarcinoma.

scholarly journals Identification and Evaluation of Circulating Small Extracellular Vesicle Micrornas as Diagnostic Biomarkers for Patients with Indeterminate Pulmonary Nodules

2021 ◽  
Author(s):  
Di Zheng ◽  
Yuming Zhu ◽  
Jiyang Zhang ◽  
Wei Zhang ◽  
Huizhen Wang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Lung Adenocarcinoma ◽  
Expression Patterns ◽  
Pulmonary Nodules ◽  
Small Rna Sequencing ◽  
Adenocarcinoma In Situ ◽  
Invasive Adenocarcinoma ◽  
Training Cohort ◽  
Increased Risk ◽  
Risk Of Cancer

Abstract Background: The identification of indeterminate pulmonary nodules (IPNs) following a low-dose computed tomography is a major challenge for early diagnosis of lung cancer. The inadequate assessment of IPNs’ malignancy risk results in a large number of unnecessary surgeries or an increased risk of cancer metastases. However, limited studies on non-invasive diagnosis of IPNs have been reported.Methods: In this study, we identified and evaluated the diagnostic value of circulating sEV miRNAs in patients with IPNs that had been newly detected using LDCT scanning and were scheduled for surgery. Out of 459 recruited patients, 109 eligible patients with IPNs were enrolled in the training cohort (n = 47) and the test cohort (n = 62). An external cohort (n=99) was used for validation. MiRNAs were extracted from plasma sEVs, and assessed using Small RNA sequencing. 490 lung adenocarcinoma samples and follow-up data were used to investigate the role of miRNAs in overall survival.Results: A circulating sEV miRNA (CirsEV-miR) model was constructed from five differentially expressed miRNAs (DEMs), showing 0.920 AUC in the training cohort (n = 47), and further identified in the test cohort (n = 62) and in an external validation cohort (n = 99). Among five DEMs of the CirsEV-miR model, miR-101-3p and miR-150-5p were significantly associated with better overall survival (p = 0.0001 and p = 0.0069). The CirsEV-miR scores were calculated, which significantly correlated with IPNs diameters (p < 0.05), and were able to discriminate between benign and malignant PNs (diameter ≤ 1 cm). The expression patterns of sEV miRNAs in the benign, adenocarcinoma in situ/minimally invasive adenocarcinoma, and invasive adenocarcinoma subgroups were found to gradually change with the increase in aggressiveness for the first time. Among all DEMs of the three subgroups, five miRNAs (miR-30c-5p, miR-30e-5p, miR-500a-3p, miR-125a-5p, and miR-99a-5p) were also significantly associated with overall survival of lung adenocarcinoma patients.Conclusions: Our results indicate that the CirsEV-miR model could help distinguish between benign and malignant PNs, providing insights into the feasibility of circulating sEV miRNAs in diagnostic biomarker development.Trial registration: Chinese Clinical Trials, ChiCTR1800019877. Registered 05 December 2018, https://www.chictr.org.cn/showproj.aspx?proj=31346.

A Clinicopathological Study of Small Lung Adenocarcinoma 1 cm or Less in Size: Emphasis on Histological Subtypes Associated With Lymph Node Metastasis and Recurrence

2017 ◽  
Vol 26 (1) ◽  
pp. 4-11 ◽  
Author(s):  
Wei Zhao ◽  
Hui Wang ◽  
Jun Xie ◽  
Bo Tian
Keyword(s):  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Lung Adenocarcinoma ◽  
Who Classification ◽  
Limited Resection ◽  
Adenocarcinoma In Situ ◽  
Invasive Adenocarcinoma ◽  
Node Metastasis ◽  
Minimally Invasive Adenocarcinoma

Background. The aim of this study was to assess the prognostic significance of the newly proposed 2015 World Health Organization (WHO) lung adenocarcinoma classification for patients undergoing resection for small (≤1 cm) lung adenocarcinoma. We also investigated whether lobectomy offers prognostic advantage over limited resection for this category of tumors. Methods. A retrospective study of resected pulmonary adenocarcinomas (n = 83) in sizes 1 cm or less was carried out in which comprehensive histologic subtyping was assessed according to the 2015 WHO classification on all consecutive patients who underwent lobectomy or limited resection between 1998 and 2012. Correlation between clinicopathologic parameters and the difference in recurrence between lobectomy and limited resection group was evaluated. Results. Our data show that the proposed 2015 WHO classification identifies histological subsets of small lung adenocarcinomas with significant differences in prognosis. No recurrence was noted for patients with adenocarcinoma in situ and minimally invasive adenocarcinoma. Invasive adenocarcinomas displayed high heterogeneity and the presence of micropapillary component of 5% or greater in adenocarcinomas was significantly related to lymph node involvement and recurrence ( P < .001). Stage IA patients who underwent limited resection had a higher risk of recurrence than did those treated by lobectomy ( P < .05). Conclusions. Application of the 2015 WHO classification identifies patients with adenocarcinoma in situ and minimally invasive adenocarcinoma had excellent prognosis. Micropapillary pattern was associated with high risk of lymph node metastasis and recurrence.

