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Mechanism of lung development in the aetiology of adult congenital pulmonary airway malformations.

ABSTRACT: Congenital pulmonary airway malformations (CPAMs) are rare lung abnormalities that result in cyst formation and are associated with respiratory distress in infants and malignant potential in adults. The pathogenesis of CPAMs remains unknown but data suggest disruption of the normal proximo-distal programme of airway branching and differentiation. Here, we demonstrate that adult human CPAM are lined with epithelium that retains SOX-2 and thyroid transcription factor-1 immunohistochemical markers, characteristic of the developing lung. However, RALDH-1, another key marker, is absent. This suggests a more complex aetiology for CPAM than complete focal arrest of lung development and may provide insight to the associated risk of malignancy.

SUBMITTER: Taylor B

PROVIDER: S-EPMC7569368 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Mechanism of lung development in the aetiology of adult congenital pulmonary airway malformations.

Taylor Bethany B Rice Alexandra A Nicholson Andrew G AG Hind Matthew M Dean Charlotte H CH

Thorax 20200730 11

Congenital pulmonary airway malformations (CPAMs) are rare lung abnormalities that result in cyst formation and are associated with respiratory distress in infants and malignant potential in adults. The pathogenesis of CPAMs remains unknown but data suggest disruption of the normal proximo-distal programme of airway branching and differentiation. Here, we demonstrate that adult human CPAM are lined with epithelium that retains SOX-2 and thyroid transcription factor-1 immunohistochemical markers, ...[more]

PMID: 32732323

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The application of second-generation sequencing in congenital pulmonary airway malformations

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2022-12-07 | GSE190620 | GEO

Development of a core outcome set for congenital pulmonary airway malformations: study protocol of an international Delphi survey.

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| S-EPMC8047990 | biostudies-literature

Analysis of miRNA Profiles and the Regulatory Network in Congenital Pulmonary Airway Malformations.

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Global interpretation of novel alternative splicing events in human congenital pulmonary airway malformations

Project description:To explore the long non-coding RNA (lncRNA) expression pattern of congenital lung malformations on a genome-wide scale and investigate their potential biological function in four types of congenital lung malformations.

2021-12-07 | GSE179404 | GEO

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Project description:RATIONALE:Disruption of normal pulmonary development is a leading cause of morbidity and mortality in infants. Congenital lung malformations are a unique model to study the molecular pathogenesis of isolated structural birth defects, as they are often surgically resected. OBJECTIVES:To provide insight into the molecular pathogenesis of congenital lung malformations through analysis of cell-type and gene expression changes in these lesions. METHODS:Clinical data, and lung tissue for DNA, RNA, and histology, were obtained from 58 infants undergoing surgical resection of a congenital lung lesion. Transcriptome-wide gene expression analysis was performed on paired affected and unaffected samples from a subset of infants (n = 14). A three-dimensional organoid culture model was used to assess isolated congenital lung malformation epithelium (n = 3). MEASUREMENTS AND MAIN RESULTS:Congenital lung lesions express higher levels of airway epithelial related genes, and dysregulated expression of genes related to the Ras and PI3K-AKT-mTOR (phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin) signaling pathways. Immunofluorescence confirmed differentiated airway epithelial cell types throughout all major subtypes of congenital lung lesions, and three-dimensional cell culture demonstrated a cell-autonomous defect in the epithelium of these lesions. CONCLUSIONS:This study provides the first comprehensive analysis of the congenital lung malformation transcriptome and suggests that disruptions in Ras or PI3K-AKT-mTOR signaling may contribute to the pathology through an epithelial cell-autonomous defect.

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Novel molecular and phenotypic insights into congenital lung malformations

Project description:The purpose of this study was to identify gene expression changes associated with congenital lung malformations.

2018-01-23 | GSE100442 | GEO

New insights on congenital pulmonary airways malformations revealed by proteomic analyses.

