Cancer arises as a consequence of cumulative disruptions to cellular growth control with Darwinian selection for those heritable changes that provide the greatest clonal advantage. These traits can ...be acquired and stably maintained by either genetic or epigenetic means. Here, we explore the ways in which alterations in the genome and epigenome influence each other and cooperate to promote oncogenic transformation. Disruption of epigenomic control is pervasive in malignancy and can be classified as an enabling characteristic of cancer cells, akin to genome instability and mutation.
Microsatellites—simple tandem repeats present at millions of sites in the human genome—can shorten or lengthen due to a defect in DNA mismatch repair. We present here a comprehensive genome-wide ...analysis of the prevalence, mutational spectrum, and functional consequences of microsatellite instability (MSI) in cancer genomes. We analyzed MSI in 277 colorectal and endometrial cancer genomes (including 57 microsatellite-unstable ones) using exome and whole-genome sequencing data. Recurrent MSI events in coding sequences showed tumor type specificity, elevated frameshift-to-inframe ratios, and lower transcript levels than wild-type alleles. Moreover, genome-wide analysis revealed differences in the distribution of MSI versus point mutations, including overrepresentation of MSI in euchromatic and intronic regions compared to heterochromatic and intergenic regions, respectively, and depletion of MSI at nucleosome-occupied sequences. Our results provide a panoramic view of MSI in cancer genomes, highlighting their tumor type specificity, impact on gene expression, and the role of chromatin organization.
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•Analysis of genome sequencing data provides a genome-wide view of MSI in human cancers•Genes affected by MSI show tumor type specificity•Recurrent MSI in coding regions shows a high frameshift-to-in-frame ratio•MSI frequency is associated with chromatin organization and nucleosome positioning
A comprehensive analysis of data from The Cancer Genome Atlas provides a panoramic view of microsatellite instability (MSI) in colorectal and endometrial cancers, showing tumor-type-specific effects and a role for chromatin organization in determining the frequency of MSI.
Methylation of cytosine bases in DNA provides a layer of epigenetic control in many eukaryotes that has important implications for normal biology and disease. Therefore, profiling DNA methylation ...across the genome is vital to understanding the influence of epigenetics. There has been a revolution in DNA methylation analysis technology over the past decade: analyses that previously were restricted to specific loci can now be performed on a genome-scale and entire methylomes can be characterized at single-base-pair resolution. However, there is such a diversity of DNA methylation profiling techniques that it can be challenging to select one. This Review discusses the different approaches and their relative merits and introduces considerations for data analysis.
Illumina Infinium DNA Methylation BeadChips represent the most widely used genome-scale DNA methylation assays. Existing strategies for masking Infinium probes overlapping repeats or single ...nucleotide polymorphisms (SNPs) are based largely on ad hoc assumptions and subjective criteria. In addition, the recently introduced MethylationEPIC (EPIC) array expands on the utility of this platform, but has not yet been well characterized. We present in this paper an extensive characterization of probes on the EPIC and HM450 microarrays, including mappability to the latest genome build, genomic copy number of the 3΄ nested subsequence and influence of polymorphisms including a previously unrecognized color channel switch for Type I probes. We show empirical evidence for exclusion criteria for underperforming probes, providing a sounder basis than current ad hoc criteria for exclusion. In addition, we describe novel probe uses, exemplified by the addition of a total of 1052 SNP probes to the existing 59 explicit SNP probes on the EPIC array and the use of these probes to predict ethnicity. Finally, we present an innovative out-of-band color channel application for the dual use of 62 371 probes as internal bisulfite conversion controls.
The past few years have seen an explosion of interest in the epigenetics of cancer. This has been a consequence of both the exciting coalescence of the chromatin and DNA methylation fields, and the ...realization that DNA methylation changes are involved in human malignancies. The ubiquity of DNA methylation changes has opened the way to a host of innovative diagnostic and therapeutic strategies. Recent advances attest to the great promise of DNA methylation markers as powerful future tools in the clinic.
Abstract
We report a new class of artifacts in DNA methylation measurements from Illumina HumanMethylation450 and MethylationEPIC arrays. These artifacts reflect failed hybridization to target DNA, ...often due to germline or somatic deletions and manifest as incorrectly reported intermediate methylation. The artifacts often survive existing preprocessing pipelines, masquerade as epigenetic alterations and can confound discoveries in epigenome-wide association studies and studies of methylation-quantitative trait loci. We implement a solution, P-value with out-of-band (OOB) array hybridization (pOOBAH), in the R package SeSAMe. Our method effectively masks deleted and hyperpolymorphic regions, reducing or eliminating spurious reports of epigenetic silencing at oft-deleted tumor suppressor genes such as CDKN2A and RB1 in cases with somatic deletions. Furthermore, our method substantially decreases technical variation whilst retaining biological variation, both within and across HM450 and EPIC platform measurements. SeSAMe provides a light-weight, modular DNA methylation data analysis suite, with a performant implementation suitable for efficient analysis of thousands of samples.