scholarly journals A lepidic gene signature predicts patient prognosis and sensitivity to immunotherapy in lung adenocarcinoma

2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Thinh T. Nguyen ◽  
Hyun-Sung Lee ◽  
Bryan M. Burt ◽  
Jia Wu ◽  
Jianjun Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Gene Expression Analysis ◽  
Immune Cell ◽  
Expression Patterns ◽  
Immune Cell Infiltration ◽  
Histological Subtypes ◽  
Genomic Features ◽  
Differential Gene

Abstract Background Lung adenocarcinoma, the most common type of lung cancer, has a high level of morphologic heterogeneity and is composed of tumor cells of multiple histological subtypes. It has been reported that immune cell infiltration significantly impacts clinical outcomes of patients with lung adenocarcinoma. However, it is unclear whether histologic subtyping can reflect the tumor immune microenvironment, and whether histologic subtyping can be applied for therapeutic stratification of the current standard of care. Methods We inferred immune cell infiltration levels using a histological subtype-specific gene expression dataset. From differential gene expression analysis between different histological subtypes, we developed two gene signatures to computationally determine the relative abundance of lepidic and solid components (denoted as the L-score and S-score, respectively) in lung adenocarcinoma samples. These signatures enabled us to investigate the relationship between histological composition and clinical outcomes in lung adenocarcinoma using previously published datasets. Results We found dramatic immunological differences among histological subtypes. Differential gene expression analysis showed that the lepidic and solid subtypes could be differentiated based on their gene expression patterns while the other subtypes shared similar gene expression patterns. Our results indicated that higher L-scores were associated with prolonged survival, and higher S-scores were associated with shortened survival. L-scores and S-scores were also correlated with global genomic features such as tumor mutation burdens and driver genomic events. Interestingly, we observed significantly decreased L-scores and increased S-scores in lung adenocarcinoma samples with EGFR gene amplification but not in samples with EGFR gene mutations. In lung cancer cell lines, we observed significant correlations between L-scores and cell sensitivity to a number of targeted drugs including EGFR inhibitors. Moreover, lung cancer patients with higher L-scores were more likely to benefit from immune checkpoint blockade therapy. Conclusions Our findings provided further insights into evaluating histology composition in lung adenocarcinoma. The established signatures reflected that lepidic and solid subtypes in lung adenocarcinoma would be associated with prognosis, genomic features, and responses to targeted therapy and immunotherapy. The signatures therefore suggested potential clinical translation in predicting patient survival and treatment responses. In addition, our framework can be applied to other types of cancer with heterogeneous histological subtypes.

Features Based on Thin-section Computed Tomography Identify the Typeof lung Adenocarcinoma

2020 ◽  
Author(s):  
Zhiqiang Li ◽  
Hongwei Zheng ◽  
Shanshan Liu ◽  
Xinhua Wang ◽  
Lei Xiao ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Lung Adenocarcinoma ◽  
Thin Section ◽  
Ground Glass Opacity ◽  
Smoking History ◽  
Ground Glass ◽  
Quantitative Aspect ◽  
Adenocarcinoma In Situ ◽  
Invasive Adenocarcinoma ◽  
Pleural Invasion

