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1. Quantifying intra-tumoral genetic heterogeneity of glioblastoma toward precision medicine using MRI and a data-inclusive machine learning algorithm

Author

Wang, Lujia, Wang, Hairong, D'Angelo, Fulvio, Curtin, Lee, Sereduk, Christopher P., De Leon, Gustavo, Singleton, Kyle W., Urcuyo, Javier, Hawkins-Daarud, Andrea, Jackson, Pamela R., Krishna, Chandan, Zimmerman, Richard S., Patra, Devi P., Bendok, Bernard R., Smith, Kris A., Nakaji, Peter, Donev, Kliment, Baxter, Leslie C., Mrugała, Maciej M., Ceccarelli, Michele, Iavarone, Antonio, Swanson, Kristin R., Tran, Nhan L., Hu, Leland S., and Li, Jing

Subjects
Computer Science - Machine Learning, Computer Science - Computer Vision and Pattern Recognition, Mathematics - Optimization and Control
Abstract

Glioblastoma (GBM) is one of the most aggressive and lethal human cancers. Intra-tumoral genetic heterogeneity poses a significant challenge for treatment. Biopsy is invasive, which motivates the development of non-invasive, MRI-based machine learning (ML) models to quantify intra-tumoral genetic heterogeneity for each patient. This capability holds great promise for enabling better therapeutic selection to improve patient outcomes. We proposed a novel Weakly Supervised Ordinal Support Vector Machine (WSO-SVM) to predict regional genetic alteration status within each GBM tumor using MRI. WSO-SVM was applied to a unique dataset of 318 image-localized biopsies with spatially matched multiparametric MRI from 74 GBM patients. The model was trained to predict the regional genetic alteration of three GBM driver genes (EGFR, PDGFRA, and PTEN) based on features extracted from the corresponding region of five MRI contrast images. For comparison, a variety of existing ML algorithms were also applied. The classification accuracy of each gene was compared between the different algorithms. The SHapley Additive exPlanations (SHAP) method was further applied to compute contribution scores of different contrast images. Finally, the trained WSO-SVM was used to generate prediction maps within the tumoral area of each patient to help visualize the intra-tumoral genetic heterogeneity. This study demonstrated the feasibility of using MRI and WSO-SVM to enable non-invasive prediction of intra-tumoral regional genetic alteration for each GBM patient, which can inform future adaptive therapies for individualized oncology., Comment: 36 pages, 8 figures, 3 tables

Published
2023

2. Glioma progression is shaped by genetic evolution and microenvironment interactions

Author

Varn, Frederick S, Johnson, Kevin C, Martinek, Jan, Huse, Jason T, Nasrallah, MacLean P, Wesseling, Pieter, Cooper, Lee AD, Malta, Tathiane M, Wade, Taylor E, Sabedot, Thais S, Brat, Daniel, Gould, Peter V, Wöehrer, Adelheid, Aldape, Kenneth, Ismail, Azzam, Sivajothi, Santhosh K, Barthel, Floris P, Kim, Hoon, Kocakavuk, Emre, Ahmed, Nazia, White, Kieron, Datta, Indrani, Moon, Hyo-Eun, Pollock, Steven, Goldfarb, Christine, Lee, Ga-Hyun, Garofano, Luciano, Anderson, Kevin J, Nehar-Belaid, Djamel, Barnholtz-Sloan, Jill S, Bakas, Spyridon, Byrne, Annette T, D’Angelo, Fulvio, Gan, Hui K, Khasraw, Mustafa, Migliozzi, Simona, Ormond, D Ryan, Paek, Sun Ha, Van Meir, Erwin G, Walenkamp, Annemiek ME, Watts, Colin, Weiss, Tobias, Weller, Michael, Palucka, Karolina, Stead, Lucy F, Poisson, Laila M, Noushmehr, Houtan, Iavarone, Antonio, Verhaak, Roel GW, Consortium, The GLASS, Alfaro, Kristin D, Amin, Samirkumar B, Ashley, David M, Bock, Christoph, Brodbelt, Andrew, Bulsara, Ketan R, and Castro, Ana Valeria

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Brain Disorders, Brain Cancer, Genetics, Cancer, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Adult, Brain Neoplasms, Evolution, Molecular, Genes, p16, Glioma, Humans, Isocitrate Dehydrogenase, Mutation, Neoplasm Recurrence, Local, Tumor Microenvironment, GLASS Consortium, genomics, glioblastoma, glioma, hypermutation, macrophages, microenvironment, neurons, single-cell, spatial imaging, treatment resistance, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

Published
2022

3. Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures

Author

Hu, Leland S., D’Angelo, Fulvio, Weiskittel, Taylor M., Caruso, Francesca P., Fortin Ensign, Shannon P., Blomquist, Mylan R., Flick, Matthew J., Wang, Lujia, Sereduk, Christopher P., Meng-Lin, Kevin, De Leon, Gustavo, Nespodzany, Ashley, Urcuyo, Javier C., Gonzales, Ashlyn C, Curtin, Lee, Lewis, Erika M., Singleton, Kyle W., Dondlinger, Timothy, Anil, Aliya, Semmineh, Natenael B., Noviello, Teresa, Patel, Reyna A., Wang, Panwen, Wang, Junwen, Eschbacher, Jennifer M., Hawkins-Daarud, Andrea, Jackson, Pamela R., Grunfeld, Itamar S., Elrod, Christian, Mazza, Gina L., McGee, Sam C., Paulson, Lisa, Clark-Swanson, Kamala, Lassiter-Morris, Yvette, Smith, Kris A., Nakaji, Peter, Bendok, Bernard R., Zimmerman, Richard S., Krishna, Chandan, Patra, Devi P., Patel, Naresh P., Lyons, Mark, Neal, Matthew, Donev, Kliment, Mrugala, Maciej M., Porter, Alyx B., Beeman, Scott C., Jensen, Todd R., Schmainda, Kathleen M., Zhou, Yuxiang, Baxter, Leslie C., Plaisier, Christopher L., Li, Jing, Li, Hu, Lasorella, Anna, Quarles, C. Chad, Swanson, Kristin R., Ceccarelli, Michele, Iavarone, Antonio, and Tran, Nhan L.

