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Methylation Heterogeneity within Human Lung Carcinoids (LCs) Tumors

ABSTRACT: DNA CpG methylation profiling of LC patients samples were performed to understand genotype to phenotype corrlelations , novel molecular subtypes and cell of origins Lung carcinoids (LCs) are rare and slow growing primary lung neoplasms that are understudied. Here, we performed targeted exome sequencing using a 354-cancer gene panel (n=29), mRNA sequencing (n=30) and DNA methylation assay (n=18) on macro-dissected lung carcinoids. The mutations we identified were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%) (MEN1, ARID1A, KMT2C and KMT2A were recurrently mutated) as well as DNA repair (17.2%) pathways. Unsupervised clustering and principle component analysis on gene expression and DNA methylation profiles showed 3 robust molecular subtypes (LC1, LC2, LC3) with distinct clinical features. MEN1 gene mutations were found to be enriched and exclusively in the LC2 subtype (p-value<0.001). The LC3 subtype is predominately found at endobronchial lung and earlier age of diagnosis. Immunohistochemical staining of two biomarkers, ASCL1 and S100, is sufficient to stratify the three subtypes. This molecular classification of lung carcinoids into three subtypes may help improve treatment decision and clinical management.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118132 | GEO | 2019/07/01

REPOSITORIES: GEO

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Transcriptomic profiling of human Lung Carcinoids (LCs)

Project description:Lung carcinoids (LCs) are rare and slow growing primary lung neoplasms that are understudied. Here, we performed targeted exome sequencing using a 354-cancer gene panel (n=29), mRNA sequencing (n=30) and DNA methylation assay (n=18) on macro-dissected lung carcinoids. The mutations we identified were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%) (MEN1, ARID1A, KMT2C and KMT2A were recurrently mutated) as well as DNA repair (17.2%) pathways. Unsupervised clustering and principle component analysis on gene expression and DNA methylation profiles showed 3 robust molecular subtypes (LC1, LC2, LC3) with distinct clinical features. MEN1 gene mutations were found to be enriched and exclusively in the LC2 subtype (p-value<0.001). The LC3 subtype is predominately found at endobronchial lung and earlier age of diagnosis. Immunohistochemical staining of two biomarkers, ASCL1 and S100, is sufficient to stratify the three subtypes. This molecular classification of lung carcinoids into three subtypes may help improve treatment decision and clinical management.

2019-07-01 | GSE118131 | GEO

Methylation Heterogeneity within Human Lung Carcinoids (LCs) Tumors

Project description:Methylation Heterogeneity within Human Lung Carcinoids (LCs) Tumors

| PRJNA484666 | ENA

Transcriptomic profiling of human Lung Carcinoids (LCs)

Project description:Transcriptomic profiling of human Lung Carcinoids (LCs)

| PRJNA484631 | ENA

Loss of MEN1 activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis

Project description:Multiple endocrine neoplasia type 1 (MEN1) syndrome is the result of mutations in the MEN1 gene and results in tumor formation via mechanisms that are not well understood. Using a novel genome-wide methylation analysis, we studied tissues from patients with MEN1-parathyroid tumors, tissues from Men1 knockout (KO) mouse models, and mouse Men1 null mouse embryonic fibroblast (MEF) cell lines. Tissues from KO mice were used to confirm and assess the findings from the MEN1 clinical samples and further explore the molecular mechanisms of global epigenetic changes following the inactivation of menin. We demonstrated that the inactivation of menin results in enhanced activity of DNA (cytosine-5)-methyltransferase 1 (DNMT1) by retinoblastoma-binding protein 5 (Rbbp5) activation in MEN1 tumor tissues. The increased activity of DNMT1 mediated global DNA hypermethylation, which in turn resulted in aberrant activation of the Wnt/Î²-catenin signaling pathway through inactivation of Sox regulatory genes. Our study provides important insights into the possible regulatory role of menin in DNA methylation and its impact on the pathogenesis of MEN1 tumor development. Global DNA methylation in tissues from patients with MEN1-parathyroid tumors. Thirty-eight human parathyroid specimens were used: 13 sporadic (non-MEN1) parathyroid adenomas, 12 MEN1-parathyroid tumors, 4 parathyroid carcinomas, and 9 normal parathyroids.

