TMOD-23. MODELING PEDIATRIC BRAIN CANCER WITH HUMAN ORGANOIDS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi220-vi220
Author(s):  
Luca Tiberi
Keyword(s):  
Dna Methylation ◽  
Brain Cancer ◽  
Cancer Biology ◽  
Genetic Alterations ◽  
Cancer Model ◽  
The Past ◽  
Pediatric Medulloblastoma ◽  
Infant Brain ◽  
Human Ipsc ◽  
Pediatric Brain

Abstract Among children/infant brain tumors, Medulloblastoma (MB) is the most common and stands as a cause for a high percentage of morbidity and mortality among patients During the past few years, studies on human MB have uncovered the existence of four major MB groups: WNT, SHH, Group3 and Group4. Patients with Group3 MB currently have the worst outcome among the four groups, and nearly 50% are metastatic at the time of diagnosis. In the last 3 years in our laboratory, we have developed a novel pediatric Medulloblastoma organoid model. We generated human iPSC-derived cancer organoids upon c-MYC/OTX2 and C-MYC/Gfi1 overexpression, mimicking human MB genetic alterations. Furthermore, the use of DNA methylation signature in combination with MB-specific markers analysis indicates that our organoid-based cancer model recapitulates several features of human MB. Now, we are taking advantage of this technology to produce novel brain cancer organoids that we are using to address cancer biology questions.

scholarly journals Reliable tumor detection by whole-genome methylation sequencing of cell-free DNA in cerebrospinal fluid of pediatric medulloblastoma

2020 ◽  
Vol 6 (42) ◽  
pp. eabb5427
Author(s):  
Jia Li ◽  
Sibo Zhao ◽  
Minjung Lee ◽  
Yue Yin ◽  
Jin Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cerebrospinal Fluid ◽  
Low Frequency ◽  
Pediatric Medulloblastoma ◽  
Oncogenic Mutations ◽  
Genome Methylation ◽  
Epigenetic Analysis ◽  
Public Datasets ◽  
Pediatric Brain ◽  
Normal Cerebellum

Medulloblastoma (MB), the most common form of pediatric brain malignancy, has a low frequency of oncogenic mutations but pronouncedly abnormal DNA methylation changes. Epigenetic analysis of circulating cell-free tumor DNA (ctDNA) by liquid biopsy offers an approach for real-time monitoring of tumor status without tumor dissection. In this study, we identified 6598 differentially methylated CpGs in both MB tumors and the ctDNA isolated from matched cerebrospinal fluid (CSF) compared with normal cerebellum, which could be used to detect MB tumor occurrence and determine its subtype. Furthermore, DNA methylation changes in serial CSF samples could be used to monitor the treatment response and tumor recurrence. Integrating our data with large public datasets, we identified reliable MB DNA methylation signatures in ctDNA that have potential diagnostic and prognostic values. Our study sets the stage for exploiting epigenetic markers in CSF to improve the clinical management of patients with MB.

scholarly journals TMOD-05. GENOME-WIDE DNA METHYLATION PROFILE: A POWERFUL STRATEGY TO RECAPITULATE HETEROGENEITY OF PEDIATRIC BRAIN TUMORS IN PRIMARY CELL LINES

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i36-i36
Author(s):  
Lucia Pedace ◽  
Simone Pizzi ◽  
Maria Vinci ◽  
Giulia Pericoli ◽  
Giuseppina Catanzaro ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Lines ◽  
Pediatric Brain Tumors ◽  
Genetic Alterations ◽  
In Vitro Models ◽  
Primary Cell ◽  
Genome Wide ◽  
Primary Cell Lines ◽  
Pediatric Brain

Abstract Background Development of in vitro models of pediatric brain tumors (pBT) is instrumental for both understanding the contributing oncogenic molecular mechanisms and identifying and testing new therapeutic strategies. Primary cell lines should be established and managed to prevent epigenetic and genetic alterations and thus recapitulating the original tumor. DNA methylation (DM) is a stable epigenetic modification, altered in cancer and recently used to classify tumors. We aim to apply DM and Copy Number Variation (CNV) profiling to characterize pBT primary cell lines and tumors. Methods We investigated 34 pBT tissues from different histology paired to 52 their derived primary cultures in both 2D and 3D conditions, as stem-cells or in serum-supplemented medium, and both short and long-terms in culture. We studied 18 additional pBT-derived cell-lines, 9 organoids, 5 commercial cell-lines, and 122 pBT tissues from the same histological categories, as controls, for a total of 240 genome-wide DM profiles. We analyzed DM and CNV profiles by using Illumina EPIC-arrays. By means of a bump hunting strategy, we identified differentially methylated regions in faithful vs unfaithful cell lines, and performed a functional characterization using over-representation analysis. Results The 69% (25/36) of cells at early passages retained genetic alteration and the same DM patterns of the original tumors, with no differences related to 2D/3D methods or the presence of serum in media. The 70% (24/34) of primary cell lines analyzed at later passages (>5 or >14 days in culture) diverged from the primary tumor, the totality of those cultured with serum. All divergent cells clustered together acquiring common deregulated epigenetic signature induced by serum culture media, 2D methods and longer time in culture. Conclusions We have shown that global DM profiles, along with CNV analysis are useful tools to detect the recapitulation of pBT-derived primary cell-lines from the original tumor. Whatever subgroups tested, our results suggest that in vitro models should be passaged as little as possible to retain the epigenetic and genetic alterations of the tumors and thus to be considered relevant for basic and translational biology.