Published
2023
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4. Temporospatial genomic profiling in glioblastoma identifies commonly altered core pathways underlying tumor progression

Author

Blomquist, Mylan R, Ensign, Shannon Fortin, D’Angelo, Fulvio, Phillips, Joanna J, Ceccarelli, Michele, Peng, Sen, Halperin, Rebecca F, Caruso, Francesca P, Garofano, Luciano, Byron, Sara A, Liang, Winnie S, Craig, David W, Carpten, John D, Prados, Michael D, Trent, Jeffrey M, Berens, Michael E, Iavarone, Antonio, Dhruv, Harshil, and Tran, Nhan L

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Brain Cancer, Rare Diseases, Genetics, Human Genome, Cancer, Neurosciences, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, clonal evolution, contrast enhancement, glioblastoma, PI3K signaling, temporospatial heterogeneity
Abstract

BackgroundTumor heterogeneity underlies resistance and disease progression in glioblastoma (GBM), and tumors most commonly recur adjacent to the surgical resection margins in contrast non-enhancing (NE) regions. To date, no targeted therapies have meaningfully altered overall patient survival in the up-front setting. The aim of this study was to characterize intratumoral heterogeneity in recurrent GBM using bulk samples from primary resection and recurrent samples taken from contrast-enhancing (EN) and contrast NE regions.MethodsWhole exome and RNA sequencing were performed on matched bulk primary and multiple recurrent EN and NE tumor samples from 16 GBM patients who received standard of care treatment alone or in combination with investigational clinical trial regimens.ResultsPrivate mutations emerge across multi-region sampling in recurrent tumors. Genomic clonal analysis revealed increased enrichment in gene alterations regulating the G2M checkpoint, Kras signaling, Wnt signaling, and DNA repair in recurrent disease. Subsequent functional studies identified augmented PI3K/AKT transcriptional and protein activity throughout progression, validated by phospho-protein levels. Moreover, a mesenchymal transcriptional signature was observed in recurrent EN regions, which differed from the proneural signature in recurrent NE regions.ConclusionsSubclonal populations observed within bulk resected primary GBMs transcriptionally evolve across tumor recurrence (EN and NE regions) and exhibit aberrant gene expression of common signaling pathways that persist despite standard or targeted therapy. Our findings provide evidence that there are both adaptive and clonally mediated dependencies of GBM on key pathways, such as the PI3K/AKT axis, for survival across recurrences.

Published
2020

6. Quantifying intra-tumoral genetic heterogeneity of glioblastoma toward precision medicine using MRI and a data-inclusive machine learning algorithm

Author

Wang, Lujia, primary, Wang, Hairong, additional, D’Angelo, Fulvio, additional, Curtin, Lee, additional, Sereduk, Christopher P., additional, Leon, Gustavo De, additional, Singleton, Kyle W., additional, Urcuyo, Javier, additional, Hawkins-Daarud, Andrea, additional, Jackson, Pamela R., additional, Krishna, Chandan, additional, Zimmerman, Richard S., additional, Patra, Devi P., additional, Bendok, Bernard R., additional, Smith, Kris A., additional, Nakaji, Peter, additional, Donev, Kliment, additional, Baxter, Leslie C., additional, Mrugała, Maciej M., additional, Ceccarelli, Michele, additional, Iavarone, Antonio, additional, Swanson, Kristin R., additional, Tran, Nhan L., additional, Hu, Leland S., additional, and Li, Jing, additional

Published
2024
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7. First access to mental health services during COVID-19 pandemic: A multicenter study

Author

Eleonora Petri, Cristina Nardoni, Erika Fui, Elisa Gulino, Lachheb Abdelghani, Raffaele Barone, Paolo Angelo Fulvio Miragoli, Giuseppe Cardamone, and Agnese Ciberti

Subjects
Depression, Anxiety, post-traumatic, COVID-19, Pandemic, Mental health services, Mental healing, RZ400-408
Abstract

Background: The impact of the COVID-19 pandemic on mental health is complex and affects a broad segment of the population. Several studies indicate that depressive, anxious and post-traumatic symptoms are common in people exposed to SARS-Cov2.Methods: 458 subjects were recruited during their first consultation in outpatient psychiatric services between June 2020 and October 2021. Post-traumatic, depressive and anxious symptoms were assessed using the Impact of Event Scale-Revised (IES-R), the Beck Depression Inventory Scale-second edition (BDI-II), and the Self Rating Anxiety Scale (SAS). A specific set of questions was developed, with the aim of evaluating socio-demographic variables and work, environmental and personal characteristics related to the pandemic.Results: Prevalence rates of clinically significant depressive, anxious and post-traumatic symptoms were 57.6%, 63.5% and 54.8%, respectively. Female gender, worsening of relationship status and financial consequences due to the pandemic were the conditions most strongly associated with the presence of psychopathology.Limitation: The cross-sectional design of the study doesn't allow an evaluation over time of the sample. No assumption of causality can be made due to the lack of pre-pandemic assessments for the investigated variables.Conclusions: The impact of the pandemic involves depressive, anxious and post-traumatic dimensions. The investigated psychopathology correlates with several variables expressing the personal and environmental changes that occurred in the population due to the COVID-19 emergency. The study is multicentric and the recruitment of participants was held in a clinical setting, providing a realistic picture of the consequences of the pandemic in clinical practice within mental health services.

Published
2023
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9. Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma

