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1.
Mol Cancer ; 20(1): 36, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608029

RESUMO

Early detection is crucial to improve breast cancer (BC) patients' outcomes and survival. Mammogram and ultrasound adopting the Breast Imaging Reporting and Data System (BI-RADS) categorization are widely used for BC early detection, while suffering high false-positive rate leading to unnecessary biopsy, especially in BI-RADS category-4 patients. Plasma cell-free DNA (cfDNA) carrying on DNA methylation information has emerged as a non-invasive approach for cancer detection. Here we present a prospective multi-center study with whole-genome bisulfite sequencing data to address the clinical utility of cfDNA methylation markers from 203 female patients with breast lesions suspected for malignancy. The cfDNA is enriched with hypo-methylated genomic regions. A practical computational framework was devised to excavate optimal cfDNA-rich DNA methylation markers, which significantly improved the early diagnosis of BI-RADS category-4 patients (AUC from 0.78-0.79 to 0.93-0.94). As a proof-of-concept study, we performed the first blood-based whole-genome DNA methylation study for detecting early-stage breast cancer from benign tumors at single-base resolution, which suggests that combining the liquid biopsy with the traditional diagnostic imaging can improve the current clinical practice, by reducing the false-positive rate and avoiding unnecessary harms.

2.
J Nanobiotechnology ; 19(1): 22, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436002

RESUMO

BACKGROUND: Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer-associated deaths in women. Recent studies have indicated that microRNA (miRNA) regulation in genomic instability (GI) is associated with disease risk and clinical outcome. Herein, we aimed to identify the GI-derived miRNA signature in extracellular vesicles (EVs) as a minimally invasive biomarker for early diagnosis and prognostic risk stratification. EXPERIMENTAL DESIGN: Integrative analysis of miRNA expression and somatic mutation profiles was performed to identify GI-associated miRNAs. Then, we constructed a discovery and validation study with multicenter prospective cohorts. The GI-derived miRNA signature (miGISig) was developed in the TCGA discovery cohort (n = 261), and was subsequently independently validated in internal TCGA validation (n = 261) and GSE22220 (n = 210) cohorts for prognosis prediction, and in GSE73002 (n = 3966), GSE41922 (n = 54), and in-house clinical exosome (n = 30) cohorts for diagnostic performance. RESULTS: We identified a GI-derived three miRNA signature (MIR421, MIR128-1 and MIR128-2) in the serum extracellular vesicles of BC patients, which was significantly associated with poor prognosis in all the cohorts tested and remained as an independent prognostic factor using multivariate analyses. When integrated with the clinical characteristics, the composite miRNA-clinical prognostic indicator showed improved prognostic performance. The miGISig also showed high accuracy in differentiating BC from healthy controls with the area under the receiver operating characteristics curve (ROC) with 0.915, 0.794 and 0.772 in GSE73002, GSE41922 and TCGA cohorts, respectively. Furthermore, circulating EVs from BC patients in the in-house cohort harbored elevated levels of miGISig, with effective diagnostic accuracy. CONCLUSIONS: We report a novel GI-derived three miRNA signature in EVs, as an excellent minimally invasive biomarker for the early diagnosis and unfavorable prognosis in BC.

3.
Nat Commun ; 12(1): 400, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452255

RESUMO

Promoter DNA methylation is a well-established mechanism of transcription repression, though its global correlation with gene expression is weak. This weak correlation can be attributed to the failure of current methylation quantification methods to consider the heterogeneity among sequenced bulk cells. Here, we introduce Cell Heterogeneity-Adjusted cLonal Methylation (CHALM) as a methylation quantification method. CHALM improves understanding of the functional consequences of DNA methylation, including its correlations with gene expression and H3K4me3. When applied to different methylation datasets, the CHALM method enables detection of differentially methylated genes that exhibit distinct biological functions supporting underlying mechanisms.


