scholarly journals EPCO-29. EPIGENOMICS OF THE GLIOMA LONGITUDINAL ANALYSIS (GLASS) CONSORTIUM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii75-ii75
Author(s):  
Thais Sabedot ◽  
Michael Wells ◽  
Indrani Datta ◽  
Tathiane Malta ◽  
Ana Valeria Castro ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Longitudinal Analysis ◽  
Copy Number ◽  
Large Scale ◽  
Molecular Classification ◽  
Tumor Burden ◽  
Copy Number Alterations ◽  
Unsupervised Analysis ◽  
Diffuse Gliomas ◽  
New Biomarkers

Abstract Adult diffuse gliomas are central nervous system (CNS) tumors that arise from the malignant transformation of glial cells. Nearly all gliomas will recur despite standard treatment however, current histopathological grading fails to predict which of them will relapse and/or progress. The Glioma Longitudinal AnalySiS (GLASS) consortium is a large-scale collaboration that aims to investigate the molecular profiling of matched primary and recurrent glioma samples from multiple institutions in order to better understand the dynamic evolution of these tumors. At this time, the cohort comprises 946 samples across 11 institutions and among those, 864 have DNA methylation data available. The current molecular classification based on 7 subtypes published by TCGA in 2016 was applied to the dataset. Among the IDH wildtype tumors, 33% (16/49) of the patients showed a change of subtype upon recurrence, whereas most of them (9/16) were Classic-like at the primary stage but changed to either Mesenchymal-like or PA-like at the recurrent level. Among the IDH mutant tumors, 15% (22/142) showed a change of subtype at recurrent stage, in which 16 out of 22 progressed from G-CIMP-high to G-CIMP-low. Although some tumors progressed to a different subtype upon recurrence, an unsupervised analysis showed that the samples tend to cluster by patient instead of by subtype. By estimating the copy number alterations of these tumors using DNA methylation, the overall copy number profile of the recurrent samples remains similar to their primary counterpart. From this initial analysis using epigenomic data, we were able to characterize some aspects of glioma evolution and how the DNA methylation is associated with the progression of these tumors to different subtypes. These findings corroborate the importance of epigenetics in gliomas and can potentially lead to the identification of new biomarkers that can reflect tumor burden and predict its development.

scholarly journals Pervasive cis effects of variation in copy number of large tandem repeats on local epigenetics and gene expression

2020 ◽  
Author(s):  
Paras Garg ◽  
Alejandro Martin-Trujillo ◽  
Oscar L. Rodriguez ◽  
Scott J. Gies ◽  
Bharati Jadhav ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Copy Number ◽  
Large Scale ◽  
Tandem Repeats ◽  
Local Variation ◽  
Read Depth ◽  
Variable Number ◽  
Human Populations ◽  
Functional Variation

ABSTRACTVariable Number Tandem Repeats (VNTRs) are composed of large tandemly repeated motifs, many of which are highly polymorphic in copy number. However, due to their large size and repetitive nature, they remain poorly studied. To investigate the regulatory potential of VNTRs, we used read-depth data from Illumina whole genome sequencing to perform association analysis between copy number of ~70,000 VNTRs (motif size ≥10bp) with both gene expression (404 samples in 48 tissues) and DNA methylation (235 samples in peripheral blood), identifying thousands of VNTRs that are associated with local gene expression (eVNTRs) and DNA methylation levels (mVNTRs). Using large-scale replication analysis in an independent cohort we validated 73-80% of signals observed in the two discovery cohorts, providing robust evidence to support that these represent genuine associations. Further, conditional analysis indicated that many eVNTRs and mVNTRs act as QTLs independently of other local variation. We also observed strong enrichments of eVNTRs and mVNTRs for regulatory features such as enhancers and promoters. Using the Human Genome Diversity Panel, we defined sets of VNTRs that show highly divergent copy numbers among human populations, show that these are enriched for regulatory effects on gene expression and epigenetics, and preferentially associate with genes that have been linked with human phenotypes through GWAS. Our study provides strong evidence supporting functional variation at thousands of VNTRs, and defines candidate sets of VNTRs, copy number variation of which potentially plays a role in numerous human phenotypes.