Author

Ceccarelli, Michele, Barthel, Floris P, Malta, Tathiane M, Sabedot, Thais S, Salama, Sofie R, Murray, Bradley A, Morozova, Olena, Newton, Yulia, Radenbaugh, Amie, Pagnotta, Stefano M, Anjum, Samreen, Wang, Jiguang, Manyam, Ganiraju, Zoppoli, Pietro, Ling, Shiyun, Rao, Arjun A, Grifford, Mia, Cherniack, Andrew D, Zhang, Hailei, Poisson, Laila, Carlotti, Carlos Gilberto, da Cunha Tirapelli, Daniela Pretti, Rao, Arvind, Mikkelsen, Tom, Lau, Ching C, Yung, WK Alfred, Rabadan, Raul, Huse, Jason, Brat, Daniel J, Lehman, Norman L, Barnholtz-Sloan, Jill S, Zheng, Siyuan, Hess, Kenneth, Rao, Ganesh, Meyerson, Matthew, Beroukhim, Rameen, Cooper, Lee, Akbani, Rehan, Wrensch, Margaret, Haussler, David, Aldape, Kenneth D, Laird, Peter W, Gutmann, David H, Network, TCGA Research, Arachchi, Harindra, Auman, J Todd, Balasundaram, Miruna, Balu, Saianand, Barnett, Gene, Baylin, Stephen, Bell, Sue, Benz, Christopher, Bir, Natalie, Black, Keith L, Bodenheimer, Tom, Boice, Lori, Bootwalla, Moiz S, Bowen, Jay, Bristow, Christopher A, Butterfield, Yaron SN, Chen, Qing-Rong, Chin, Lynda, Cho, Juok, Chuah, Eric, Chudamani, Sudha, Coetzee, Simon G, Cohen, Mark L, Colman, Howard, Couce, Marta, D’Angelo, Fulvio, Davidsen, Tanja, Davis, Amy, Demchok, John A, Devine, Karen, Ding, Li, Duell, Rebecca, Elder, J Bradley, Eschbacher, Jennifer M, Fehrenbach, Ashley, Ferguson, Martin, Frazer, Scott, Fuller, Gregory, Fulop, Jordonna, Gabriel, Stacey B, Garofano, Luciano, Gastier-Foster, Julie M, Gehlenborg, Nils, Gerken, Mark, Getz, Gad, Giannini, Caterina, Gibson, William J, Hadjipanayis, Angela, Hayes, D Neil, Heiman, David I, Hermes, Beth, Hilty, Joe, Hoadley, Katherine A, Hoyle, Alan P, and Huang, Mei

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Bioinformatics and Computational Biology, Genetics, Oncology and Carcinogenesis, Orphan Drug, Brain Cancer, Brain Disorders, Biotechnology, Human Genome, Rare Diseases, Neurosciences, Cancer, Adult, Brain Neoplasms, Cell Proliferation, Cluster Analysis, DNA Helicases, DNA Methylation, Epigenesis, Genetic, Glioma, Humans, Isocitrate Dehydrogenase, Middle Aged, Mutation, Nuclear Proteins, Promoter Regions, Genetic, Signal Transduction, Telomerase, Telomere, Transcriptome, X-linked Nuclear Protein, TCGA Research Network, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.

Published
2016

10. The molecular landscape of glioma in patients with Neurofibromatosis 1

Author

D’Angelo, Fulvio, Ceccarelli, Michele, Tala, Garofano, Luciano, Zhang, Jing, Frattini, Véronique, Caruso, Francesca P., Lewis, Genevieve, Alfaro, Kristin D., Bauchet, Luc, Berzero, Giulia, Cachia, David, Cangiano, Mario, Capelle, Laurent, de Groot, John, DiMeco, Francesco, Ducray, François, Farah, Walid, Finocchiaro, Gaetano, Goutagny, Stéphane, Kamiya-Matsuoka, Carlos, Lavarino, Cinzia, Loiseau, Hugues, Lorgis, Véronique, Marras, Carlo E., McCutcheon, Ian, Nam, Do-Hyun, Ronchi, Susanna, Saletti, Veronica, Seizeur, Romuald, Slopis, John, Suñol, Mariona, Vandenbos, Fanny, Varlet, Pascale, Vidaud, Dominique, Watts, Colin, Tabar, Viviane, Reuss, David E., Kim, Seung-Ki, Meyronet, David, Mokhtari, Karima, Salvador, Hector, Bhat, Krishna P., Eoli, Marica, Sanson, Marc, Lasorella, Anna, and Iavarone, Antonio

Published
2019
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11. Abstract 5621: Multi-parametric MRI maps regional heterogeneity of high grade glioma phenotypes

Author

Flick, Matthew, primary, Weiskittel, Taylor, additional, Meng-Lin, Kevin, additional, D'Angelo, Fulvio, additional, Caruso, Francesca, additional, Ensign, Shannon, additional, Blomquist, Mylan, additional, Wang, Luija, additional, Sereduk, Christopher, additional, De Leon, Gustavo, additional, Nespodzany, Ashley, additional, Urcuyo, Javier, additional, Gonzalez, Ashlynn, additional, Curtin, Lee, additional, Singleton, Kyle, additional, Anil, Aliya, additional, Simmineh, Natenael, additional, Lewis, Erika, additional, Noviello, Teresa, additional, Patel, Reyna, additional, Wang, Panwen, additional, Wang, Junwen, additional, Eschbacher, Jennifer, additional, Hawkins-Daarud, Andrea, additional, Jackson, Pamela, additional, Smith, Kris, additional, Nakaji, Peter, additional, Bendok, Bernard, additional, Zimmerman, Richard, additional, Krishna, Chandan, additional, Patra, Devi, additional, Patel, Naresh, additional, Lyons, Mark, additional, Neal, Matthew, additional, Donev, Kliment, additional, Mrugala, Maciej, additional, Porter, Alyx, additional, Beeman, Scott, additional, Zhou, Yuxiang, additional, Baxter, Leslie, additional, Plaisier, Christopher, additional, Li, Jing, additional, Li, Hu, additional, Lasorella, Anna, additional, Quarles, Chad, additional, Swanson, Kristin, additional, Ceccarelli, Michele, additional, Iavarone, Antonio, additional, Tran, Nhan, additional, and Hu, Leland, additional

Published
2023
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12. Abstract 1507: Multiregional sampling of high grade glioma identifies regional biologic signatures

Author

Blomquist, Mylan R., primary, Hu, Leland S., additional, D'Angelo, Fulvio, additional, Weiskittel, Taylor M., additional, Caruso, Francesca P., additional, Ensign, Shannon P. Fortin, additional, Sereduk, Christopher, additional, De Leon, Gustavo, additional, Curtin, Lee, additional, Urcuyo, Javier, additional, Gonzalez, Ashlynn, additional, Nespodzany, Ashley, additional, Noviello, Teresa, additional, Eschbacher, Jennifer M., additional, Smith, Kris A., additional, Nakaji, Peter, additional, Bendok, Bernard R., additional, Zimmerman, Richard S., additional, Krishna, Chandan, additional, Patra, Devi, additional, Patel, Naresh, additional, Lyons, Mark, additional, Donev, Kliment, additional, Mrugala, Maciej, additional, Porter, Alyx, additional, Lasorella, Anna, additional, Swanson, Kristin R., additional, Ceccarelli, Michele, additional, Iavarone, Antonio, additional, and Tran, Nhan L., additional