scholarly journals Perceptions and Opinions towards Cell Phone Use as a Risk Factor of Brain Cancer among University Students in Malaysia

2013 ◽  
Vol 4 (1) ◽  
pp. 1-4
Author(s):  
Redhwan Ahmed Al-Naggar ◽  
Yuri V Bobryshev
Keyword(s):  
University Students ◽  
Mobile Phones ◽  
Brain Cancer ◽  
Cell Phone ◽  
Cell Phones ◽  
Medical Sciences ◽  
Cell Phone Use ◽  
The Past ◽  
Carcinogenic Effects ◽  
Study Participants

The worldwide use of cell phones has rapidly increased over the past decades. With the increasing use of mobile phones, concern has been raised about the possible carcinogenic effects as a result of exposure to radiofrequency electromagnetic fields. The objective of this study was to explore the perceptions and opinions towards brain cancer related to cell phone use among university students in Malaysia. The study revealed that the majority of the study participants believe that there is no relationship between brain cancer and hand phone use.DOI: http://dx.doi.org/10.3126/ajms.v4i1.7808 Asian Journal of Medical Sciences 4(2013) 1-4

scholarly journals DNA Methylation Profiles of Tph1A and BDNF in Gut and Brain of L. Rhamnosus-Treated Zebrafish

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 142
Author(s):  
Mariella Cuomo ◽  
Luca Borrelli ◽  
Rosa Della Monica ◽  
Lorena Coretti ◽  
Giulia De Riso ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
The Past ◽  
Targeted Analysis ◽  
Lack Of Information ◽  
High Resolution Power ◽  
Resolution Level ◽  
Health And Disease ◽  
High Doses ◽  
The Brain

The bidirectional microbiota–gut–brain axis has raised increasing interest over the past years in the context of health and disease, but there is a lack of information on molecular mechanisms underlying this connection. We hypothesized that change in microbiota composition may affect brain epigenetics leading to long-lasting effects on specific brain gene regulation. To test this hypothesis, we used Zebrafish (Danio Rerio) as a model system. As previously shown, treatment with high doses of probiotics can modulate behavior in Zebrafish, causing significant changes in the expression of some brain-relevant genes, such as BDNF and Tph1A. Using an ultra-deep targeted analysis, we investigated the methylation state of the BDNF and Tph1A promoter region in the brain and gut of probiotic-treated and untreated Zebrafishes. Thanks to the high resolution power of our analysis, we evaluated cell-to-cell methylation differences. At this resolution level, we found slight DNA methylation changes in probiotic-treated samples, likely related to a subgroup of brain and gut cells, and that specific DNA methylation signatures significantly correlated with specific behavioral scores.

scholarly journals Aging-associated distinctive DNA methylation changes of LINE-1 retrotransposons in pure cell-free DNA from human blood

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Wardah Mahmood ◽  
Lars Erichsen ◽  
Pauline Ott ◽  
Wolfgang A. Schulz ◽  
Johannes C. Fischer ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Free Dna ◽  
The Past ◽  
Free Dna ◽  
Genome Wide ◽  
Cancerous Cell ◽  
Pure Cell ◽  
Epigenetic Biomarker ◽  
Methylation Patterns ◽  
Cancerous Cells

AbstractLINE-1 hypomethylation of cell-free DNA has been described as an epigenetic biomarker of human aging. However, in the past, insufficient differentiation between cellular and cell-free DNA may have confounded analyses of genome-wide methylation levels in aging cells. Here we present a new methodological strategy to properly and unambiguously extract DNA methylation patterns of repetitive, as well as single genetic loci from pure cell-free DNA from peripheral blood. Since this nucleic acid fraction originates mainly in apoptotic, senescent and cancerous cells, this approach allows efficient analysis of aged and cancerous cell-specific DNA methylation patterns for diagnostic and prognostic purposes. Using this methodology, we observe a significant age-associated erosion of LINE-1 methylation in cfDNA suggesting that the threshold of hypomethylation sufficient for relevant LINE-1 activation and consequential harmful retrotransposition might be reached at higher age. We speculate that this process might contribute to making aging the main risk factor for many cancers.

