1.A Rare Missense Variant in Telomerase Reverse Transcriptase is Associated with Idiopathic Pulmonary Fibrosis in a Chinese Han Family.
Chun-Ming ZHENG ; Xi ZHAN ; Yuan-Hua YANG ; Tao JIANG ; Qiao YE ; Yong LU
Chinese Medical Journal 2018;131(18):2205-2209
BackgroundIdiopathic pulmonary fibrosis (IPF) is an age-related and progressive interstitial lung disease. Up to 20% of cases of IPF cluster in families, genetic factors contribute significantly to the pathogenesis of the disease. This study aimed to explore the association between rare genetic variants and IPF in Chinese Han families.
MethodsA Han family, comprising three IPF patients and five unaffected their first-degree relatives, and 100 ethnically matched control individuals from North China were enrolled in this study. Peripheral blood was collected, and genomic DNA was extracted. To elucidate if rare genetic variants are associated with the familial IPF, we performed whole-exome sequencing of affected members from a Chinese Han IPF family. Candidate rare variants were then confirmed by Sanger sequencing.
ResultsWe identified a potentially damaging rare variant-a heterozygous mutation c.2146G>A in exon 6 of the gene encoding for telomerase reverse transcriptase (TERT), which results in an amino acid substitution (p.Ala716Thr). We confirmed the missense mutation by Sanger sequencing in all the affected family members but did not detect this mutation in 100 ethnically matched healthy controls. Patients carried this mutation were characterized by the frequently acute exacerbation of IPF phenotype, with poor prognosis. The mean time to death was 2.8 years after diagnosis.
ConclusionUsing next-generation sequencing technology in familial IPF patients, we identified the heterozygous rare variant in TERT gene, and strengthened the importance of genetic variants in telomere-related pathogenesis in Chinese IPF patients.
China ; Female ; Humans ; Idiopathic Pulmonary Fibrosis ; genetics ; Male ; Middle Aged ; Mutation ; Mutation, Missense ; Pulmonary Fibrosis ; Telomerase ; genetics ; Telomere
4.Role of various imbalances centered on alveolar epithelial cell/fibroblast apoptosis imbalance in the pathogenesis of idiopathic pulmonary fibrosis.
Qing WANG ; Zhao-Liang XIE ; Qi WU ; Zhi-Xian JIN ; Chao YANG ; Jing FENG
Chinese Medical Journal 2021;134(3):261-274
There have been recent extensive studies and rapid advancement on the pathogenesis underlying idiopathic pulmonary fibrosis (IPF), and intricate pathogenesis of IPF has been suggested. The purpose of this study was to clarify the logical relationship between these mechanisms. An extensive search was undertaken of the PubMed using the following keywords: "etiology," "pathogenesis," "alveolar epithelial cell (AEC)," "fibroblast," "lymphocyte," "macrophage," "epigenomics," "histone," acetylation," "methylation," "endoplasmic reticulum stress," "mitochondrial dysfunction," "telomerase," "proteases," "plasminogen," "epithelial-mesenchymal transition," "oxidative stress," "inflammation," "apoptosis," and "idiopathic pulmonary fibrosis." This search covered relevant research articles published up to April 30, 2020. Original articles, reviews, and other articles were searched and reviewed for content; 240 highly relevant studies were obtained after screening. IPF is likely the result of complex interactions between environmental, genetic, and epigenetic factors: environmental exposures affect epigenetic marks; epigenetic processes translate environmental exposures into the regulation of chromatin; epigenetic processes shape gene expression profiles; in turn, an individual's genetic background determines epigenetic marks; finally, these genetic and epigenetic factors act in concert to dysregulate gene expression in IPF lung tissue. The pathogenesis of IPF involves various imbalances including endoplasmic reticulum, telomere length homeostasis, mitochondrial dysfunction, oxidant/antioxidant imbalance, Th1/Th2 imbalance, M1-M2 polarization of macrophages, protease/antiprotease imbalance, and plasminogen activation/inhibition imbalance. These affect each other, promote each other, and ultimately promote AEC/fibroblast apoptosis imbalance directly or indirectly. Excessive AEC apoptosis and impaired apoptosis of fibroblasts contribute to fibrosis. IPF is likely the result of complex interactions between environmental, genetic, and epigenetic factors. The pathogenesis of IPF involves various imbalances centered on AEC/fibroblast apoptosis imbalance.