Assuntos
Metilação de DNA , Epigênese Genética , Epigenômica/métodos , Regiões Promotoras Genéticas/genética , Sequenciamento de Cromatina por Imunoprecipitação , Ilhas de CpG/genética , Conjuntos de Dados como Assunto , Aprendizado Profundo , Histonas , Humanos , RNA-Seq
4.
Am J Hum Genet ; 108(2): 337-345, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434492

RESUMO

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidades
5.
Proc Natl Acad Sci U S A ; 117(52): 33628-33638, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33318192

RESUMO

Retinoblastoma (Rb) is the most prevalent intraocular malignancy in children, with a worldwide survival rate <30%. We have developed a cancerous model of Rb in retinal organoids derived from genetically engineered human embryonic stem cells (hESCs) with a biallelic mutagenesis of the RB1 gene. These organoid Rbs exhibit properties highly consistent with Rb tumorigenesis, transcriptome, and genome-wide methylation. Single-cell sequencing analysis suggests that Rb originated from ARR3-positive maturing cone precursors during development, which was further validated by immunostaining. Notably, we found that the PI3K-Akt pathway was aberrantly deregulated and its activator spleen tyrosine kinase (SYK) was significantly up-regulated. In addition, SYK inhibitors led to remarkable cell apoptosis in cancerous organoids. In conclusion, we have established an organoid Rb model derived from genetically engineered hESCs in a dish that has enabled us to trace the cell of origin and to test novel candidate therapeutic agents for human Rb, shedding light on the development and therapeutics of other malignancies.


Assuntos
Células-Tronco Embrionárias Humanas/patologia , Organoides/patologia , Retinoblastoma/patologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Carcinogênese/patologia , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Camundongos Endogâmicos NOD , Mutagênese/genética , Mutação/genética , Proteína do Retinoblastoma/química , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Transcriptoma/genética
6.
Brief Bioinform ; 2020 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-33367533

RESUMO

Uveal melanoma (UVM) is the most common primary intraocular human malignancy with a high mortality rate. Aberrant DNA methylation has rapidly emerged as a diagnostic and prognostic signature in many cancers. However, such DNA methylation signature available in UVM remains limited. In this study, we performed a genome-wide integrative analysis of methylome and transcriptome and identified 40 methylation-driven prognostic genes (MDPGs) associated with the tumorigenesis and progression of UVM. Then, we proposed a machine-learning-based discovery and validation strategy to identify a DNA methylation-driven signature (10MeSig) composing of 10 MDPGs (AZGP1, BAI1, CCDC74A, FUT3, PLCD1, S100A4, SCN8A, SEMA3B, SLC25A38 and SLC44A3), which stratified 80 patients of the discovery cohort into two risk subtypes with significantly different overall survival (HR = 29, 95% CI: 6.7-126, P < 0.001). The 10MeSig was validated subsequently in an independent cohort with 57 patients and yielded a similar prognostic value (HR = 2.1, 95% CI: 1.2-3.7, P = 0.006). Multivariable Cox regression analysis showed that the 10MeSig is an independent predictive factor for the survival of patients with UVM. With a prospective validation study, this 10MeSig will improve clinical decisions and provide new insights into the pathogenesis of UVM.

7.
Sci Adv ; 6(46)2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33177077

RESUMO

Data-driven discovery of cancer driver genes, including tumor suppressor genes (TSGs) and oncogenes (OGs), is imperative for cancer prevention, diagnosis, and treatment. Although epigenetic alterations are important for tumor initiation and progression, most known driver genes were identified based on genetic alterations alone. Here, we developed an algorithm, DORGE (Discovery of Oncogenes and tumor suppressoR genes using Genetic and Epigenetic features), to identify TSGs and OGs by integrating comprehensive genetic and epigenetic data. DORGE identified histone modifications as strong predictors for TSGs, and it found missense mutations, super enhancers, and methylation differences as strong predictors for OGs. We extensively validated DORGE-predicted cancer driver genes using independent functional genomics data. We also found that DORGE-predicted dual-functional genes (both TSGs and OGs) are enriched at hubs in protein-protein interaction and drug-gene networks. Overall, our study has deepened the understanding of epigenetic mechanisms in tumorigenesis and revealed previously undetected cancer driver genes.

8.
Comput Struct Biotechnol J ; 18: 2953-2961, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33209207

RESUMO

Biological pathway analysis provides new insights for cell clustering and functional annotation from single-cell RNA sequencing (scRNA-seq) data. Many pathway analysis algorithms have been developed to transform gene-level scRNA-seq data into functional gene sets representing pathways or biological processes. Here, we collected seven widely-used pathway activity transformation algorithms and 32 available datasets based on 16 scRNA-seq techniques. We proposed a comprehensive framework to evaluate their accuracy, stability and scalability. The assessment of scRNA-seq preprocessing showed that cell filtering had the less impact on scRNA-seq pathway analysis, while data normalization of sctransform and scran had a consistent well impact across all tools. We found that Pagoda2 yielded the best overall performance with the highest accuracy, scalability, and stability. Meanwhile, the tool PLAGE exhibited the highest stability, as well as moderate accuracy and scalability.

