Project description:Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer is not well studied. We performed whole-genome methylation analysis using 450K Illumina BeadArrays on 124 tumors including 83 adenocarcinomas, 23 squamous cell carcinomas, one adenosquamous cancer, five large cell carcinomas, nine large cell neuroendocrine carcinomas (LCNEC), three small cell carcinomas (SCLC) and 12 normal lung tissues. Unsupervised class discovery was performed to identify DNA methylation subgroups with clinicopathological and molecular features. Subgroups were validated in two independent NSCLC cohorts. Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, in both discovery and validation cohorts, remaining four epitypes were associated with differences in clinicopathological and molecular features, including global hypomethylation, promoter hypermethylation, copy number alterations, expression of proliferation-associated genes, association with unsupervised and supervised gene expression phenotypes, KRAS, TP53, KEAP1, SMARCA4, and STK11 mutations, smoking history, and patient outcome. Based on a multicohort approach we conducted a comprehensive survey of genome-wide DNA methylation in lung cancer, identifying a distinct neuroendocrine epitype and four adenocarcinoma epitypes associated with molecular and clinicopathological characteristics, and patient outcome. Our results bring further understanding of the epigenetic characteristics and molecular diversity in lung cancer generally and in adenocarcinoma specifically. Genome-wide DNA methylation analysis of 124 lung carcinomas and 12 normal lung tissues using Illumina Human Methylation 450K v1.0 Beadchips.
Project description:Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer is not well studied. We performed whole-genome methylation analysis using 450K Illumina BeadArrays on 124 tumors including 83 adenocarcinomas, 23 squamous cell carcinomas, one adenosquamous cancer, five large cell carcinomas, nine large cell neuroendocrine carcinomas (LCNEC), three small cell carcinomas (SCLC) and 12 normal lung tissues. Unsupervised class discovery was performed to identify DNA methylation subgroups with clinicopathological and molecular features. Subgroups were validated in two independent NSCLC cohorts. Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, in both discovery and validation cohorts, remaining four epitypes were associated with differences in clinicopathological and molecular features, including global hypomethylation, promoter hypermethylation, copy number alterations, expression of proliferation-associated genes, association with unsupervised and supervised gene expression phenotypes, KRAS, TP53, KEAP1, SMARCA4, and STK11 mutations, smoking history, and patient outcome. Based on a multicohort approach we conducted a comprehensive survey of genome-wide DNA methylation in lung cancer, identifying a distinct neuroendocrine epitype and four adenocarcinoma epitypes associated with molecular and clinicopathological characteristics, and patient outcome. Our results bring further understanding of the epigenetic characteristics and molecular diversity in lung cancer generally and in adenocarcinoma specifically.
Project description:To characterize DNA methylation-based subgroups in colorectal cancer, we performed genome-scale DNA methylation profiling of 125 colorectal tumor samples and 29 histologically normal-adjacent colonic tissue samples using the Illumina Infinium DNA methylation assay, which assesses the DNA methylation status of 27,578 CpG sites located at the promoter regions of 14,495 protein-coding genes. We identified four DNA methylation-based subgroups of CRC using model-based cluster analyses. Each subtype shows characteristic genetic and clinical features, indicating that they represent biologically distinct subgroups. Bisulfite converted DNA from fresh frozen 125 colorectal tumors and 29 adjacent normal tissues were hybridized to the Illumina Infinium 27k Human Methylation Beadchip v1.2
Project description:To characterize DNA methylation-based subgroups in colorectal cancer, we performed genome-scale DNA methylation profiling of 125 colorectal tumor samples and 29 histologically normal-adjacent colonic tissue samples using the Illumina Infinium DNA methylation assay, which assesses the DNA methylation status of 27,578 CpG sites located at the promoter regions of 14,495 protein-coding genes. We identified four DNA methylation-based subgroups of CRC using model-based cluster analyses. Each subtype shows characteristic genetic and clinical features, indicating that they represent biologically distinct subgroups.
Project description:(Purpose) Biological classification of colorectal cancer (CRC) can help to understand its heterogeneous background. The purpose of this study is to classify CRC based on gene expression profiles using formalin-fixed paraffin-embedded (FFPE) samples and to correlate subgroups of CRC with biological features and clinical outcomes. (Results) CRC was clustered into four subgroups by unsupervised hierarchical clustering method. These subgroups show different biological and clinical features. (Conclusion) Gene expression profiles of CRC using FFPE samples distinguish four subgroups that had different biological features and clinical outcomes. These subgroups may explain heterogeneity of CRC and be useful biomarker for clinical. Patients and Methods: One hundred patients with unresectable and advanced or recurrent CRC who underwent the surgical resection from 1998 to 2010 were enrolled in this study. RNA extracted from FFPE samples was subjected to gene expression microarray. After comprehensive gene expression analysis, CRC were classified by an unsupervised hierarchical clustering and a principle component analysis (PCA). Mutation analysis of KRAS, BRAF, PIK3CA and TP53 genes were performed by direct DNA sequencing. Correlation between the biological information, clinicopathological factors and clinical outcomes were analyzed.
Project description:The concept of the CpG island methylator phenotype (CIMP) in colorectal cancers (CRCs) is widely accepted, though the timing of its occurrence and its interaction with other genetic defects early during carcinogenesis remains largely unknown. Our aim was to uncover the molecular evolution of CIMP CRCs through integrative analysis of endoscopic, histological and molecular signatures in precancerous and malignant colorectal lesions. A total of 84 endoscopically obtained human colorectal tumor was analyzed using Agilent CGH microarray. Copy number aberration was compared with clinicopathological features and DNA methylation status.
Project description:The concept of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) is widely accepted, though the timing of its occurrence and its interaction with other genetic defects are not fully understood. Our aim in this study was to unravel the molecular development of CIMP cancers by dissecting their genetic and epigenetic signatures in precancerous and malignant colorectal lesions. A total of 88 samples (16 normal colon tissues taken from adjacent tumor tissue, 70 colorectal tumor tissues and 2 cell lines) was analyzed using MCA microarray. Aberrant DNA methylation was compared with clinicopathological features and copy number.
Project description:This study reports clinical, genetic, epigenetic, gene expression, and cellular features distinguishing meningioma DNA methylation subgroups within meningioma DNA methylation groups. We present these data in the context of molecular and clinical models predicting postoperative outcomes across 565 meningiomas with comprehensive clinical follow-up from independent discovery and validation institutions. By discovering meningioma DNA methylation subgroups within meningioma DNA methylation groups, we provide an opportunity to resolve inconsistencies in the recent literature. In doing so, our study establishes an architecture that unifies opposing biological theories for the most common primary intracranial tumor
Project description:Molecular subtypes of lung adenocarcinoma (LUAD) with varying prognosis and characteristics have been proposed based on one or two-dimensional studies but are not yet implemented into clinical routine. Epigenetic modifications in cancer cells are independent of sequence variants, directly linked to gene and genome regulation, and thus provide important information to guide subclassification efforts. We performed in-depth epigenomic profiling of 95 primary LUAD samples from a Swedish discovery cohort with comprehensive clinicopathological, epigenomic, genomic, transcriptomic, proteomic, and metabolomic data. Not all samples have all omics data, and data have been deposited at different timepoints. Here we include DNA methylation values for 13 LUAD samples. In this project, we subdivided the 95 samples into four epigenetic subtypes, or epitypes, reflecting distinct tumor cell methylation states. Resulting epitypes were contrasted based on clinicopathological and molecular features, and our main findings were validated in two additional primary tumor cohorts totaling over 700 samples.