Abstract Background: To investigate whether thin-section computed tomography (TSCT) features may efficiently guide the invasiveness basedclassification of lung adenocarcinoma. Methods: Totally, 316 lung adenocarcinoma patients (from 2011-2015) were divided into three groups: 56 adenocarcinoma in situ (AIS), 98 minimally invasive adenocarcinoma (MIA), and 162 invasive adenocarcinoma (IAC) according their pathological results. Their TSCT features, including nodule pattern, shape, pleural invasion, solid proportion, border, margin, vascular convergence, air bronchograms, vacuole sign, pleural indentation, diameter, solid diameter, and CT values of ground-glass nodules (GGN) were analyzed. Pearson’s chi-square test, Fisher’s exact test and One-way ANOVA were adopted tocomparebetweengroups. Receiver operating characteristic (ROC) analysis wereperformedto assess its value for prediction and diagnosis. Results: Patients with IAC were significantly elder than those in AIS or MIA group,and more MIA patients had a smoking history than AIS and IAC. No recurrence happened in the AIS and MIA groups, while 4.3% recurrences were confirmed in the IAC group. As for TSCT variables, we found AIS group showed dominantly higher 91.07%PGGN pattern and 87.50% round/oval nodules than that in MIA and IAC group. In contrast, MIA group showed more cases with undefined border and vascular convergence than AIS and IAC group. Importantly, IAC group uniquely showed higher frequency of pleural invasion compared with MIA and AIS group. The majority of patients (82.1%) in IAC group showed ≥ 50% solid proportion. We found diameter and solid diameter of the lesions were notably larger in the IAC group compared with AIS and MIA groupin quantitative aspect. In addition, for MGGNs, the CT values of ground-glass opacity (GGO) and ground-glass opacity solid portion (GGO-solid) were both higher in the IAC group than AIS and MIA. Finally, we also observed that smooth margin took a dominant proportion in the AIS group while most cases in the IAC group had a lobulate margin. Patients in MIA and IAC group shared higher level of air bronchograms and vacuole signs than AIS group. Conclusions: The unique features in different groups identified by TSCT had diagnosis value for lung adenocarcinoma.

scholarly journals Features Based on Thin-section Computed Tomography Identify the Type of lung Adenocarcinoma

2020 ◽  
Author(s):  
Zhiqiang Li ◽  
Hongwei Zheng ◽  
Shanshan Liu ◽  
Xinhua Wang ◽  
Lei Xiao ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Lung Adenocarcinoma ◽  
Thin Section ◽  
Ground Glass Opacity ◽  
Smoking History ◽  
Ground Glass ◽  
Quantitative Aspect ◽  
Adenocarcinoma In Situ ◽  
Invasive Adenocarcinoma ◽  
Pleural Invasion

Abstract Background: To investigate whether thin-section computed tomography (TSCT) features may efficiently guide the invasiveness basedclassification of lung adenocarcinoma. Methods: Totally, 316 lung adenocarcinoma patients (from 2011-2015) were divided into three groups: 56 adenocarcinoma in situ (AIS), 98 minimally invasive adenocarcinoma (MIA), and 162 invasive adenocarcinoma (IAC) according their pathological results. Their TSCT features, including nodule pattern, shape, pleural invasion, solid proportion, border, margin, vascular convergence, air bronchograms, vacuole sign, pleural indentation, diameter, solid diameter, and CT values of ground-glass nodules (GGN) were analyzed. Pearson’s chi-square test, Fisher’s exact test and One-way ANOVA were adopted tocomparebetweengroups. Receiver operating characteristic (ROC) analysis wereperformedto assess its value for prediction and diagnosis. Results: Patients with IAC were significantly elder than those in AIS or MIA group,and more MIA patients had a smoking history than AIS and IAC. No recurrence happened in the AIS and MIA groups, while 4.3% recurrences were confirmed in the IAC group. As for TSCT variables, we found AIS group showed dominantly higher 91.07%PGGN pattern and 87.50% round/oval nodules than that in MIA and IAC group. In contrast, MIA group showed more cases with undefined border and vascular convergence than AIS and IAC group. Importantly, IAC group uniquely showed higher frequency of pleural invasion compared with MIA and AIS group. The majority of patients (82.1%) in IAC group showed ≥ 50% solid proportion. We found diameter and solid diameter of the lesions were notably larger in the IAC group compared with AIS and MIA groupin quantitative aspect. In addition, for MGGNs, the CT values of ground-glass opacity (GGO) and ground-glass opacity solid portion (GGO-solid) were both higher in the IAC group than AIS and MIA. Finally, we also observed that smooth margin took a dominant proportion in the AIS group while most cases in the IAC group had a lobulate margin. Patients in MIA and IAC group shared higher level of air bronchograms and vacuole signs than AIS group. Conclusions: The unique features in different groups identified by TSCT had diagnosis value for lung adenocarcinoma.

