DNA methylation alterations exhibit striking intra-individual stability and inter-individual heterogeneity across metastatic dissemination
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE38242 | GEO | 2013/02/04
SECONDARY ACCESSION(S): PRJNA167520
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-02-04 | E-GEOD-38242 | biostudies-arrayexpress
Project description:Human cancers almost ubiquitously harbor epigenetic alterations. Although such alterations in epigenetic marks, including DNA methylation, are potentially heritable, they can also be dynamically altered. Given this potential for plasticity, the degree to which epigenetic changes can be subject to selection and act as drivers of neoplasia has been questioned. We carried out genome-scale analyses of DNA methylation alterations in lethal metastatic prostate cancer and created DNA methylation "cityscape" plots to visualize these complex data. We show that somatic DNA methylation alterations, despite showing marked interindividual heterogeneity among men with lethal metastatic prostate cancer, were maintained across all metastases within the same individual. The overall extent of maintenance in DNA methylation changes was comparable to that of genetic copy number alterations. Regions that were frequently hypermethylated across individuals were markedly enriched for cancer- and development/differentiation-related genes. Additionally, regions exhibiting high consistency of hypermethylation across metastases within individuals, even if variably hypermethylated across individuals, showed enrichment for cancer-related genes. Whereas some regions showed intraindividual metastatic tumor heterogeneity in promoter methylation, such methylation alterations were generally not correlated with gene expression. This was despite a general tendency for promoter methylation patterns to be strongly correlated with gene expression, particularly at regions that were variably methylated across individuals. These findings suggest that DNA methylation alterations have the potential for producing selectable driver events in carcinogenesis and disease progression and highlight the possibility of targeting such epigenome alterations for development of longitudinal markers and therapeutic strategies.
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Project description:There is growing evidence that sperm DNA methylation is important in maintaining proper sperm health and function. Previous studies have associated sperm DNA methylation levels with sperm quality and function, however, little is known regarding the intra- and inter-individual variability in sperm methylation levels. This study characterizes this variation. Sperm epigenetic differences between successive semen samples from 12 patients were examined to identify the intra- and inter-individual differences globally across the genome, and in specifically defined genomic regions using the Illumina Infinium HumanMethylation450 BeadChips. Methylation analysis identified a bimodal distribution in the methylation levels that were non-uniformly distributed across the different genomic regions. The methylation levels were highly correlated in both the intra- and inter-individual comparisons. The intra-individual methylation levels were more highly correlated than the inter-individual comparison both globally and across the defined genomic regions, demonstrating that sperm DNA methylation levels are relatively stable between semen sample collections.
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Project description:We report the application of single molecule-based sequencing technology in combination with MBD affinity purifcation (MAP-seq) to generate methylation maps in a panel of human brain samples. Here we assay the methylation status of the human genome in eight distinct brain regions from three individuals in addition to a further thirty six hippocampal samples. The cerebellum was a consistent outlier compared to all other regions, showing over 16,000 differentially methylated regions (DMRs). Unexpectedly, the sequence properties of hypo- and hyper- methylated domains in cerebellum were distinct. In contrast we found very few DMRs that could distinguish between regions of the cortex, limbic system and brain stem. Inter-individual DMRs were readily detectable, however with the exception of cerebellum, DNA methylation patterns are more similar between different brain regions from the same individual, than they are for a single brain region between different individuals.
2014-12-01 | GSE50960 | GEO
Project description:MAPK inhibitors (MAPKi) are active in BRAF-mutant metastatic melanoma patients, but the extent of response and progression-free survival (PFS) is variable, and complete responses are rare. We sought to examine the patterns of response and progression in patients treated with targeted therapy.MAPKi-naïve patients treated with combined dabrafenib and trametinib had all metastases ?5 mm (lymph nodes ?15 mm in short axis) visible on computed tomography measured at baseline and throughout treatment.24 patients had 135 measured metastases (median 4.5/patient, median diameter 16 mm). Time to best response (median 5.5 mo, range 1.7-20.1 mo), and the degree of best response (median -70%, range +9 to -100%) varied amongst patients. 17% of patients achieved complete response (CR), whereas 53% of metastases underwent CR, including 42% ?10 mm. Metastases that underwent CR were smaller than non-CR metastases (median 11 vs 20 mm, P<0.001). PFS was variable among patients (median 8.2 mo, range 2.6-18.3 mo), and 50% of patients had disease progression in new metastases only. Only 1% (1/71) of CR-metastases subsequently progressed. Twelve-month overall survival was poorer in those with a more heterogeneous initial response to therapy than less heterogeneous (67% vs 93%, P?=?0.009).Melanoma response and progression with MAPKi displays marked inter- and intra-patient heterogeneity. Most metastases undergo complete response, yet only a small proportion of patients achieve an overall complete response. Similarly, disease progression often occurs only in a subset of the tumor burden, and often in new metastases alone. Clinical heterogeneity, likely reflecting molecular heterogeneity, remains a barrier to the effective treatment of melanoma patients.