Alveolar Epithelial Cells
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Apoptosis
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Endoplasmic Reticulum Stress
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Fibroblasts
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Humans
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Idiopathic Pulmonary Fibrosis/genetics*
5.Identification of SULF1 as a Shared Gene in Idiopathic Pulmonary Fibrosis and Lung Adenocarcinoma.
Junyi WANG ; Lu LU ; Xiang HE ; Lijuan MA ; Tao CHEN ; Guoping LI ; Haijie YU
Chinese Journal of Lung Cancer 2023;26(9):669-683
BACKGROUND:
Idiopathic pulmonary fibrosis (IPF) is an idiopathic chronic, progressive interstitial lung disease with a diagnosed median survival of 3-5 years. IPF is associated with an increased risk of lung cancer. Therefore, exploring the shared pathogenic genes and molecular pathways between IPF and lung adenocarcinoma (LUAD) holds significant importance for the development of novel therapeutic approaches and personalized precision treatment strategies for IPF combined with lung cancer.
METHODS:
Bioinformatics analysis was conducted using publicly available gene expression datasets of IPF and LUAD from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis was employed to identify common genes involved in the progression of both diseases, followed by functional enrichment analysis. Subsequently, additional datasets were used to pinpoint the core shared genes between the two diseases. The relationship between core shared genes and prognosis, as well as their expression patterns, clinical relevance, genetic characteristics, and immune-related functions in LUAD, were analyzed using The Cancer Genome Atlas (TCGA) database and single-cell RNA sequencing datasets. Finally, potential therapeutic drugs related to the identified genes were screened through drug databases.
RESULTS:
A total of 529 shared genes between IPF and LUAD were identified. Among them, SULF1 emerged as a core shared gene associated with poor prognosis. It exhibited significantly elevated expression levels in LUAD tissues, concomitant with high mutation rates, genomic heterogeneity, and an immunosuppressive microenvironment. Subsequent single-cell RNA-seq analysis revealed that the high expression of SULF1 primarily originated from tumor-associated fibroblasts. This study further demonstrated an association between SULF1 expression and tumor drug sensitivity, and it identified potential small-molecule drugs targeting SULF1 highly expressed fibroblasts.
CONCLUSIONS
This study identified a set of shared molecular pathways and core genes between IPF and LUAD. Notably, SULF1 may serve as a potential immune-related biomarker and therapeutic target for both diseases.
Humans
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Lung Neoplasms/genetics*
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Adenocarcinoma of Lung/genetics*
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Idiopathic Pulmonary Fibrosis/genetics*
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Adenocarcinoma
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Cancer-Associated Fibroblasts
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Prognosis
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Tumor Microenvironment
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Sulfotransferases
6.Idiopathic pulmonary fibrosis will increase the risk of lung cancer.
Junyao LI ; Ming YANG ; Ping LI ; Zhenzhong SU ; Peng GAO ; Jie ZHANG
Chinese Medical Journal 2014;127(17):3142-3149
OBJECTIVETo review the studies investigating the increased risk of lung cancer in patients with idiopathic pulmonary fibrosis (IPF).
DATA SOURCESData cited in this review were obtained mainly from PubMed and Medline from 1999 to 2013 and highly regarded older publications were also included.
STUDY SELECTIONWe identified, retrieved and reviewed the information on the frequency, risk factors, anatomical features, histological types, clinical manifestations, computed tomography findings and underlying mechanisms of lung cancer in IPF patients.
RESULTSThe prevalence rates of lung cancer in patients with IPF (4.8% to 48%) are much higher than patients without IPF (2.0% to 6.4%). The risk factors for lung cancer in IPF include smoking, male gender, and age. Lung cancers often occur in the peripheral lung zones where fibrotic changes are predominant. Adenocarcinoma and squamous cell carcinoma are the most common types of lung cancer in patients with IPF. Radiologic features of these patients include peripherally located, ill-defined mass mimicking air-space disease. The underlying mechanisms of the development of lung cancer in patients with IPF have not been fully understood, but may include the inflammatory response, epithelial injury and/or abnormalities, aberrant fibroblast proliferation, epigenetic and genetic changes, reduced cell-to-cell communication, and activation of specific signaling pathways.