9.
Invest Ophthalmol Vis Sci ; 61(12): 13, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33049061

RESUMO

Purpose: The coronavirus disease 2019 (COVID-19) pandemic severely challenges public health and necessitates the need for increasing our understanding of COVID-19 pathogenesis, especially host factors facilitating virus infection and propagation. The aim of this study was to investigate key factors for cellular susceptibility to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection in the ocular surface cells. Methods: We combined co-expression and SARS-CoV-2 interactome network to predict key genes at COVID-19 in ocular infection based on the premise that genes underlying a disease are often functionally related and functionally related genes are often co-expressed. Results: The co-expression network was constructed by mapping the well-known angiotensin converting enzyme (ACE2), TMPRSS2, and host susceptibility genes implicated in COVID-19 genomewide association study (GWAS) onto a cornea, retinal pigment epithelium, and lung. We found a significant co-expression module of these genes in the cornea, revealing that cornea is potential extra-respiratory entry portal of SARS-CoV-2. Strikingly, both co-expression and interaction networks show a significant enrichment in mitochondrial function, which are the hub of cellular oxidative homeostasis, inflammation, and innate immune response. We identified a corneal mitochondrial susceptibility module (CMSM) of 14 mitochondrial genes by integrating ACE2 co-expression cluster and SARS-CoV-2 interactome. The gene ECSIT, as a cytosolic adaptor protein involved in inflammatory responses, exhibits the strongest correlation with ACE2 in CMSM, which has shown to be an important risk factor for SARS-CoV-2 infection and prognosis. Conclusions: Our co-expression and protein interaction network analysis uncover that the mitochondrial function related genes in cornea contribute to the dissection of COVID-19 susceptibility and potential therapeutic interventions.


Assuntos
Betacoronavirus , Córnea/metabolismo , Infecções por Coronavirus/genética , Regulação da Expressão Gênica , Genes Mitocondriais/genética , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , RNA/genética , Linhagem Celular , Córnea/patologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Humanos , Pandemias , Peptidil Dipeptidase A/biossíntese , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo
10.
Mol Cell ; 78(3): 506-521.e6, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32386543

RESUMO

Higher-order chromatin structure and DNA methylation are implicated in multiple developmental processes, but their relationship to cell state is unknown. Here, we find that large (>7.3 kb) DNA methylation nadirs (termed "grand canyons") can form long loops connecting anchor loci that may be dozens of megabases (Mb) apart, as well as inter-chromosomal links. The interacting loci cover a total of ∼3.5 Mb of the human genome. The strongest interactions are associated with repressive marks made by the Polycomb complex and are diminished upon EZH2 inhibitor treatment. The data are suggestive of the formation of these loops by interactions between repressive elements in the loci, forming a genomic subcompartment, rather than by cohesion/CTCF-mediated extrusion. Interestingly, unlike previously characterized subcompartments, these interactions are present only in particular cell types, such as stem and progenitor cells. Our work reveals that H3K27me3-marked large DNA methylation grand canyons represent a set of very-long-range loops associated with cellular identity.


Assuntos
Cromatina/química , Cromatina/genética , Metilação de DNA , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Diferenciação Celular , Cromatina/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética , Regulação da Expressão Gênica , Histonas/genética , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Hibridização in Situ Fluorescente , Lisina/genética , Lisina/metabolismo , Proteínas Nucleares/genética , Fatores de Transcrição SOXB1/genética , Proteína de Homoeobox de Baixa Estatura/genética , Fatores de Transcrição/genética
11.
Brief Bioinform ; 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32382761