Gene expression identifies heterogeneity of soft tissue sarcomas

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9574-9574
Author(s):  
K. M. Skubitz ◽  
S. Pambuccian ◽  
A. P. Skubitz
Keyword(s):  
Gene Expression ◽  
Soft Tissue ◽  
Expression Patterns ◽  
Soft Tissue Sarcomas ◽  
Gene Expression Patterns ◽  
Histological Subtypes ◽  
Normal Tissues ◽  
Gene Sets ◽  
Histological Appearance ◽  
Gene Logic

9574 Background: Soft tissue sarcomas (STS) exhibit heterogeneity in their clinical behavior, even within histological subtypes. Histological appearance is determined by gene expression. However, metastatic propensity, tumor growth, and response to chemotherapy may be determined by gene expression patterns that do not correlate well with morphology. One approach to identify heterogeneity is to search for markers that correlate with differences in tumor behavior. Alternatively, subsets may be identified based on gene expression patterns independent of knowledge of clinical outcome. We have reported gene expression patterns that distinguish two broad classes of clear cell renal carcinoma (ccRCC) independent of histological appearance, and other patterns that can distinguish heterogeneity of serous ovarian carcinoma (OVCA). Methods: In this study, gene expression in 41 samples of STS (including malignant fibrous histiocytoma (MFH), leiomyosarcoma, liposarcoma, and synovial sarcoma), 12 samples of fibromatosis, and 17 normal tissues was determined at Gene Logic Inc. (Gaithersburg, MD) using Affymetrix GeneChip U_133 arrays containing approximately 40,000 genes/ESTs. Gene expression analysis was performed with the Gene Logic Genesis Enterprise System Software. Results: Hierarchical clustering using two gene sets, one that distinguished two subsets of ccRCC, and a second set that distinguished two subsets of OVCA, both generated subgroups within the STS that for some, but not all, subtypes correlated with histology, and also suggested the existence of subsets of MFH. Both gene sets also identified the same two subsets of the fibromatosis samples. In addition, genes expressed uniquely in MFH, leiomyosarcomas, and liposarcomas among these and 512 samples from 17 other normal tissue types were identified. Conclusions: The ability to sub-classify histological subtypes of STS, including identifying possible subsets of MFH, using gene sets derived from studies of two different carcinomas suggests that these subgroups may have biological significance. Some of the genes identified as over-expressed in particular subsets of STS compared with a variety of normal tissues may reflect possible targets to which anti-tumor therapy could be directed, and may also be useful for sub-classification of STS. No significant financial relationships to disclose.

scholarly journals Genomic and immune profiling of pre-invasive lung adenocarcinoma

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Haiquan Chen ◽  
Jian Carrot-Zhang ◽  
Yue Zhao ◽  
Haichuan Hu ◽  
Samuel S. Freeman ◽  
...  
Keyword(s):  
Minimally Invasive ◽  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Adenocarcinoma In Situ ◽  
Copy Number Alterations ◽  
Invasive Adenocarcinoma ◽  
Minimally Invasive Adenocarcinoma ◽  
Invasive Lung Adenocarcinoma ◽  
Hla Loss

AbstractAdenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR, RBM10, BRAF, ERBB2, TP53, KRAS, MAP2K1 and MET as significantly mutated genes in the pre/minimally invasive group. Classes of genome alterations that increase in frequency during the progression to malignancy are revealed. These include mutations in TP53, arm-level copy number alterations, and HLA loss of heterozygosity. Immune infiltration is correlated with copy number alterations of chromosome arm 6p, suggesting a link between arm-level events and the tumor immune environment.

scholarly journals Genome-Wide Gene Expression in relation to Age in Large Laboratory Cohorts of Drosophila melanogaster

2015 ◽  
Vol 2015 ◽  
pp. 1-19 ◽  
Author(s):  
Kimberly A. Carlson ◽  
Kylee Gardner ◽  
Anjeza Pashaj ◽  
Darby J. Carlson ◽  
Fang Yu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drosophila Melanogaster ◽  
Immune Function ◽  
Expression Patterns ◽  
Self Organizing Map ◽  
Control Of Gene Expression ◽  
Genome Wide ◽  
Complex Process ◽  
Temporal Variance ◽  
And Function

Aging is a complex process characterized by a steady decline in an organism’s ability to perform life-sustaining tasks. In the present study, two cages of approximately 12,000 mated Drosophila melanogaster females were used as a source of RNA from individuals sampled frequently as a function of age. A linear model for microarray data method was used for the microarray analysis to adjust for the box effect; it identified 1,581 candidate aging genes. Cluster analyses using a self-organizing map algorithm on the 1,581 significant genes identified gene expression patterns across different ages. Genes involved in immune system function and regulation, chorion assembly and function, and metabolism were all significantly differentially expressed as a function of age. The temporal pattern of data indicated that gene expression related to aging is affected relatively early in life span. In addition, the temporal variance in gene expression in immune function genes was compared to a random set of genes. There was an increase in the variance of gene expression within each cohort, which was not observed in the set of random genes. This observation is compatible with the hypothesis that D. melanogaster immune function genes lose control of gene expression as flies age.

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