CONCLUSIONSThese findings suggest that IPF is associated with increased lung cancer risk. It is necessary to raise the awareness of lung cancer risk in IPF patients among physicians and patients.
Age Factors ; Female ; Humans ; Idiopathic Pulmonary Fibrosis ; complications ; epidemiology ; genetics ; Lung Neoplasms ; epidemiology ; etiology ; genetics ; Male ; Risk Factors ; Sex Factors
7.Research Progress on Pathogenic Mechanism and Potential Therapeutic Drugs of Idiopathic Pulmonary Fibrosis Complicated with Non-small Cell Lung Cancer.
Ting XIAO ; Jiali BAO ; Xiangning LIU ; Hui HUANG ; Honggang ZHOU
Chinese Journal of Lung Cancer 2022;25(10):756-763
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrous interstitial lung disease of unknown etiology. IPF is also considered to be among the independent risk factors for lung cancer, increasing the risk of lung cancer by 7% and 20%. The incidence of IPF complicated with lung cancer, especially non-small cell lung cancer (NSCLC), is increasing gradually, but there is no consensus on unified management and treatment. IPF and NSCLC have similar pathological features. Both appear in the surrounding area of the lung. In pathients with IPF complicated with NSCLC, NSCLC often develops from the honeycomb region of IPF, but the mechanism of NSCLC induced by IPF remains unclear. In addition, IPF and NSCLC have similar genetic, molecular and cellular processes and common signal transduction pathways. The universal signal pathways targeting IPF and NSCLC will become potential therapeutic drugs for IPF complicated with NSCLC. This article examines the main molecular mechanisms involved in IPF and NSCLC and the research progress of drugs under development targeting these signal pathways.
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Humans
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Carcinoma, Non-Small-Cell Lung/genetics*
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Idiopathic Pulmonary Fibrosis/drug therapy*
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Lung Neoplasms/genetics*
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Lung/pathology*
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Signal Transduction
8.Expression of interleukin-11 and its receptor in lung of mice with idiopathic pulmonary fibrosis.
Liming ZHANG ; Jun ZHANG ; Ying ZHANG ; Zongwei YI
Journal of Central South University(Medical Sciences) 2018;43(10):1083-1088
To observe the expression changes of interleukin-11 (IL-11) and its receptor in mice with pulmonary fibrosis.
Methods: C57BL/6 mice were randomly divided into a control group and a bleomycin (BLM) group (6 mice per group). BLM was injected into mice to induce idiopathic pulmonary fibrosis, while 50 μL PBS was injected into the control rats. The lung tissue was collected 21 d later. HE staining was used to observe morphological changes in lung tissue. Real-time PCR was used to detect IL-11 and its receptor gene expression. Western blot and immunohistochemical staining were used to detect IL-11 receptor expression. ELISA was used to detect the content of serum IL-11 in mice. In addition, the gene and protein expression of IL-11 receptor in mouse fibroblasts were detected by real-time PCR and Western blot, respectively.
Results: HE staining showed a significant change in pulmonary fibrosis in mice 21 d after BLM injection. The IL-11 mRNA expression in lung and IL-11 level in serum were up-regulated. The gene and protein expression of IL-11 receptor in mice with pulmonary fibrosis were significantly increased. The results from the cell experiments showed that the gene and protein expression of IL-11 receptor in mouse fibroblasts were significantly increased by TGF-β1.
Conclusion: The expression of IL-11 and its receptor are up-regulated in mice with pulmonary fibrosis induced by BLM, which might be an important mechanism for the development of pulmonary fibrosis.
Animals
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Bleomycin
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Gene Expression Regulation
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Idiopathic Pulmonary Fibrosis
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physiopathology
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Interleukin-11
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genetics
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Lung
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metabolism
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Mice
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Mice, Inbred C57BL
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Rats
9.Genetic characterization of a Chinese family with familial idiopathic pulmonary fibrosis.
Xin ZHANG ; Jun JIANG ; Wei-Jun CHEN ; Long-Xiang SU ; Li-Xin XIE
Chinese Medical Journal 2012;125(11):1945-1951
BACKGROUNDIdiopathic pulmonary fibrosis (IPF) is a chronic inflammatory interstitial lung disease with an unknown cause. Recent studies have shown that genetic factors play an important role in the pathogenesis of IPF.