Published
2023
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15. EPCO-03. PATHWAY-BASED STRATIFICATION OF GLIOBLASTOMA BY MULTI-OMICS INFORMS SUBTYPE-SPECIFIC MASTER KINASES-PHOSPHOSITE SUBSTRATES

Author

Migliozzi, Simona, primary, Oh, Young Taek, additional, Hasanain, Mohammad, additional, Garofano, Luciano, additional, D'Angelo, Fulvio, additional, Picca, Alberto, additional, Bielle, Franck, additional, Sarkaria, Jann, additional, Ceccarelli, Michele, additional, Sanson, Marc, additional, Lasorella, Anna, additional, and Iavarone, Antonio, additional

Published
2022
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16. EXTH-21. DEVELOPMENT OF THERAPEUTIC STRATEGIES BY PATHWAY-BASED MULTI-OMICS APPROACH AND MASTER KINASE ANALYSIS IN GLIOBLASTOMA MULTIFORME

Author

Oh, Michael, primary, Hasanain, Mohammad, additional, Migliozzi, Simona, additional, Garofano, Luciano, additional, D'Angelo, Fulvio, additional, Stefano, Anna Luisa Di, additional, Lerond, Julie, additional, Sarkaria, Jann, additional, Ceccarelli, Michele, additional, Sanson, Marc, additional, Lasorella, Anna, additional, and Iavarone, Antonio, additional

Published
2022
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18. CSIG-01. EGFR AND AXL RECEPTOR TYROSINE KINASES DRIVE ONCOGENESIS BY LZTR1 MUTATION

Author

Ko, Aram, primary, Hasanain, Mohammad, additional, Oh, Young Taek, additional, D'Angelo, Fulvio, additional, Sommer, Danika, additional, Frangaj, Brulinda, additional, Tran, Suzanne, additional, Bielle, Franck, additional, Pollo, Bianca, additional, Paterra, Rosina, additional, Mokhtari, Karima, additional, Soni, Rajesh, additional, Peyre, Matthieu, additional, Eoli, Marica, additional, Kalamarides, Michel, additional, Sanson, Marc, additional, Iavarone, Antonio, additional, and Lasorella, Anna, additional

Published
2022
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19. Abstract 4014: Pathway based analysis of glioblastoma by multi-omics with applications in targeted therapy, prognosis and probabilistic classification

Author

Migliozzi, Simona, primary, Oh, Young Taek, additional, Garofano, Luciano, additional, Mohammad, Hasanain, additional, D'Angelo, Fulvio, additional, Najac, Ryan D., additional, Bielle, Franck, additional, Mokhtari, Karima, additional, Sarkaria, Jann N., additional, Ceccarelli, Michele, additional, Sanson, Marc, additional, Lasorella, Anna, additional, and Iavarone, Antonio, additional

Published
2022
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20. Abstract 770: Multiregional imaging and genomic analysis in high-grade IDH-mutant astrocytoma identifies intratumor subclones with aggressive features

Author

Ensign, Shannon P. Fortin, primary, D'Angelo, Fulvio, additional, Caruso, Francesca P., additional, Sereduk, Christopher, additional, Singleton, Kyle, additional, Eschbacher, Jennifer, additional, Mazza, Gina, additional, Mrugala, Maciej, additional, Porter, Alyx, additional, Bendok, Bernard, additional, Zimmerman, Richard, additional, Smith, Kris, additional, Nakaji, Peter, additional, Swanson, Kamala, additional, Wang, Junwen, additional, Semmineh, Nathenael, additional, Quarles, Christopher, additional, Lasorella, Anna, additional, Swanson, Kristin, additional, Ceccarelli, Michele, additional, Iavarone, Antonio, additional, Hu, Leland, additional, and Tran, Nhan L., additional

Published
2022
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21. CSIG-08. ABT-414 RESISTANT GBM TUMORS HARBOR THE TEK S466I MUTATION AND EXHIBIT INCREASED STEMNESS

Author

Blomquist, Mylan, primary, Noviello, Teresa, additional, D'Angelo, Fulvio, additional, Sereduk, Christopher, additional, Rabichow, Benjamin, additional, Miller, Aunay, additional, Marin, Bianca-Maria, additional, White, Forest, additional, Sarkaria, Jann, additional, Lasorella, Anna, additional, Iavarone, Antonio, additional, Ceccarelli, Michele, additional, and Tran, Nhan, additional

Published
2021
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22. EPCO-09. LONGITUDINAL ANALYSIS OF DIFFUSE GLIOMA REVEALS CELL STATE DYNAMICS AT RECURRENCE ASSOCIATED WITH CHANGES IN GENETICS AND THE MICROENVIRONMENT

Author

Varn, Frederick, primary, Johnson, Kevin, additional, Wade, Taylor, additional, Malta, Tathiane, additional, Sabedot, Thais, additional, Barthel, Floris, additional, Kim, Hoon, additional, Ahmed, Nazia, additional, Datta, Indrani, additional, Barnholtz-Sloan, Jill, additional, Bakas, Spyridon, additional, D'Angelo, Fulvio, additional, Gan, Hui, additional, Garofano, Luciano, additional, Huse, Jason, additional, Khasraw, Mustafa, additional, Kocakavuk, Emre, additional, Migliozzi, Simona, additional, Ormond, David, additional, Paek, Sun Ha, additional, Van Meir, Erwin, additional, Walenkamp, Annemiek, additional, Watts, Colin, additional, Weller, Michael, additional, Weiss, Tobias, additional, Wesseling, Pieter, additional, Stead, Lucy, additional, Poisson, Laila, additional, Noushmehr, Houtan, additional, Iavarone, Antonio, additional, and Verhaak, Roel, additional

Published
2021
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24. Dysregulation of Principal Cell miRNAs Facilitates Epigenetic Regulation of AQP2 and Results in Nephrogenic Diabetes Insipidus

Author

Petrillo, Federica, primary, Iervolino, Anna, additional, Angrisano, Tiziana, additional, Jelen, Sabina, additional, Costanzo, Vincenzo, additional, D’Acierno, Mariavittoria, additional, Cheng, Lei, additional, Wu, Qi, additional, Guerriero, Ilaria, additional, Mazzarella, Maria Cristina, additional, De Falco, Alfonso, additional, D’Angelo, Fulvio, additional, Ceccarelli, Michele, additional, Caraglia, Michele, additional, Capasso, Giovambattista, additional, Fenton, Robert A., additional, and Trepiccione, Francesco, additional