RESUMO

Long noncoding RNAs (lncRNAs) have been associated with cancer immunity regulation and the tumor microenvironment (TME). However, functions of lncRNAs of tumor-infiltrating B lymphocytes (TIL-Bs) and their clinical significance have not yet been fully elucidated. In the present study, a machine learning-based computational framework is presented for the identification of lncRNA signature of TIL-Bs (named 'TILBlncSig') through integrative analysis of immune, lncRNA and clinical profiles. The TILBlncSig comprising eight lncRNAs (TNRC6C-AS1, WASIR2, GUSBP11, OGFRP1, AC090515.2, PART1, MAFG-DT and LINC01184) was identified from the list of 141 B-cell-specific lncRNAs. The TILBlncSig was capable of distinguishing worse compared with improved survival outcomes across different independent patient datasets and was also independent of other clinical covariates. Functional characterization of TILBlncSig revealed it to be an indicator of infiltration of mononuclear immune cells (i.e. natural killer cells, B-cells and mast cells), and it was associated with hallmarks of cancer, as well as immunosuppressive phenotype. Furthermore, the TILBlncSig revealed predictive value for the survival outcome and immunotherapy response of patients with anti-programmed death-1 (PD-1) therapy and added significant predictive power to current immune checkpoint gene markers. The present study has highlighted the value of the TILBlncSig as an indicator of immune cell infiltration in the TME from a noncoding RNA perspective and strengthened the potential application of lncRNAs as predictive biomarkers of immunotherapy response, which warrants further investigation.

12.
J Med Genet ; 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381727

RESUMO

BACKGROUND: Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening. METHODS: In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited. RESULTS: After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis. CONCLUSION: ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.

13.
Bioinformatics ; 36(14): 4217-4219, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32437538

RESUMO

MOTIVATION: At present, a fundamental challenge in single-cell RNA-sequencing data analysis is functional interpretation and annotation of cell clusters. Biological pathways in distinct cell types have different activation patterns, which facilitates the understanding of cell functions using single-cell transcriptomics. However, no effective web tool has been implemented for single-cell transcriptome data analysis based on prior biological pathway knowledge. RESULTS: Here, we present scTPA, a web-based platform for pathway-based analysis of single-cell RNA-seq data in human and mouse. scTPA incorporates four widely-used gene set enrichment methods to estimate the pathway activation scores of single cells based on a collection of available biological pathways with different functional and taxonomic classifications. The clustering analysis and cell-type-specific activation pathway identification were provided for the functional interpretation of cell types from a pathway-oriented perspective. An intuitive interface allows users to conveniently visualize and download single-cell pathway signatures. Overall, scTPA is a comprehensive tool for the identification of pathway activation signatures for the analysis of single cell heterogeneity. AVAILABILITY AND IMPLEMENTATION: http://sctpa.bio-data.cn/sctpa. CONTACT: sujz@wmu.edu.cn or yufulong421@gmail.com or zgj@zjut.edu.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

14.
J Cell Mol Med ; 24(9): 4931-4943, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32277576

RESUMO

Tumour-induced osteomalacia (TIO) is a very rare paraneoplastic syndrome with bone pain, fractures and muscle weakness, which is mostly caused by phosphaturic mesenchymal tumours (PMTs). Cell-free DNA (cfDNA) has been regarded as a non-invasive liquid biopsy for many malignant tumours. However, it has not been studied in benign tumours, which prompted us to adopt the targeted next-generation sequencing approach to compare cfDNAs of 4 TIO patients, four patients with bone metastasis (BM) and 10 healthy controls. The mutational landscapes of cfDNA in TIO and BM groups were similar in the spectrum of allele frequencies and mutation types. Markedly, deleterious missense mutations in FGFR1 and loss-of-function mutations in MED12 were found in 3/4 TIO patients but none of BM patients. The gene ontology analysis strongly supported that these mutated genes found in TIOs would play a potential role in PMTs' process. The genetic signatures and corresponding change in expression of FGFR1 and FGF23 were further validated in PMT tissues from a test cohort of another three TIO patients. In summary, we reported the first study of the mutational landscape and genetic signatures of cfDNA in TIO/PMTs.

15.
Med Sci Monit ; 26: e920855, 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32150531

RESUMO

BACKGROUND Transplantation of exosomes derived from mesenchymal stem cells (MSCs-Exo) can improve the recovery of neurological function in rats after traumatic brain injury (TBI). We tested a new hypothesis that BDNF-mediated MSCs-Exo could effectively promote functional recovery and neurogenesis of rats after TBI. MATERIAL AND METHOD BMSCs of rats were extracted by whole bone marrow culture, BDNF was added to BMSCs for intervention, supernatant was collected, and exosomes were separated and purified by hypercentrifugation. Exosomes were identified by WB, TEM and particle size analysis and subsequently used in cell and animal experiments. We investigated the recovery of sensorimotor function and spatial learning ability, inflammation inhibition and neuron regeneration in rats after TBI. RESULTS Compared with group MSCs-Exo, group BDNF-mediated MSCs-Exo showed better effects in promoting the recovery of sensorimotor function and spatial learning ability. BDNF-mediated MSCs-Exo successfully inhibited inflammation and promoted neuronal regeneration in vivo and in vitro. We further analyzed miRNA in BDNF-mediated MSCs-Exo and MSCs-Exo, and found that the expression of miR-216a-5p in BDNF-mediated MSCs-Exo was significantly higher than that in MSCs-Exo by qRT-PCR. Rescue experiment indicated that miR-216a-5p has a similar function to BDNF-mediated MSCs-Exo. CONCLUSIONS In conclusion, we found that BDNF-mediated MSCs-Exo can better promote neurogenesis and inhibit apoptosis than MSCs-Exo in rats after TBI, and the mechanism may be related to the high expression of miR-216a-5p.