scholarly journals MODL-21. INTEGRATIVE APPROACHES IN FUNCTIONAL GENOMICS TO IDENTIFY GENETIC DEPENDENCIES IN PEDIATRIC BRAIN CANCER

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii415-iii415
Author(s):  
Claire Sun ◽  
Caroline Drinkwater ◽  
Dhanya Sooraj ◽  
Gabrielle Bradshaw ◽  
Claire Shi ◽  
...  
Keyword(s):  
Functional Genomics ◽  
Precision Medicine ◽  
Brain Cancer ◽  
Human Genomes ◽  
Pediatric Cancer Patients ◽  
Crispr Screen ◽  
The Central Nervous System ◽  
Molecular Aberrations ◽  
Genetic Profiles ◽  
Pediatric Brain

Abstract The precise decoding of human genomes facilitated by the advancements in next-generation sequencing has led to a better understanding of genetic underpinnings of pediatric brain cancers. Indeed, it is now evident that tumours of the same type harbour distinct driving mutations and molecular aberrations that can result in different prognosis and treatment outcomes. The profounder insight into the the identity, amount and types of molecular aberrations has paved the way for the advent of targeted therapies in precision medicine. Nevertheless, less than 10% of pediatric cancer patients harbour actionable mutations. Strictly limited therapeutic options that are firstly available for brain cancers and secondly acceptable for children’s development further impede the breakthrough in the survival rate in pediatric brain cancers. This underscores a desperate need to delve beyond genomic sequencing to identify biomarker coupled therapies that not only featured with treatment efficacy in the central nervous system but also acceptable side effects for children. The Hudson-Monash Paediatric Precision Medicine (HMPPM) Program focuses on utilising genetic profiles of patients’ tumour models to identify new therapeutic targets and repurpose existing ones using high-throughput functional genomics screens (2220 drugs and CRISPR screen of 300 oncogenic genes). Using a large compendium of over sixty patient derived paediatric brain cancer models, we provide proof-of-concept data that shows an integrative pipeline for functional genomics with multi-omics datasets to perform genotype-phenotype correlations and, therefore, identify genetic dependencies. Herein, using several examples in ATRT, DIPG and HGG, we show how functional interrogations can better define molecular subclassification of tumours and identify unique vulnerabilities.

3D RECONSTRUCTION OF BREAST CANCER FROM MAMMOGRAMS USING VOLUME RENDERING TECHNIQUES

2015 ◽  
Vol 75 (2) ◽  
Author(s):  
Ho Wei Yong ◽  
Abdullah Bade ◽  
Rajesh Kumar Muniandy
Keyword(s):  
Breast Cancer ◽  
3D Reconstruction ◽  
Computational Cost ◽  
Reconstruction Method ◽  
Cancer Model ◽  
Volume Reconstruction ◽  
The Past ◽  
Breast Cancer Model ◽  
Reconstruction Software ◽  
To Come

Over the past thirty years, a number of researchers have investigated on 3D organ reconstruction from medical images and there are a few 3D reconstruction software available on the market. However, not many researcheshave focused on3D reconstruction of breast cancer’s tumours. Due to the method complexity, most 3D breast cancer’s tumours reconstruction were done based on MRI slices dataeven though mammogram is the current clinical practice for breast cancer screening. Therefore, this research will investigate the process of creating a method that will be able to reconstruct 3D breast cancer’s tumours from mammograms effectively.  Several steps were proposed for this research which includes data acquisition, volume reconstruction, andvolume rendering. The expected output from this research is the 3D breast cancer’s tumours model that is generated from correctly registered mammograms. The main purpose of this research is to come up with a 3D reconstruction method that can produce good breast cancer model from mammograms while using minimal computational cost.

scholarly journals EWAS Data Hub: a resource of DNA methylation array data and metadata

2019 ◽  
Vol 48 (D1) ◽  
pp. D890-D895 ◽  
Author(s):  
Zhuang Xiong ◽  
Mengwei Li ◽  
Fei Yang ◽  
Yingke Ma ◽  
Jian Sang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Complex Traits ◽  
Cell Types ◽  
Great Promise ◽  
Methylation Array ◽  
Array Data ◽  
The Past ◽  
Comprehensive Collection ◽  
Dna Methylation Array ◽  
Brain Parts