Published
2021
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25. Proteogenomic and metabolomic characterization of human glioblastoma

Author

Wang, Liang-Bo, primary, Karpova, Alla, additional, Gritsenko, Marina A., additional, Kyle, Jennifer E., additional, Cao, Song, additional, Li, Yize, additional, Rykunov, Dmitry, additional, Colaprico, Antonio, additional, Rothstein, Joseph H., additional, Hong, Runyu, additional, Stathias, Vasileios, additional, Cornwell, MacIntosh, additional, Petralia, Francesca, additional, Wu, Yige, additional, Reva, Boris, additional, Krug, Karsten, additional, Pugliese, Pietro, additional, Kawaler, Emily, additional, Olsen, Lindsey K., additional, Liang, Wen-Wei, additional, Song, Xiaoyu, additional, Dou, Yongchao, additional, Wendl, Michael C., additional, Caravan, Wagma, additional, Liu, Wenke, additional, Cui Zhou, Daniel, additional, Ji, Jiayi, additional, Tsai, Chia-Feng, additional, Petyuk, Vladislav A., additional, Moon, Jamie, additional, Ma, Weiping, additional, Chu, Rosalie K., additional, Weitz, Karl K., additional, Moore, Ronald J., additional, Monroe, Matthew E., additional, Zhao, Rui, additional, Yang, Xiaolu, additional, Yoo, Seungyeul, additional, Krek, Azra, additional, Demopoulos, Alexis, additional, Zhu, Houxiang, additional, Wyczalkowski, Matthew A., additional, McMichael, Joshua F., additional, Henderson, Brittany L., additional, Lindgren, Caleb M., additional, Boekweg, Hannah, additional, Lu, Shuangjia, additional, Baral, Jessika, additional, Yao, Lijun, additional, Stratton, Kelly G., additional, Bramer, Lisa M., additional, Zink, Erika, additional, Couvillion, Sneha P., additional, Bloodsworth, Kent J., additional, Satpathy, Shankha, additional, Sieh, Weiva, additional, Boca, Simina M., additional, Schürer, Stephan, additional, Chen, Feng, additional, Wiznerowicz, Maciej, additional, Ketchum, Karen A., additional, Boja, Emily S., additional, Kinsinger, Christopher R., additional, Robles, Ana I., additional, Hiltke, Tara, additional, Thiagarajan, Mathangi, additional, Nesvizhskii, Alexey I., additional, Zhang, Bing, additional, Mani, D.R., additional, Ceccarelli, Michele, additional, Chen, Xi S., additional, Cottingham, Sandra L., additional, Li, Qing Kay, additional, Kim, Albert H., additional, Fenyö, David, additional, Ruggles, Kelly V., additional, Rodriguez, Henry, additional, Mesri, Mehdi, additional, Payne, Samuel H., additional, Resnick, Adam C., additional, Wang, Pei, additional, Smith, Richard D., additional, Iavarone, Antonio, additional, Chheda, Milan G., additional, Barnholtz-Sloan, Jill S., additional, Rodland, Karin D., additional, Liu, Tao, additional, Ding, Li, additional, Agarwal, Anupriya, additional, Amin, Mitual, additional, An, Eunkyung, additional, Anderson, Matthew L., additional, Andrews, David W., additional, Bauer, Thomas, additional, Birger, Chet, additional, Birrer, Michael J., additional, Blumenberg, Lili, additional, Bocik, William E., additional, Borate, Uma, additional, Borucki, Melissa, additional, Burke, Meghan C., additional, Cai, Shuang, additional, Calinawan, Anna P., additional, Carr, Steven A., additional, Cerda, Sandra, additional, Chan, Daniel W., additional, Charamut, Alyssa, additional, Chen, Lin S., additional, Chesla, David, additional, Chinnaiyan, Arul M., additional, Chowdhury, Shrabanti, additional, Cieślik, Marcin P., additional, Clark, David J., additional, Culpepper, Houston, additional, Czernicki, Tomasz, additional, D'Angelo, Fulvio, additional, Day, Jacob, additional, De Young, Stephanie, additional, Demir, Emek, additional, Dhanasekaran, Saravana Mohan, additional, Dhir, Rajiv, additional, Domagalski, Marcin J., additional, Druker, Brian, additional, Duffy, Elizabeth, additional, Dyer, Maureen, additional, Edwards, Nathan J., additional, Edwards, Robert, additional, Elburn, Kimberly, additional, Ellis, Matthew J., additional, Eschbacher, Jennifer, additional, Francis, Alicia, additional, Gabriel, Stacey, additional, Gabrovski, Nikolay, additional, Garofano, Luciano, additional, Getz, Gad, additional, Gillette, Michael A., additional, Godwin, Andrew K., additional, Golbin, Denis, additional, Hanhan, Ziad, additional, Hannick, Linda I., additional, Hariharan, Pushpa, additional, Hindenach, Barbara, additional, Hoadley, Katherine A., additional, Hostetter, Galen, additional, Huang, Chen, additional, Jaehnig, Eric, additional, Jewell, Scott D., additional, Ji, Nan, additional, Jones, Corbin D., additional, Karz, Alcida, additional, Kaspera, Wojciech, additional, Kim, Lyndon, additional, Kothadia, Ramani B., additional, Kumar-Sinha, Chandan, additional, Lei, Jonathan, additional, Leprevost, Felipe D., additional, Li, Kai, additional, Liao, Yuxing, additional, Lilly, Jena, additional, Liu, Hongwei, additional, Lubínski, Jan, additional, Madan, Rashna, additional, Maggio, William, additional, Malc, Ewa, additional, Malovannaya, Anna, additional, Mareedu, Sailaja, additional, Markey, Sanford P., additional, Marrero-Oliveras, Annette, additional, Martinez, Nina, additional, Maunganidze, Nicollette, additional, McDermott, Jason E., additional, McGarvey, Peter B., additional, McGee, John, additional, Mieczkowski, Piotr, additional, Migliozzi, Simona, additional, Modugno, Francesmary, additional, Montgomery, Rebecca, additional, Newton, Chelsea J., additional, Omenn, Gilbert S., additional, Ozbek, Umut, additional, Paklina, Oxana V., additional, Paulovich, Amanda G., additional, Perou, Amy M., additional, Pico, Alexander R., additional, Piehowski, Paul D., additional, Placantonakis, Dimitris G., additional, Polonskaya, Larisa, additional, Potapova, Olga, additional, Pruetz, Barbara, additional, Qi, Liqun, additional, Ramkissoon, Shakti, additional, Resnick, Adam, additional, Richey, Shannon, additional, Riggins, Gregory, additional, Robinson, Karna, additional, Roche, Nancy, additional, Rohrer, Daniel C., additional, Rood, Brian R., additional, Rossell, Larissa, additional, Savage, Sara R., additional, Schadt, Eric E., additional, Shi, Yan, additional, Shi, Zhiao, additional, Shutack, Yvonne, additional, Singh, Shilpi, additional, Skelly, Tara, additional, Sokoll, Lori J., additional, Stawicki, Jakub, additional, Stein, Stephen E., additional, Suh, James, additional, Szopa, Wojciech, additional, Tabor, Dave, additional, Tan, Donghui, additional, Tansil, Darlene, additional, Thangudu, Ratna R., additional, Tognon, Cristina, additional, Traer, Elie, additional, Tsang, Shirley, additional, Tyner, Jeffrey, additional, Um, Ki Sung, additional, Valley, Dana R., additional, Vasaikar, Suhas, additional, Vatanian, Negin, additional, Velvulou, Uma, additional, Vernon, Michael, additional, Wan, Weiqing, additional, Wang, Junmei, additional, Webster, Alex, additional, Wen, Bo, additional, Whiteaker, Jeffrey R., additional, Wilson, George D., additional, Zakhartsev, Yuriy, additional, Zelt, Robert, additional, Zhang, Hui, additional, Zhang, Liwei, additional, Zhang, Zhen, additional, Zhao, Grace, additional, and Zhu, Jun, additional