scholarly journals DNA Analysis by Restriction Enzyme (DARE) enables concurrent genomic and epigenomic characterization of single cells

2019 ◽  
Vol 47 (19) ◽  
pp. e122-e122
Author(s):  
Ramya Viswanathan ◽  
Elsie Cheruba ◽  
Lih Feng Cheow
Keyword(s):  
Dna Methylation ◽  
Restriction Enzyme ◽  
Copy Number ◽  
Dna Analysis ◽  
Whole Genome Amplification ◽  
Single Cells ◽  
Whole Genome ◽  
Copy Number Alterations ◽  
Genome Wide

Abstract Genome-wide profiling of copy number alterations and DNA methylation in single cells could enable detailed investigation into the genomic and epigenomic heterogeneity of complex cell populations. However, current methods to do this require complex sample processing and cleanup steps, lack consistency, or are biased in their genomic representation. Here, we describe a novel single-tube enzymatic method, DNA Analysis by Restriction Enzyme (DARE), to perform deterministic whole genome amplification while preserving DNA methylation information. This method was evaluated on low amounts of DNA and single cells, and provides accurate copy number aberration calling and representative DNA methylation measurement across the whole genome. Single-cell DARE is an attractive and scalable approach for concurrent genomic and epigenomic characterization of cells in a heterogeneous population.

scholarly journals Copy number alterations in urothelial carcinomas: their clinicopathological significance and correlation with DNA methylation alterations

2010 ◽  
Vol 32 (4) ◽  
pp. 462-469 ◽  
Author(s):  
Naotaka Nishiyama ◽  
Eri Arai ◽  
Ryo Nagashio ◽  
Hiroyuki Fujimoto ◽  
Fumie Hosoda ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Copy Number Alterations ◽  
Urothelial Carcinomas ◽  
Clinicopathological Significance

Comprehensive Genomic and DNA Methylation Analysis in Twins with ETV6-RUNX1 Acute Lymphoblastic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 597-597
Author(s):  
Manoo Bhakta ◽  
Mathias Ehrich ◽  
Eric J. Gratias ◽  
James R. Downing ◽  
Charles G Mullighan
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Copy Number Alterations ◽  
Methylation Analysis ◽  
Dna Copy Number ◽  
Dna Copy Number Alterations ◽  
Control Samples

Abstract DNA methylation as a source for epigenetic variability has been implicated in a variety of different cancer types. Often these studies are confounded by inter-individual differences in the epigenetic profiles. The pattern of epigenetic marks can be altered by factors like age, nutrition, behavior or other environmental factors, which are difficult to control. We had the unique opportunity to study DNA methylation profiles in a pair of monozygotic twin boys who developed ETV6-RUNX1 B-progenitor acute lymphoblastic leukemia at 2 years of age within 3 weeks of each other. ETV6-RUNX1 ALL is characterized by a high frequency of recurring genetic alterations, but the full complement of genomic and epigenetic alterations contributing to leukemogenesis is unknown. For these twin cases, environmental influences upon epigenetic variation are largely eliminated. We used a mass spectrometry-based quantitative DNA methylation analysis technique (Sequenom’s® EpiTYPER™ application) to investigate 597 amplicons covering the promoter regions of 190 genes. The genomic target regions were selected to be enriched for genes involved in transcriptional regulation (n=130) and/or genes known to be targeted by recurring DNA copy number alterations in childhood leukemia (n= 60). Methylation analysis were performed on DNA extracted from cryopreserved, Ficoll enriched bone leukemic blasts obtained from diagnostic bone marrow aspirates, and non-leukemic peripheral blood leukocytes obtained at remission. We also examined DNA copy number alterations (CNAs) and loss-of- heterozygosity (LOH) using Affymetrix single nucleotide polymorphism (SNP) 6.0 arrays, which examine over 1.8 million loci, in both tumor and normal tissue for both twins. Analysis of SNP array data identified different somatic CNAs in the tumor samples of the two twins involving 9p21.3 (the CDKN2A/B tumor suppressor locus), 12p13.2 (ETV6) and trisomy 21, indicating that the shared ETV6-RUNX1 positive pre-leukemic clone acquired different secondary genetic alterations during leukemogenesis in each twin. Despite these genetic differences, the methylation profiles of the tumor samples were remarkably similar. Unsupervised two-dimensional clustering of quantitative methylation data revealed that the tumor samples clustered separately from the control samples. Based on these findings we calculated the methylation differences in each genomic target region. A total of 51 genomic regions were significantly differentially methylated between tumor and control samples (paired t-test P<0.001, and an average methylation difference > 10%). Within the differentially methylated genomic regions, a subset of approximately 20 exhibited strong regional differences, indicating that DNA methylation changes can be limited to certain areas of the promoter. In the group of genes known to be involved in transcriptional regulation, 32% were differentially methylated, including the HOXA, HOXB, HOXC and HOXD regions, while in the remaining genes only 15% were differentially methylated. This enrichment is significant on the level of 0.05 (Fisher’s exact test, odds ratio: 2.7). This represents the first study comparing genomic and epigenetic alterations in B-precursor ALL involving monozygotic twins. Notably, different DNA copy number alterations are acquired in each twin during leukemogeneis. In contrast, the tumor samples exhibit similar methylation patterns that are strikingly different to control samples obtained from the same individuals. These results indicate that combined genomic and epigenetic analyses will be important to characterize the full repertoire of genomic alterations in acute lymphoblastic leukemia.