Abstract Epigenome-Wide Association Study (EWAS) has become an effective strategy to explore epigenetic basis of complex traits. Over the past decade, a large amount of epigenetic data, especially those sourced from DNA methylation array, has been accumulated as the result of numerous EWAS projects. We present EWAS Data Hub (https://bigd.big.ac.cn/ewas/datahub), a resource for collecting and normalizing DNA methylation array data as well as archiving associated metadata. The current release of EWAS Data Hub integrates a comprehensive collection of DNA methylation array data from 75 344 samples and employs an effective normalization method to remove batch effects among different datasets. Accordingly, taking advantages of both massive high-quality DNA methylation data and standardized metadata, EWAS Data Hub provides reference DNA methylation profiles under different contexts, involving 81 tissues/cell types (that contain 25 brain parts and 25 blood cell types), six ancestry categories, and 67 diseases (including 39 cancers). In summary, EWAS Data Hub bears great promise to aid the retrieval and discovery of methylation-based biomarkers for phenotype characterization, clinical treatment and health care.

scholarly journals Dysregulated TET Family Genes and Aberrant 5mC Oxidation in Breast Cancer: Causes and Consequences

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6039
Author(s):  
Bo Xu ◽  
Hao Wang ◽  
Li Tan
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Embryonic Development ◽  
Cellular Differentiation ◽  
Epigenetic Modification ◽  
Current Understanding ◽  
Future Perspectives ◽  
Cancer Hallmarks ◽  
The Past

DNA methylation (5-methylcytosine, 5mC) was once viewed as a stable epigenetic modification until Rao and colleagues identified Ten-eleven translocation 1 (TET1) as the first 5mC dioxygenase in 2009. TET family genes (including TET1, TET2, and TET3) encode proteins that can catalyze 5mC oxidation and consequently modulate DNA methylation, not only regulating embryonic development and cellular differentiation, but also playing critical roles in various physiological and pathophysiological processes. Soon after the discovery of TET family 5mC dioxygenases, aberrant 5mC oxidation and dysregulation of TET family genes have been reported in breast cancer as well as other malignancies. The impacts of aberrant 5mC oxidation and dysregulated TET family genes on the different aspects (so-called cancer hallmarks) of breast cancer have also been extensively investigated in the past decade. In this review, we summarize current understanding of the causes and consequences of aberrant 5mC oxidation in the pathogenesis of breast cancer. The challenges and future perspectives of this field are also discussed.

scholarly journals MBRS-14. INTEGRATING CLINICAL AND GENOMIC CHARACTERISTICS IN PEDIATRIC MEDULLOBLASTOMA SUBTYPES IN A SINGLE COHORT IN TAIWAN

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii400-iii401
Author(s):  
Kuo-Sheng Wu ◽  
Tai-Tong Wong
Keyword(s):  
Dna Methylation ◽  
Cluster Analysis ◽  
Treatment Strategies ◽  
Clinical Results ◽  
Tumor Location ◽  
Molecular Subgroups ◽  
Methylation Array ◽  
Metastatic Rate ◽  
Pediatric Medulloblastoma ◽  
Dna Methylation Array

Abstract BACKGROUND Medulloblastoma (MB) was classified to 4 molecular subgroups: WNT, SHH, group 3 (G3), and group 4 (G4) with the demographic and clinical differences. In 2017, The heterogeneity within MB was proposed, and 12 subtypes with distinct molecular and clinical characteristics. PATIENTS AND METHODS: PATIENTS AND METHODS We retrieved 52 MBs in children to perform RNA-Seq and DNA methylation array. Subtype cluster analysis performed by similarity network fusion (SNF) method. With clinical results and molecular profiles, the characteristics including age, gender, histological variants, tumor location, metastasis status, survival, cytogenetic and genetic aberrations among MB subtypes were identified. RESULTS In this cohort series, 52 childhood MBs were classified into 11 subtypes by SNF cluster analysis. WNT tumors shown no metastasis and 100% survival rate. All WNT tumors located on midline in 4th ventricle. Monosomy 6 presented in WNT α, but not in β subtype. SHH α and β occurred in children, while SHH γ in infant. Among SHH tumors, α subtype showed the worst outcome. G3 γ showed the highest metastatic rate and worst survival associated with MYC amplification. G4 α has the highest metastatic rate, however G4 γ showed the worst survival. CONCLUSION We identified molecular subgroups and subtypes of MBs based on gene expression and DNA methylation profile in children in our cohort series. The results may contribute to the establishment of nation-wide correlated optimal diagnosis and treatment strategies for MBs in infant and children.

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