Methylation Heterogeneity within Human Lung Carcinoids (LCs) Tumors
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PROVIDER: PRJNA484666 | ENA |
REPOSITORIES: ENA
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Project description: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.
2019-07-01 | GSE118132 | GEO
Project description:Methylation Heterogeneity within Human non-functional Pancreatic neuroendocrine tumors (PanNETs)
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Project description:Background: A feature of glioblastoma (GBM) is the cellular and molecular heterogeneity, both within and between tumors. This variability results in a risk for sampling bias and potential tumor escape from future targeted therapy. Heterogeneous gene expression within GBM is well documented, but little is known regarding the epigenetic heterogeneity. We therefore aimed to profile the intra-tumor DNA methylation heterogeneity in GBM. Methods: 3-4 biopsies per tumor from spatially separated regions were collected from 12 GBM patients. We performed genome-wide DNA methylation analysis (~850,000 CpG sites) and compared inter- and intra-tumor variation. Results: All samples were classified as GBM IDH wt or IDH mutated by DNA methylation profiling, but the GBM subtype differed within five tumors. Some GBM samples exhibited higher DNA methylation differences within tumors than between, and many CpG sites (mean: 17,000) had different methylation levels within the tumors. Conclusions: We demonstrated that intra-tumor DNA methylation heterogeneity is a feature of GBM. Although all biopsies were classified as GBM IDH wt/mutated by DNA methylation analysis, the assigned subtype differed in samples from the same patient. The observed DNA methylation heterogeneity within tumors is important to consider for methylation-based biomarkers and future improvements in stratification of GBM patients.
2019-02-27 | GSE116298 | GEO
Project description:DNA CpG methylation profiling of PanNETs patients samples were performed to understand genotype to phenotype corrlelations , novel molecular subtypes and cell of origins The most commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. Little is known about the cells-of-origin for non-functional neuroendocrine tumors. Here, we genotyped 64 PanNETs for mutations in ATRX, DAXX, and MEN1 and found 37 tumors (58%) carry mutations in these three genes (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis on 33 randomly selected cases to reveal two distinct subgroups with one group consisting entirely of A-D-M mutant PanNETs. Two biomarkers differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX gene expression and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha cells (pval < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells.
2018-10-01 | GSE117852 | GEO
Project description:Human cancers result from a complex series of genetic alterations resulting in heterogeneous disease states. Dissecting this heterogeneity is critical for understanding underlying mechanisms and providing opportunities for therapeutics matching the complexity. Mouse models of cancer have generally been employed to reduce this complexity and focus on the role of single genes. Nevertheless, our analysis of tumors arising in the MMTV-Myc model of mammary carcinogenesis reveals substantial heterogeneity, seen in both histological and expression phenotypes. One contribution to this heterogeneity is the substantial frequency of activating Ras mutations, the frequency of which can be changed by alterations in Myc. Additionally, we show that these Myc-induced mammary tumors exhibit even greater heterogeneity, revealed by distinct histological subtypes as well as distinct patterns of gene expression, than many other mouse models of tumorigenesis. Two of the major histological subtypes are characterized by differential patterns of cellular signaling pathways, including B-Catenin and Stat3 activities. We also demonstrate the predictive nature of this approach though examining metastatic potential. Together, these data reveal that a combination of histological and genomic analyses can uncover substantial heterogeneity in mammary tumor formation and therefore highlight aspects of tumor phenotype not evident in the population as a whole. Keywords: Transcription factor expression analysis 20 MMTV-Neu Tumors, 25 Papillary MMTV-Myc T58A and 81 MMTV-Myc tumors of various histological subtypes were arrayed.
2010-03-03 | E-GEOD-15904 | biostudies-arrayexpress