METHODSTo explore the genetic background of patients with IPF, a candidate gene approach was employed to screen for mutations in seven genes among members with familial IPF in mainland of China.
RESULTSWithin six of the candidate genes, a total of 31 point mutations were identified. Among the missense mutations, the SFTPA1 exon 6 CAG > AAG (Gln238Lys) and SFTPB exon 2 CAC > CCC (His2Pro) mutations caused changes in the physical and chemical properties of amino acids. Each sequence alteration was identified in sporadic IPF patients, control specimens (pneumonia patients and healthy persons). Genotype frequencies and allele frequencies of codon 238 in exon 6 of SFTPA1 were noted significantly higher in patients with IPF than those in other two control subjects. The computational protein structure prediction by protein homology modeling confirmed differences in three-dimensional structure between mutant SFTPA1 and original SFTPA1.
CONCLUSIONSAlthough the functions of the mutant candidate genes vary, these genes may ultimately result in damage to alveolar epithelial cells, initiating the progress of pulmonary fibrosis. In particular, while pathophysiological mechanisms need to be illustrated, the Gln238Lys missense variant of exon 6 in the SFTPA1 may have potential susceptibility in the development of IPF, which was shown in patients with sporadic IPF with a statistically higher frequency.
Adult ; China ; Exons ; genetics ; Female ; Gene Frequency ; genetics ; Genetic Predisposition to Disease ; genetics ; Genotype ; Humans ; Idiopathic Pulmonary Fibrosis ; genetics ; Male ; Mutation ; genetics ; Mutation, Missense ; genetics ; Pulmonary Surfactant-Associated Protein A ; genetics
10.Association between chronic lung diseases and the risk of lung cancer in UK Biobank: observational and Mendelian randomization analyses.
Jing ZHANG ; Zhi Min MA ; Hui WANG ; Ya Ting FU ; Chen JI ; Meng ZHU ; Hong Bing SHEN ; Hong Xia MA
Chinese Journal of Preventive Medicine 2023;57(8):1147-1152
Objective: To investigate the association between chronic lung diseases and the risk of lung cancer. Methods: Using UK Biobank (UKB) survey data, 472 397 participants who had not previously been diagnosed with cancer and whose self-reported sex was consistent with their genetic sex were studied. Information on the prevalence of previous chronic lung diseases, general demographic characteristics and the prevalence of lung cancer was collected using baseline questionnaires and national health system data. The multivariate Cox proportional risk regression model was used to analyze the association between four previous chronic lung diseases (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and interstitial pulmonary disease) and the risk of lung cancer. A total of 458 526 participants with genotype data in the observational study were selected as research objects, and the closely related and independent genetic loci with four chronic lung diseases were selected as instrumental variables, and the association between four chronic lung diseases and the risk of lung cancer was analyzed by Mendelian randomization (MR). The dose-response relationship between genetic risk score and the risk of lung cancer in different chronic lung diseases was evaluated using a restricted cubic spline function. Results: The age [M (Q1, Q3)] of the subjects was 57 (50, 63) years old, and there were 3 516 new cases of lung cancer (0.74%) during follow-up. The multivariate Cox proportional hazard regression model analysis showed that previous chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis were associated with the risk of lung cancer, about 1.61 (1.49-1.75) and 2.61 (1.24-5.49), respectively. MR Studies showed that genetically predicted chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis were associated with the risk of lung cancer, with HR (95%CI) of 1.10 (1.03-1.19) and 1.04 (1.01-1.08), respectively. The results of restricted cubic spline function analysis showed that the risk of lung cancer increased linearly with the increase of genetic risk scores for chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (P<0.05). Neither observational studies nor Mendelian randomization analysis found an association between previous asthma or interstitial lung disease and the risk of lung cancer (both P values>0.05). Conclusion: Chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis are potential risk factors for lung cancer.
Humans
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Middle Aged
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Mendelian Randomization Analysis
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Biological Specimen Banks
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Lung Neoplasms/genetics*
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Pulmonary Disease, Chronic Obstructive/genetics*
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Asthma/genetics*
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Idiopathic Pulmonary Fibrosis/genetics*
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United Kingdom/epidemiology*
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Genome-Wide Association Study