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2022-05-13 | GSE202695 | GEO
Project description:Prostate cancers exhibit a spectrum of molecular aberrations of which a substantial subset are amenable to targeted therapeutics. To determine the diversity of somatic alterations present in metastasis within and between individuals we characterized the genomic landscapes of 176 tumors acquired from 63 men. In contrast to the considerable variation across individuals, the molecular diversity of tumors within an individual was substantially less: alterations in putative drivers of cancer growth and cell cycle progression status were highly concordant. While androgen receptor activity was inversely related to proliferation, the expression of Fanconi Anemia complex genes was strongly associated with increased cell cycle progression. Inhibition of FANCA, FANCC, FANCD2 and BRCA2 expression reduced prostate cancer growth. The limited molecular diversity across metastases may result from bottlenecks imposed by the dissemination process, limited evolutionary time between metastatic seeding and tumor sampling, intermixing of tumor clones, and selection resulting from treatment pressures. Though exceptions exist, evaluating a single metastasis provides a reasonable assessment of the key molecular processes that occur throughout the spectrum of disseminated tumors within an individual, and may be used for selecting treatments based on predicted molecular vulnerabilities. Custom Agilent 44K whole human genome expression oligonucleotide microarrays were used to profile 171 CRPC tumors from 63 patients. RNA was amplified prior to hybridization against a common reference pool of prostate tumor cell lines.
2015-12-18 | E-GEOD-74685 | biostudies-arrayexpress
Project description:In this study, we performed single-cell transcriptome data analysis of fifty primary and metastatic lung adenocarcinoma (LUAD) samples from the GSE123902 and GSE131907 datasets to determine the landscape of inter-patient and intra-tumoral heterogeneity. The gene expression profiles and copy number variations (CNV) showed significant heterogeneity in the primary and metastatic LUAD samples. We observed upregulation of pathways related to translational initiation, endoplasmic reticulum stress, exosomes, and unfolded protein response in the brain metastasis samples as compared to the primary tumor samples. Pathways related to exosomes, cell adhesion and metabolism were upregulated and the epithelial-to-mesenchymal-transition (EMT) pathway was downregulated in brain metastasis samples from chemotherapy-treated LUAD patients as compared to those from the untreated LUAD patients. Tumor cell subgroups in the brain metastasis samples showed differential expression of genes related to type II alveolar cells, chemoresistance, glycolysis and oxidative phosphorylation (metabolic reprogramming), and EMT. Thus, single-cell transcriptome analysis demonstrated intra-patient and intra-tumor heterogeneity in the regulation of pathways related to tumor progression, chemoresistance and metabolism in the primary and metastatic LUAD tissues. Moreover, our study demonstrates that single cell transcriptome analysis is a potentially useful tool for accurate diagnosis and personalized targeted treatment of LUAD patients.
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Project description:Each expressed gene was tested for differential expression in three mouse tissues (Brain, Kidney, Liver) in a direct comparison of SJL/J vs. C57BL/6J Keywords: direct comparison, multiple tissues
2009-12-31 | GSE8358 | GEO
Project description:BackgroundLong interspersed nucleotide element 1 (LINE-1) hypomethylation is suggested to play a role in the progression of colorectal cancer (CRC). To assess intra-patient heterogeneity of LINE-1 methylation in CRC and to understand its biological relevance in invasion and metastasis, we evaluated the LINE-1 methylation at multiple tumor sites. In addition, the influence of stromal cell content on the measurement of LINE-1 methylation in tumor tissue was analyzed.MethodsFormalin-fixed paraffin-embedded primary tumor tissue was obtained from 48 CRC patients. Matched adjacent normal colon tissue, lymph node metastases and distant metastases were obtained from 12, 18 and 7 of these patients, respectively. Three different areas were microdissected from each primary tumor and included the tumor center and invasive front. Normal mucosal and stromal cells were also microdissected for comparison with the tumor cells. The microdissected samples were compared in LINE-1 methylation level measured by multicolor MethyLight assay. The assay results were also compared between microdissected and macrodissected tissue samples.ResultsLINE-1 methylation within primary tumors showed no significant intra-tumoral heterogeneity, with the tumor center and invasive front showing identical methylation levels. Moreover, no difference in LINE-1 methylation was observed between the primary tumor and lymph node and distant metastases from the same patient. Tumor cells showed significantly less LINE-1 methylation compared to adjacent stromal and normal mucosal epithelial cells. Consequently, LINE-1 methylation was significantly lower in microdissected samples compared to macrodissected samples. A trend for less LINE-1 methylation was also observed in more advanced stages of CRC.ConclusionsLINE-1 methylation shows little intra-patient tumor heterogeneity, indicating the suitability of its use for molecular diagnosis in CRC. The methylation is relatively stable during CRC progression, leading us to propose a new concept for the association between LINE-1 methylation and disease stage.
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