16.
J Immunother Cancer ; 8(1)2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32041817

RESUMO

BACKGROUND: Increasing evidence has demonstrated the functional relevance of long non-coding RNAs (lncRNAs) to immunity regulation and the tumor microenvironment in non-small cell lung cancer (NSCLC). However, tumor immune infiltration-associated lncRNAs and their value in improving clinical outcomes and immunotherapy remain largely unexplored. METHODS: We developed a computational approach to identify an lncRNA signature (TILSig) as an indicator of immune cell infiltration in patients with NSCLC through integrative analysis for lncRNA, immune and clinical profiles of 115 immune cell lines, 187 NSCLC cell lines and 1533 patients with NSCLC. Then the influence of the TILSig on the prognosis and immunotherapy in NSCLC was comprehensively investigated. RESULTS: Computational immune and lncRNA profiling analysis identified an lncRNA signature (TILSig) consisting of seven lncRNAs associated with tumor immune infiltration. The TILSig significantly stratified patients into the immune-cold group and immune-hot group in both training and validation cohorts. These immune-hot patients exhibit significantly improved survival outcome and greater immune cell infiltration compared with immune-cold patients. Multivariate analysis revealed that the TILSig is an independent predictive factor after adjusting for other clinical factors. Further analysis accounting for TILSig and immune checkpoint gene revealed that the TILSig has a discriminatory power in patients with similar expression levels of immune checkpoint genes and significantly prolonged survival was observed for patients with low TILSig and low immune checkpoint gene expression implying a better response to immune checkpoint inhibitor (ICI) immunotherapy. CONCLUSIONS: Our finding demonstrated the importance and value of lncRNAs in evaluating the immune infiltrate of the tumor and highlighted the potential of lncRNA coupled with specific immune checkpoint factors as predictive biomarkers of ICI response to enable a more precise selection of patients.

17.
Blood ; 135(11): 845-856, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31932841

RESUMO

Mutations in the epigenetic regulators DNMT3A and IDH1/2 co-occur in patients with acute myeloid leukemia and lymphoma. In this study, these 2 epigenetic mutations cooperated to induce leukemia. Leukemia-initiating cells from Dnmt3a-/- mice that express an IDH2 neomorphic mutant have a megakaryocyte-erythroid progenitor-like immunophenotype, activate a stem-cell-like gene signature, and repress differentiated progenitor genes. We observed an epigenomic dysregulation with the gain of repressive H3K9 trimethylation and loss of H3K9 acetylation in diseased mouse bone marrow hematopoietic stem and progenitor cells (HSPCs). HDAC inhibitors rapidly reversed the H3K9 methylation/acetylation imbalance in diseased mouse HSPCs while reducing the leukemia burden. In addition, using targeted metabolomic profiling for the first time in mouse leukemia models, we also showed that prostaglandin E2 is overproduced in double-mutant HSPCs, rendering them sensitive to prostaglandin synthesis inhibition. These data revealed that Dnmt3a and Idh2 mutations are synergistic events in leukemogenesis and that HSPCs carrying both mutations are sensitive to induced differentiation by the inhibition of both prostaglandin synthesis and HDAC, which may reveal new therapeutic opportunities for patients carrying IDH1/2 mutations.