Published
2021
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26. The molecular landscape of glioma in patients with Neurofibromatosis 1

Author

D'Angelo, Fulvio, Ceccarelli, Michele, Tala, Garofano, Luciano, Zhang, Jing, Frattini, Véronique, and Caruso, Francesca P.

Subjects
Neurofibromatosis -- Physiological aspects, Gliomas -- Genetic aspects -- Development and progression -- Care and treatment, Gene mutation -- Health aspects, Gene expression -- Health aspects, Biological sciences, Health
Abstract

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors. An integrated analysis of glioma samples from patients with neurofibromatosis 1 annotates their mutational, epigenetic, transcriptional, and immunological features and uncovers similitudes with a subset of sporadic gliomas., Author(s): Fulvio D'Angelo [sup.1] [sup.2] , Michele Ceccarelli [sup.2] [sup.3] , Tala [sup.1] , Luciano Garofano [sup.1] [sup.2] , Jing Zhang [sup.1] , Véronique Frattini [sup.1] , Francesca P. Caruso [...]

Published
2019
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27. Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma

Author

Huang, Chen, primary, Chen, Lijun, additional, Savage, Sara R., additional, Eguez, Rodrigo Vargas, additional, Dou, Yongchao, additional, Li, Yize, additional, da Veiga Leprevost, Felipe, additional, Jaehnig, Eric J., additional, Lei, Jonathan T., additional, Wen, Bo, additional, Schnaubelt, Michael, additional, Krug, Karsten, additional, Song, Xiaoyu, additional, Cieślik, Marcin, additional, Chang, Hui-Yin, additional, Wyczalkowski, Matthew A., additional, Li, Kai, additional, Colaprico, Antonio, additional, Li, Qing Kay, additional, Clark, David J., additional, Hu, Yingwei, additional, Cao, Liwei, additional, Pan, Jianbo, additional, Wang, Yuefan, additional, Cho, Kyung-Cho, additional, Shi, Zhiao, additional, Liao, Yuxing, additional, Jiang, Wen, additional, Anurag, Meenakshi, additional, Ji, Jiayi, additional, Yoo, Seungyeul, additional, Zhou, Daniel Cui, additional, Liang, Wen-Wei, additional, Wendl, Michael, additional, Vats, Pankaj, additional, Carr, Steven A., additional, Mani, D.R., additional, Zhang, Zhen, additional, Qian, Jiang, additional, Chen, Xi S., additional, Pico, Alexander R., additional, Wang, Pei, additional, Chinnaiyan, Arul M., additional, Ketchum, Karen A., additional, Kinsinger, Christopher R., additional, Robles, Ana I., additional, An, Eunkyung, additional, Hiltke, Tara, additional, Mesri, Mehdi, additional, Thiagarajan, Mathangi, additional, Weaver, Alissa M., additional, Sikora, Andrew G., additional, Lubiński, Jan, additional, Wierzbicka, Małgorzata, additional, Wiznerowicz, Maciej, additional, Satpathy, Shankha, additional, Gillette, Michael A., additional, Miles, George, additional, Ellis, Matthew J., additional, Omenn, Gilbert S., additional, Rodriguez, Henry, additional, Boja, Emily S., additional, Dhanasekaran, Saravana M., additional, Ding, Li, additional, Nesvizhskii, Alexey I., additional, El-Naggar, Adel K., additional, Chan, Daniel W., additional, Zhang, Hui, additional, Zhang, Bing, additional, Agarwal, Anupriya, additional, Anderson, Matthew L., additional, Avanessian, Shayan C., additional, Avtonomov, Dmitry, additional, Bathe, Oliver F., additional, Birger, Chet, additional, Birrer, Michael J., additional, Blumenberg, Lili, additional, Bocik, William E., additional, Borate, Uma, additional, Borucki, Melissa, additional, Burke, Meghan C., additional, Cai, Shuang, additional, Calinawan, Anna Pamela, additional, Cerda, Sandra, additional, Charamut, Alyssa, additional, Chen, Lin S., additional, Chowdhury, Shrabanti, additional, Clauser, Karl R., additional, Culpepper, Houston, additional, Czernicki, Tomasz, additional, D'Angelo, Fulvio, additional, Day, Jacob, additional, De Young, Stephanie, additional, Demir, Emek, additional, Ding, Fei, additional, Domagalski, Marcin J., additional, Dort, Joseph C., additional, Druker, Brian, additional, Duffy, Elizabeth, additional, Dyer, Maureen, additional, Edwards, Nathan J., additional, Elburn, Kimberly, additional, Ermakova, Tatiana S., additional, Fenyo, David, additional, Ferrarotto, Renata, additional, Francis, Alicia, additional, Gabriel, Stacey, additional, Garofano, Luciano, additional, Geffen, Yifat, additional, Getz, Gad, additional, Goldthwaite, Charles A., additional, Hannick, Linda I., additional, Hariharan, Pushpa, additional, Hayes, David N., additional, Heiman, David, additional, Hindenach, Barbara, additional, Hoadley, Katherine A., additional, Hostetter, Galen, additional, Hyrcza, Martin, additional, Jewell, Scott D., additional, Jones, Corbin D., additional, Kane, M. Harry, additional, Karz, Alicia, additional, Kothadia, Ramani