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.

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.

Genomic characterization of sub-centimeter pulmonary nodules.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13530-e13530
Author(s):  
Muyun Peng ◽  
Guanlan Xing ◽  
Bingyu Zhang ◽  
Yaping Xu ◽  
Fenglei Yu
Keyword(s):  
Lung Adenocarcinoma ◽  
Pulmonary Nodules ◽  
Driver Mutations ◽  
Adenocarcinoma In Situ ◽  
Lung Carcinogenesis ◽  
Braf Mutations ◽  
Invasive Adenocarcinoma ◽  
Driver Genes ◽  
Invasive Group ◽  
Genomic Landscape

e13530 Background: There has been a dramatic increase in the detection of indeterminate pulmonary nodules (IPNs), many of which are 10 mm or less in diameter. The management of subcentimeter pulmonary nodules remains controversial. Deciphering the genomic landscape of subcentimeter pulmonary nodules will provide critical insights to the mechanisms of carcinogenesis and pave the way for the early prevention and interception of lung cancer. Methods: We subjected 439 IPN samples including 249 subcentimeter pulmonary nodules (≤10 mm in diameter) and 190 larger pulmonary nodules (>10 and ≤30mm in diameter) to deep next generation sequencing by using customized panels of 1021 genes. Clinical parameters of these IPNs were collected. The genomic landscape of subcentimeter pulmonary nodules and differences from that of larger pulmonary nodules were defined. Results: The proportions of atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (ADC) in the subcentimeter group and the larger nodule group were 2.81% vs 0.00%, 13.25% vs 0.80%, 28.92% vs 4.82% and 55.02% vs 70.68%, respectively. The most commonly mutated genes in subcentimeter group were in EGFR, ERBB2, BRAF, MED12 and MAP2K1. Compared with the larger nodule group, the subcentimeter nodule group had lower TMB ( p< 0.0001), lower mutation frequencies in EGFR, TP53, RBM10, and SMARCA4 ( p< 0.05), but higher mutation frequencies in ERBB2, BRAF, MAP2K1, and TSC1 ( p< 0.05). In the subset of ADC, the subcentimeter nodule group had lower TMB ( p< 0.0001), lower mutation frequencies in EGFR, TP53, RBM10, and PIK3CA ( p< 0.05), but higher mutation frequencies in ERBB2, BRAF ( p< 0.05). Clonal index analysis of driver genes in lung adenocarcinoma showed that the larger nodule group had more driver mutations, but the clonality index of BRAF was higher in the subcentimeter group ( p= 0.0014). Furthermore, in the subcentimeter nodule group, the mutation frequency of BRAF was significantly higher in pre-invasive group (AAH/AIS) than that in the invasive group (IAC). And BRAF and EGFR were significantly mutually exclusive ( q< 0.001) in subcentimeter nodules, which showed the subgroup with BRAF mutations was a special subtype. Conclusions: Our results provided the distinct mutation pattern of subcentimeter nodules and showed that BRAF could play different roles in early phase of lung carcinogenesis. It would be helpful for understanding the genomic evolution mechanisms underlying the progression and invasiveness of early lung adenocarcinoma.

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.

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.

scholarly journals Systematic Analyses of a Chemokine Family-Based Risk Model Predicting Clinical Outcome and Immunotherapy Response in Lung Adenocarcinoma

2021 ◽  
Vol 30 ◽  
pp. 096368972110550
Author(s):  
Jiarui Chen ◽  
Xingyu Liu ◽  
Qiuji Wu ◽  
Xueping Jiang ◽  
Zihang Zeng ◽  
...  
Keyword(s):  
Overall Survival ◽  
Lung Adenocarcinoma ◽  
Risk Model ◽  
Cox Regression ◽  
Expression Patterns ◽  
Low Risk ◽  
The Cancer Genome Atlas ◽  
Cox Regression Analysis ◽  
Family Based ◽  
Chemokine Family

Chemokines exhibited complicated functions in antitumor immunity, with their expression profile and clinical importance of lung adenocarcinoma (LUAD) patients remaining largely undetermined. This study aimed to explore the expression patterns of chemokine family in LUAD and construct a predictive chemokine family-based signature. A total of 497 samples were downloaded from the Cancer Genome Atlas (TCGA) data portal as the training set, and the combination of 4 representative Gene Expression Omnibus (GEO) datasets, including GSE30219, GSE50081, GSE37745, and GSE31210, were utilized as the validation set. A three gene-based signature was constructed using univariate and stepwise multivariate Cox regression analysis, classifying patients into high and low risk groups according to the overall survival. The independent GEO datasets were utilized to validate this signature. Another multivariate analysis revealed that this signature remained an independent prognostic factor in LUAD patients. Furthermore, patients in the low risk group featured immunoactive tumor microenvironment (TME), higher IPS scores and lower TIDE scores, and was regarded as the potential beneficiaries of immunotherapy. Finally, the role of risky CCL20 was validated by immunohistochemistry (IHC), and patients possessed higher CCL20 expression presented shorter overall survival ( P = 0.011).

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 Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xin Hu ◽  
Marcos R. Estecio ◽  
Runzhe Chen ◽  
Alexandre Reuben ◽  
Linghua Wang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
T Regulatory Cells ◽  
Precancerous Lesions ◽  
Adenocarcinoma In Situ ◽  
Neoplastic Progression ◽  
Invasive Adenocarcinoma ◽  
Reduced Representation ◽  
Dna Methylome ◽  
Lung Adenocarcinomas ◽  
Early Carcinogenesis

AbstractThe evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of methylation aberrations and significantly higher level of methylation ITH in later-stage lesions. The phylogenetic patterns inferred from methylation aberrations resemble those based on somatic mutations suggesting parallel methylation and genetic evolution. De-convolution reveal higher ratio of T regulatory cells (Tregs) versus CD8 + T cells in later-stage diseases, implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation is associated with higher mutation burden, copy number variation burden and AI burden as well as higher Treg/CD8 ratio, highlighting the potential impact of methylation on chromosomal instability, mutagenesis and tumor immune microenvironment during early carcinogenesis of lung adenocarcinomas.

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