Assuntos
Transformação Celular Neoplásica/genética , DNA (Citosina-5-)-Metiltransferases/genética , Neoplasias Hematológicas/genética , Hematopoese/genética , Isocitrato Desidrogenase/genética , Mutação , Animais , Linhagem Celular , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Sequenciamento de Cromatina por Imunoprecipitação , Metilação de DNA , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Histonas/metabolismo , Humanos , Metaboloma , Metabolômica/métodos , Camundongos , Camundongos Knockout
18.
Nucleic Acids Res ; 48(D1): D40-D44, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31428785

RESUMO

Epigenetic alterations, including 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and nucleosome positioning (NP), in cell-free DNA (cfDNA) have been widely observed in human diseases, and many available cfDNA-based epigenome-wide profiles exhibit high sensitivity and specificity in disease detection and classification. However, due to the lack of efficient collection, standardized quality control, and analysis procedures, efficiently integrating and reusing these data remain considerable challenges. Here, we introduce CFEA (http://www.bio-data.cn/CFEA), a cell-free epigenome database dedicated to three types of widely adopted epigenetic modifications (5mC, 5hmC and NP) involved in 27 human diseases. We developed bioinformatic pipelines for quality control and standard data processing and an easy-to-use web interface to facilitate the query, visualization and download of these cell-free epigenome data. We also manually curated related biological and clinical information for each profile, allowing users to better browse and compare cfDNA epigenomes at a specific stage (such as early- or metastasis-stage) of cancer development. CFEA provides a comprehensive and timely resource to the scientific community and supports the development of liquid biopsy-based biomarkers for various human diseases.


Assuntos
Ácidos Nucleicos Livres , Bases de Dados Genéticas , Epigênese Genética , Epigenoma , Epigenômica/métodos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Biomarcadores , Biologia Computacional/métodos , Epigenômica/normas , Humanos , Software , Navegador
19.
Brief Bioinform ; 21(5): 1742-1755, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31665214

RESUMO

Emerging evidence revealed the critical roles of long non-coding RNAs (lncRNAs) in maintaining genomic instability. However, identification of genome instability-associated lncRNAs and their clinical significance in cancers remain largely unexplored. Here, we developed a mutator hypothesis-derived computational frame combining lncRNA expression profiles and somatic mutation profiles in a tumor genome and identified 128 novel genomic instability-associated lncRNAs in breast cancer as a case study. We then identified a genome instability-derived two lncRNA-based gene signature (GILncSig) that stratified patients into high- and low-risk groups with significantly different outcome and was further validated in multiple independent patient cohorts. Furthermore, the GILncSig correlated with genomic mutation rate in both ovarian cancer and breast cancer, indicating its potential as a measurement of the degree of genome instability. The GILncSig was able to divide TP53 wide-type patients into two risk groups, with the low-risk group showing significantly improved outcome and the high-risk group showing no significant difference compared with those with TP53 mutation. In summary, this study provided a critical approach and resource for further studies examining the role of lncRNAs in genome instability and introduced a potential new avenue for identifying genomic instability-associated cancer biomarkers.

20.
J Hum Genet ; 65(3): 221-230, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31827250

RESUMO

Congenital scoliosis (CS) is a form of scoliosis caused by congenital vertebral malformations. Genetic predisposition has been demonstrated in CS. We previously reported that TBX6 loss-of-function causes CS in a compound heterozygous model; however, this model can explain only 10% of CS. Many monogenic and polygenic CS genes remain to be elucidated. In this study, we analyzed exome sequencing (ES) data of 615 Chinese CS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) project. Cosegregation studies for 103 familial CS identified a novel heterozygous nonsense variant, c.2649G>A (p.Trp883Ter) in FBN1. The association between FBN1 and CS was then analyzed by extracting FBN1 variants from ES data of 574 sporadic CS and 828 controls; 30 novel variants were identified and prioritized for further analyses. A mutational burden test showed that the deleterious FBN1 variants were significantly enriched in CS subjects (OR = 3.9, P = 0.03 by Fisher's exact test). One missense variant, c.2613A>C (p.Leu871Phe) was recurrent in two unrelated CS subjects, and in vitro functional experiments for the variant suggest that FBN1 may contribute to CS by upregulating the transforming growth factor beta (TGF-ß) signaling. Our study expanded the phenotypic spectrum of FBN1, and provided nove insights into the genetic etiology of CS.


Assuntos
Anormalidades Congênitas/genética , Fibrilina-1/genética , Predisposição Genética para Doença , Escoliose/genética , Criança , Pré-Escolar , Códon sem Sentido/genética , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/fisiopatologia , Exoma/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Mutação , Mutação de Sentido Incorreto/genética , Linhagem , Escoliose/diagnóstico por imagem , Escoliose/fisiopatologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/fisiopatologia , Fator de Crescimento Transformador beta/genética
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