2015-12-22 | E-GEOD-64412 | biostudies-arrayexpress

Loss of MEN1 activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis

2015-12-22 | GSE64412 | GEO

Luminal B breast cancer subtype displays a dichotomic epigenetic pattern

Project description:Purpose In breast cancer, specific aberrant methylation patterns have been associated with different BC histologic and molecular subtypes and data suggest that DNA methylation profiles may play an important role in the development and progression of distinct breast subtypes. However, the epigenome of the newly defined luminal B and luminal B-HER2 positive breast cancers has not yet been characterized. Therefore the main goal of the current study is to deciphered the aberrant DNA methylation profiles associated with these breast cancer subtypes. Experimental Design 29 luminal subtype breast cancer samples along with 8 control tissue were epigenetically interrogated using the HumanMethylation27 DNA Analysis BeadChip. Results Luminal B-HER2 + subtype displays the most aggressive phenotype and shows the highest number of aberrantly methylated CpG markers. On the other hand, the luminal B subtype harbours an heterogeneous DNA methylation profile that seems to be half way between the luminal A and luminalB-HER2+ subtypes. Conclusions The heterogeneous epigenetic and genetic profile of the luminal B subtype, might indicate that a further stratification has to be done for this specific breast cancer subtype.

2016-12-18 | GSE73808 | GEO

Human Lung Carcinoids

Project description:Human Lung Carcinoids

| PRJNA484632 | ENA

DNA methylation pattern in somatotroph pituitary neuroendocrine tumors

Project description:Secretion of growth hormone by sporadic somatotroph neuroendocrine pituitary tumors (PitNETs) is the most common cause of acromegaly.Genome-wide DNA methylation was investigated in 48 somatotroph PitNETs with EPIC microarrays. Three subtypes of the tumors were identified. Subtype 1 tumors are densely granulated tumors without GNAS mutation characterized by high expression of NR5A1 (SF-1) and GIPR. The expression of both genes is correlated with specific methylation pattern at gene body and promoter methylation. Subtype 1 has generally lower methylation level at 5’ gene regulatory regions and CpG islands as compared to other tumor clusters. Subtype 2 are densely granulated PiNETs with common GNAS-mutations while Subtype 3 are mainly sparsely granulated tumors. Methylation/expression analysis indicate that the levels of ~50% genes differentially expressed genes between tumor subtypes that are located at in differentially methylated regions are DNA methylation dependent. These DNA methylation-controlled genes include CDKN1B, CCND2, EBF3, CDH4, CDH12 MGMT, STAT5A, PLXND1, PTPRE and MMP16 as wells as genes encoding ion channels and semaphorins. Results of DNA methylation profiling confirms three molecular subtypes of somatotroph PitNETs that differ in both gene expression and methylation pattern. High expression of NR5A1 and GIPR in subtype 1 tumors is correlated to specific methylation at both genes.

2023-09-25 | GSE226764 | GEO

Association of frequent hypermethylation with high grade histological subtype in lung adenocarcinoma. (Infinium Methylation450K)

Project description:Comprehensive DNA methylation analysis of each histological LUAD subtype. Infinium HumanMethylation450 BeadChip was used to obtain DNA methylation profiles across 485,577 CpG sites. Samples included 6 Micropapillary subtype, 5 Papillary subtype, 5 Lepidic subype and 3 normal lung tissues.

2023-09-11 | GSE217732 | GEO

Epigenomic profiling of Acute myeloid leukemia subtypes from primary tumor samples

Project description:Here we used Illumina NGS for high-throughput profiling of the DNA methylome(ERRBS) and hydroxymethylome(hMe-Seal) of primary tumor samples with Acute Myeloid Leukemia(AML). The data can be used to compare hydroxymethylation and methylation patterns from different AML subtypes and normal bone marrow samples. We have sequenced 4 subtypes of AML with hydroxymethylation decrease and 1 subtype with no decrease. We have sequenced 2-5 primary tumor samples for each subtype, and comprated the epigenomic profiles ( ERRBS and hMe-Seal ) of hydroxymethylation deficient subtypes to the control subtype and normal bone marrow samples.

2014-11-20 | E-GEOD-52945 | biostudies-arrayexpress

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