B., additional, Krek, Azra, additional, Kumar-Sinha, Chandan, additional, Liu, Tao, additional, Liu, Hongwei, additional, Ma, Weiping, additional, Malc, Ewa, additional, Malovannaya, Anna, additional, Mareedu, Sailaja, additional, Markey, Sanford P., additional, Marrero-Oliveras, Annette, additional, Maunganidze, Nicollette, additional, McDermott, Jason E., additional, McGarvey, Peter B., additional, McGee, John, additional, Mieczkowski, Piotr, additional, Migliozzi, Simona, additional, Montgomery, Rebecca, additional, Newton, Chelsea J., additional, Ozbek, Umut, additional, Paulovich, Amanda G., additional, Payne, Samuel H., additional, Pazardzhikliev, Dimitar Dimitrov, additional, Perou, Amy M., additional, Petralia, Francesca, additional, Petrenko, Lyudmila, additional, Piehowski, Paul D., additional, Placantonakis, Dmitris, additional, Polonskaya, Larisa, additional, Ponomareva, Elena V., additional, Potapova, Olga, additional, Qi, Liqun, additional, Qu, Ning, additional, Ramkissoon, Shakti, additional, Reva, Boris, additional, Richey, Shannon, additional, Robinson, Karna, additional, Roche, Nancy, additional, Rodland, Karin, additional, Rohrer, Daniel C., additional, Rykunov, Dmitry, additional, Schadt, Eric E., additional, Shi, Yan, additional, Shutack, Yvonne, additional, Singh, Shilpi, additional, Skelly, Tara, additional, Smith, Richard, additional, Sokoll, Lori J., additional, Stawicki, Jakub, additional, Stein, Stephen E., additional, Suh, James, additional, Szopa, Wojciech, additional, Tabor, Dave, additional, Tan, Donghui, additional, Tansil, Darlene, additional, Teo, Guo Ci, additional, Thangudu, Ratna R., additional, Tognon, Cristina, additional, Traer, Elie, additional, Tsang, Shirley, additional, Tyner, Jeffrey, additional, Um, Ki Sung, additional, Valley, Dana R., additional, Vasilev, Lyubomir Valkov, additional, Vatanian, Negin, additional, Velvulou, Uma, additional, Vernon, Michael, additional, Westbrook, Thomas F., additional, Whiteaker, Jeffrey R., additional, Wu, Yige, additional, Xu, Midie, additional, Yao, Lijun, additional, Yi, Xinpei, additional, Yu, Fengchao, additional, Zaalishvili, Kakhaber, additional, Zakhartsev, Yuriy, additional, Zelt, Robert, additional, Zhao, Grace, additional, and Zhu, Jun, additional

Published
2021
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28. Modulation of Nogo receptor 1 expression orchestrates myelin-associated infiltration of glioblastoma

Author

Hong, Jun-Hee, primary, Kang, Sangjo, additional, Sa, Jason K, additional, Park, Gunwoo, additional, Oh, Young Taek, additional, Kim, Tae Hoon, additional, Yin, Jinlong, additional, Kim, Sung Soo, additional, D’Angelo, Fulvio, additional, Koo, Harim, additional, You, Yeonhee, additional, Park, Saewhan, additional, Kwon, Hyung Joon, additional, Kim, Chan Il, additional, Ryu, Haseo, additional, Lin, Weiwei, additional, Park, Eun Jung, additional, Kim, Youn-Jae, additional, Park, Myung-Jin, additional, Kim, Hyunggee, additional, Kim, Mi-Suk, additional, Chung, Seok, additional, Park, Chul-Kee, additional, Park, Sung-Hye, additional, Kang, Yun Hee, additional, Kim, Jong Heon, additional, Saya, Hideyuki, additional, Nakano, Ichiro, additional, Gwak, Ho-Shin, additional, Yoo, Heon, additional, Lee, Jeongwu, additional, Hur, Eun-Mi, additional, Shi, Bingyang, additional, Nam, Do-Hyun, additional, Iavarone, Antonio, additional, Lee, Seung-Hoon, additional, and Park, Jong Bae, additional

Published
2021
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29. A map of tumor–host interactions in glioma at single-cell resolution

Author

Caruso, Francesca Pia, primary, Garofano, Luciano, additional, D'Angelo, Fulvio, additional, Yu, Kai, additional, Tang, Fuchou, additional, Yuan, Jinzhou, additional, Zhang, Jing, additional, Cerulo, Luigi, additional, Pagnotta, Stefano M, additional, Bedognetti, Davide, additional, Sims, Peter A, additional, Suvà, Mario, additional, Su, Xiao-Dong, additional, Lasorella, Anna, additional, Iavarone, Antonio, additional, and Ceccarelli, Michele, additional

Published
2020
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31. Exploring the Molecular Crosstalk between Pancreatic Bud and Mesenchyme in Embryogenesis: Novel Signals Involved

Author

Guerriero, Ilaria, primary, De Angelis, Maria Teresa, additional, D’Angelo, Fulvio, additional, Leveque, Rita, additional, Savignano, Eleonora, additional, Roberto, Luca, additional, Lucci, Valeria, additional, Mazzone, Pellegrino, additional, Laurino, Simona, additional, Storto, Giovanni, additional, Nardelli, Anna, additional, Sgambato, Alessandro, additional, Ceccarelli, Michele, additional, De Felice, Mario, additional, Amendola, Elena, additional, and Falco, Geppino, additional