Elevated serum homocysteine is associated with an increased risk of cardiovascular disease (CVD). This may reflect a reduced systemic remethylation capacity, which would be expected to cause ...decreased genomic DNA methylation in peripheral blood leukocytes (PBL).
We examined the association between prevalence of CVD (myocardial infarction, stroke) and its predisposing conditions (hypertension, diabetes) and PBL global genomic DNA methylation as represented by ALU and Satellite 2 (AS) repetitive element DNA methylation in 286 participants of the Singapore Chinese Health Study, a population-based prospective investigation of 63,257 men and women aged 45-74 years recruited during 1993-1998. Men exhibited significantly higher global DNA methylation geometric mean (95% confidence interval (CI)): 159 (143, 178) than women 133 (121, 147) (P = 0.01). Global DNA methylation was significantly elevated in men with a history of CVD or its predisposing conditions at baseline (P = 0.03) but not in women (P = 0.53). Fifty-two subjects (22 men, 30 women) who were negative for these CVD/predisposing conditions at baseline acquired one or more of these conditions by the time of their follow-up I interviews, which took place on average about 5.8 years post-enrollment. Global DNA methylation levels of the 22 incident cases in men were intermediate (AS, 177) relative to the 56 male subjects who remained free of CVD/predisposing conditions at follow-up (lowest AS, 132) and the 51 male subjects with a diagnosis of CVD or predisposing conditions reported at baseline (highest AS 184) (P for trend = 0.0008) No such association was observed in women (P = 0.91). Baseline body mass index was positively associated with AS in both men and women (P = 0.007).
Our findings indicate that elevated, not decreased, PBL DNA methylation is positively associated with prevalence of CVD/predisposing conditions and obesity in Singapore Chinese.
DNA methylation loss occurs frequently in cancer genomes, primarily within lamina-associated, late-replicating regions termed partially methylated domains (PMDs). We profiled 39 diverse primary ...tumors and 8 matched adjacent tissues using whole-genome bisulfite sequencing (WGBS) and analyzed them alongside 343 additional human and 206 mouse WGBS datasets. We identified a local CpG sequence context associated with preferential hypomethylation in PMDs. Analysis of CpGs in this context ('solo-WCGWs') identified previously undetected PMD hypomethylation in almost all healthy tissue types. PMD hypomethylation increased with age, beginning during fetal development, and appeared to track the accumulation of cell divisions. In cancer, PMD hypomethylation depth correlated with somatic mutation density and cell cycle gene expression, consistent with its reflection of mitotic history and suggesting its application as a mitotic clock. We propose that late replication leads to lifelong progressive methylation loss, which acts as a biomarker for cellular aging and which may contribute to oncogenesis.
Cancer epigenetics LAIRD, Peter W
Human molecular genetics,
04/2005, Letnik:
14, Številka:
suppl-1
Journal Article
Recenzirano
Odprti dostop
The field of cancer epigenetics is evolving rapidly on several fronts. Advances in our understanding of chromatin structure, histone modification, transcriptional activity and DNA methylation have ...resulted in an increasingly integrated view of epigenetics. In response to these insights, epigenetic therapy is expanding to include combinations of histone deacetylase inhibitors and DNA methyltransferase inhibitors. Zebularine, an orally administerable DNA methyltransferase inhibitor, has been a very promising recent addition to our arsenal of potentially useful drugs for epigenetic therapy. Aberrant DNA methylation patterns provide three powerful diagnostic applications as classification markers, sensitive detection markers, and risk assessment markers. Classification studies continue to increase in marker complexity, now incorporating microarrays, high-throughput bisulfite genomic sequencing and mass spectrometry, as the field moves to human epigenome projects. Sensitive detection technology has expanded from primarily blood-based cancer detection to include applications on a wide diversity of sample sources and is now also making inroads as a molecular risk assessment tool.
We propose a novel approach to background correction for Infinium HumanMethylation data to account for technical variation in background fluorescence signal. Our approach capitalizes on a new use for ...the Infinium I design bead types to measure non-specific fluorescence in the colour channel opposite of their design (Cy3/Cy5). This provides tens of thousands of features for measuring background instead of the much smaller number of negative control probes on the platforms (n = 32 for HumanMethylation27 and n = 614 for HumanMethylation450, respectively). We compare the performance of our methods with existing approaches, using technical replicates of both mixture samples and biological samples, and demonstrate that within- and between-platform artefacts can be substantially reduced, with concomitant improvement in sensitivity, by the proposed methods.
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