scholarly journals Hierarchical Discovery of Large-scale and Focal Copy Number Alterations in Low-coverage Cancer Genomes

2019 ◽  
Author(s):  
Ahmed Ibrahim Samir Khalil ◽  
Costerwell Khyriem ◽  
Anupam Chattopadhyay ◽  
Amartya Sanyal
Keyword(s):  
Copy Number ◽  
Large Scale ◽  
Simulated Data ◽  
Change Points ◽  
Copy Number Alterations ◽  
Biological Origin ◽  
Robust Detection ◽  
Cancer Data ◽  
Cancer Genomes ◽  
Low Coverage

AbstractMotivationDetection of copy number alterations (CNA) is critical to understand genetic diversity, genome evolution and pathological conditions such as cancer. Cancer genomes are plagued with widespread multi-level structural aberrations of chromosomes that pose challenges to discover CNAs of different length scales with distinct biological origin and function. Although several tools are available to identify CNAs using read depth (RD) of coverage, they fail to distinguish between large-scale and focal alterations due to inaccurate modeling of the RD signal of cancer genomes. These tools are also affected by RD signal variations, pronounced in low-coverage data, which significantly inflate false detection of change points and inaccurate CNA calling.ResultsWe have developed CNAtra to hierarchically discover and classify ‘large-scale’ and ‘focal’ copy number gain/loss from whole-genome sequencing (WGS) data. CNAtra provides an analytical and visualization framework for CNV profiling using single sequencing sample. CNAtra first utilizes multimodal distribution to estimate the copy number (CN) reference from the complex RD profile of the cancer genome. We utilized Savitzy-Golay filter and Modified Varri segmentation to capture the change points. We then developed a CN state-driven merging algorithm to identify the large segments with distinct copy number. Next, focal alterations were identified in each large segment using coverage-based thresholding to mitigate the adverse effects of signal variations. We tested CNAtra calls using experimentally verified segmental aneuploidies and focal alterations which confirmed CNAtra’s ability to detect and distinguish the two alteration phenomena. We used realistic simulated data for benchmarking the performance of CNAtra against other detection tools where we artificially spiked-in CNAs in the original cancer profiles. We found that CNAtra is superior in terms of precision, recall, and f-measure. CNAtra shows the highest sensitivity of 93% and 97% for detecting focal and large-scale alterations respectively. Visual inspection of CNAs showed that CNAtra is the most robust detection tool for low-coverage cancer data.Availability and implementationCNAtra is an open source software implemented in MATLAB, and is available at https://github.com/AISKhalil/CNAtra

scholarly journals A pan-cancer atlas of transcriptional dependence on DNA methylation and copy number aberrations

2020 ◽  
Author(s):  
Christian Fougner ◽  
Elen K. Höglander ◽  
Tonje G. Lien ◽  
Therese Sørlie ◽  
Silje Nord ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Copy Number ◽  
Normal Cell ◽  
Tumor Heterogeneity ◽  
Copy Number Alterations ◽  
Cell Of Origin ◽  
Online Tool ◽  
Copy Number Aberrations ◽  
Pan Cancer