Project description:BACKGROUND:Congenital Pulmonary Airway Malformation (CPAM) has an estimated prevalence between 0.87 and 1.02/10,000 live births and little is know about their pathogenesis. To improve our knowledge on these rare malformations, we analyzed the cellular origin of the two most frequent CPAM, CPAM types 1 and 2, and compared these malformations with adjacent healthy lung and human fetal lungs. METHODS:We prospectively enrolled 21 infants undergoing surgical resection for CPAM. Human fetal lung samples were collected after termination of pregnancy. Immunohistochemistry and proteomic analysis were performed on laser microdissected samples. RESULTS:CPAM 1 and 2 express mostly bronchial markers, such as cytokeratin 17 (Krt17) or ?-smooth muscle actin (ACTA 2). CPAM 1 also expresses alveolar type II epithelial cell markers (SPC). Proteomic analysis on microlaser dissected epithelium confirmed these results and showed distinct protein profiles, CPAM 1 being more heterogeneous and displaying some similarities with fetal bronchi. CONCLUSION:This study provides new insights in CPAM etiology, showing clear distinction between CPAM types 1 and 2, by immunohistochemistry and proteomics. This suggests that CPAM 1 and CPAM 2 might occur at different stages of lung branching. Finally, the comparison between fetal lung structures and CPAMs shows clearly different protein profiles, thereby arguing against a developmental arrest in a localized part of the lung.

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Whole-Genome Methylation Study of Congenital Lung Malformations in Children.

Project description:Background and objectivesThe treatment of asymptomatic patients with congenital pulmonary malformations (CPMs) remains controversial, partially because the relationship between congenital lung malformations and malignancy is still undefined. Change in methylation pattern is a crucial event in human cancer, including lung cancer. We therefore studied all differentially methylated regions (DMRs) in a series of CPMs in an attempt to find methylation anomalies in genes already described in association with malignancy.MethodsThe DNA extracted from resected congenital lung malformations and control lung tissue was screened using Illumina MethylationEPIC arrays. Comparisons between the group of malformed samples or the malformed samples of same histology or each malformed sample and the controls and between a pleuropulmonary blastoma (PPB) and controls were performed. Moreover, each malformed sample was pairwise compared with its respective control. All differentially methylated regions (DMRs) with an adjusted p-value <0,05 were studied.ResultsEvery comparison highlighted a number of DMRs closed to genes involved either in cell proliferation or in embryonic development or included in the Cancer Gene Census. Their abnormal methylation had been already described in lung tumors.ConclusionsMethylation anomalies already described in lung tumors and also shared by the PPB were found in congenital lung malformations, regardless the histology. The presence of methylation abnormalities is suggestive of a correlation between congenital lung malformations and some step of malignant transformation.

| S-EPMC8273538 | biostudies-literature

Whole-genome methylation study of congenital lung malformations in children

Project description:The treatment of asymptomatic patients with congenital pulmonary malformations (CPMs) remains controversial, partially because the relationship between congenital lung malformations and malignancy is still undefined. Change in methylation pattern is a crucial event in human cancer, including lung cancer. We therefore studied all differentially methylated regions (DMRs) in a series of CPMs in an attempt to find methylation anomalies in genes already described in association with malignancy. The DNA extracted from resected congenital lung malformations and control lung tissue was screened using Illumina MethylationEPIC arrays. Comparison between the group of malformed samples or the malformed samples of same histology or each malformed sample and the controls, and between a pleuropulmonary blastoma (PPB) and controls were performed. All differentially methylated regions (DMRs) with an adjusted p value < 0,05 were studied. Every comparison highlighted a number of DMRs closed to genes involved either in cell proliferation or in embryonic development or included in the Cancer Gene Census. Their abnormal methylation had been already described in lung tumors. The presence of methylation abnormalities is suggestive of a correlation between congenital lung malformations and some step of malignant transformation.

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Congenital cystic adenomatoid malformations of the lung: an epithelial transcriptomic approach.

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| S-EPMC7001206 | biostudies-literature

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