AbstractCancer transcriptomes are shaped by genetic and epigenetic features, such as DNA methylation and copy number aberrations. Knowledge of the relationships between gene expression and such features is fundamental to understanding the basis of tumor phenotypes. Here, we present a pan-cancer atlas of transcriptional dependence on DNA methylation and copy number aberrations (PANORAMA). Our analyses suggest that copy number alterations are a central driver of inter-tumor heterogeneity, while the majority of expression-methylation associations found in cancer are a reflection of cell-of-origin and normal cell admixture. The atlas is made available through an online tool at https://pancancer.app.

scholarly journals Pathogenesis of Penile Squamous Cell Carcinoma: Molecular Update and Systematic Review

2021 ◽  
Vol 23 (1) ◽  
pp. 251
Author(s):  
Inmaculada Ribera-Cortada ◽  
José Guerrero-Pineda ◽  
Isabel Trias ◽  
Luis Veloza ◽  
Adriana Garcia ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Copy Number ◽  
Large Scale ◽  
Somatic Mutations ◽  
Genetic Alterations ◽  
Copy Number Alterations ◽  
Hpv Status ◽  
Penile Squamous Cell Carcinoma

Penile squamous cell carcinoma (PSCC) is a rare but aggressive neoplasm with dual pathogenesis (human papillomavirus (HPV)-associated and HPV-independent). The development of targeted treatment is hindered by poor knowledge of the molecular landscape of PSCC. We performed a thorough review of genetic alterations of PSCC focused on somatic mutations and/or copy number alterations. A total of seven articles have been identified which, overall, include 268 PSCC. However, the series are heterogeneous regarding methodologies employed for DNA sequencing and HPV detection together with HPV prevalence, and include, in general, a limited number of cases, which results in markedly different findings. Reported top-ranked mutations involve TP53, CDKN2A, FAT1, NOTCH-1 and PIK3CA. Numerical alterations involve gains in MYC and EGFR, as well as amplifications in HPV integration loci. A few genes including TP53, CDKN2A, PIK3CA and CCND1 harbor both somatic mutations and copy number alterations. Notch, RTK-RAS and Hippo pathways are frequently deregulated. Nevertheless, the relevance of the identified alterations, their role in signaling pathways or their association with HPV status remain elusive. Combined targeting of different pathways might represent a valid therapeutic approach in PSCC. This work calls for large-scale sequencing studies with robust HPV testing to improve the genomic understanding of PSCC.

scholarly journals Genetic alterations in the 3q26.31-32 locus confer an aggressive prostate cancer phenotype

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Benjamin S. Simpson ◽  
Niedzica Camacho ◽  
Hayley J. Luxton ◽  
Hayley Pye ◽  
Ron Finn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Copy Number ◽  
Large Scale ◽  
Genetic Alterations ◽  
Gleason Grade ◽  
Copy Number Alterations ◽  
Aggressive Prostate Cancer ◽  
Prostate Cancer Development ◽  
Transcriptional Changes ◽  
Cancer Phenotype

AbstractLarge-scale genetic aberrations that underpin prostate cancer development and progression, such as copy-number alterations (CNAs), have been described but the consequences of specific changes in many identified loci is limited. Germline SNPs in the 3q26.31 locus are associated with aggressive prostate cancer, and is the location of NAALADL2, a gene overexpressed in aggressive disease. The closest gene to NAALADL2 is TBL1XR1, which is implicated in tumour development and progression. Using publicly-available cancer genomic data we report that NAALADL2 and TBL1XR1 gains/amplifications are more prevalent in aggressive sub-types of prostate cancer when compared to primary cohorts. In primary disease, gains/amplifications occurred in 15.99% (95% CI: 13.02–18.95) and 14.96% (95% CI: 12.08–17.84%) for NAALADL2 and TBL1XR1 respectively, increasing in frequency in higher Gleason grade and stage tumours. Gains/amplifications result in transcriptional changes and the development of a pro-proliferative and aggressive phenotype. These results support a pivotal role for copy-number gains in this genetic region.

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