Published
2019
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32. Centrosome Linker–induced Tetraploid Segregation Errors Link Rhabdoid Phenotypes and Lethal Colorectal Cancers

Author

Remo, Andrea, primary, Manfrin, Erminia, additional, Parcesepe, Pietro, additional, Ferrarini, Alberto, additional, Han, Hye Seung, additional, Mickys, Ugnius, additional, Laudanna, Carmelo, additional, Simbolo, Michele, additional, Malanga, Donatella, additional, Oliveira, Duarte Mendes, additional, Baritono, Elisabetta, additional, Colangelo, Tommaso, additional, Sabatino, Lina, additional, Giuliani, Jacopo, additional, Molinari, Enrico, additional, Garonzi, Marianna, additional, Xumerle, Luciano, additional, Delledonne, Massimo, additional, Giordano, Guido, additional, Ghimenton, Claudio, additional, Lonardo, Fortunato, additional, D'angelo, Fulvio, additional, Grillo, Federica, additional, Mastracci, Luca, additional, Viglietto, Giuseppe, additional, Ceccarelli, Michele, additional, Colantuoni, Vittorio, additional, Scarpa, Aldo, additional, and Pancione, Massimo, additional

Published
2018
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33. TCGA Workflow: Analyze cancer genomics and epigenomics data using Bioconductor packages [version 1; referees: 1 approved, 1 approved with reservations]

Author

Silva, Tiago T.C., Colaprico, Antonio, Olsen, Catharina, D'Angelo, Fulvio, Bontempi, Gianluca, Ceccarelli, Michele, Noushmehr, Houtan, Clinical sciences, Medical Genetics, and Informatics and Applied Informatics

Subjects
Epigenomics, Roadmap, Bioinformatics, Immunologie, Biophysique, Sciences pharmaceutiques, Genomics, Sciences bio-médicales et agricoles, TCGA, Microbiologie et protistologie [bacteriol.virolog.mycolog.], Cancer, ENCODE, Non-coding
Abstract

Biotechnological advances in sequencing have led to an explosion of publicly available data via large international consortia such as The Cancer Genome Atlas (TCGA), The Encyclopedia of DNA Elements (ENCODE), and The NIH Roadmap Epigenomics Mapping Consortium (Roadmap). These projects have provided unprecedented opportunities to interrogate the epigenome of cultured cancer cell lines as well as normal and tumor tissues with high genomic resolution. The bioconductor project offers more than 1,000 open-source software and statistical packages to analyze high-throughput genomic data. However, most packages are designed for specific data types (e.g. expression, epigenetics, genomics) and there is no comprehensive tool that provides a complete integrative analysis harnessing the resources and data provided by all three public projects. A need to create an integration of these different analyses was recently proposed. In this workflow, we provide a series of biologically focused integrative downstream analyses of different molecular data. We describe how to download, process and prepare TCGA data and by harnessing several key bioconductor packages, we describe how to extract biologically meaningful genomic and epigenomic data and by using Roadmap and ENCODE data, we provide a workplan to identify candidate biologically relevant functional epigenomic elements associated with cancer. To illustrate our workflow, we analyzed two types of brain tumors: low-grade glioma (LGG) versus high-grade glioma (glioblastoma multiform or GBM). This workflow introduces the following Bioconductor packages: AnnotationHub, ChIPSeeker, ComplexHeatmap, pathview, ELMER, GAIA, MINET, RTCGAtoolbox, TCGAbiolinks., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2016

35. Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Author

Porreca, Immacolata, primary, D’Angelo, Fulvio, additional, De Franceschi, Lucia, additional, Mattè, Alessandro, additional, Ceccarelli, Michele, additional, Iolascon, Achille, additional, Zamò, Alberto, additional, Russo, Filomena, additional, Ravo, Maria, additional, Tarallo, Roberta, additional, Scarfò, Marzia, additional, Weisz, Alessandro, additional, De Felice, Mario, additional, Mallardo, Massimo, additional, and Ambrosino, Concetta, additional

Published
2016
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37. “Stockpile” of Slight Transcriptomic Changes Determines the Indirect Genotoxicity of Low-Dose BPA in Thyroid Cells

Author

Porreca, Immacolata, primary, Ulloa Severino, Luisa, additional, D’Angelo, Fulvio, additional, Cuomo, Danila, additional, Ceccarelli, Michele, additional, Altucci, Lucia, additional, Amendola, Elena, additional, Nebbioso, Angela, additional, Mallardo, Massimo, additional, De Felice, Mario, additional, and Ambrosino, Concetta, additional

Published
2016
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39. Cross-species toxicogenomic analyses and phenotypic anchoring in response to groundwater low-level pollution

Author

Porreca, Immacolata, primary, D’Angelo, Fulvio, additional, Gentilcore, Daniela, additional, Carchia, Emanuele, additional, Amoresano, Angela, additional, Affuso, Andrea, additional, Ceccarelli, Michele, additional, De Luca, Pasquale, additional, Esposito, Libera, additional, Guadagno, Francesco M, additional, Mallardo, Massimo, additional, Nardone, Antonio, additional, Maccarone, Sergio, additional, Pane, Francesca, additional, Scarfò, Marzia, additional, Sordino, Paolo, additional, De Felice, Mario, additional, and Ambrosino, Concetta, additional

Published
2014
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40. Inhibition of ERK/MAPK signaling as potential therapy to prevent optic pathway glioma in infants with neurofibromatosis type 1.

Author

D'Angelo, Fulvio and Lasorella, Anna

Subjects
*NEUROFIBROMATOSIS 1, *MITOGEN-activated protein kinases, *GLIOMAS, *PROGENITOR cells
Abstract

Pediatric low-grade gliomas (pLGGs) arise primarily at early stages of development. The molecular mechanisms of pLGG gliomagenesis are unclear, as is the progenitor cell of origin. In this issue of Developmental Cell , Jecrois et al. show that NF1-associated optic pathway gliomas originate from migrating glial progenitors that have distinct MEK/ERK dependency. [ABSTRACT FROM AUTHOR]

Published
2021
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41. Integrative multi-omics networks identify PKCδ and DNA-PK as master kinases of glioblastoma subtypes and guide targeted cancer therapy

Author

Simona Migliozzi, Young Taek Oh, Mohammad Hasanain, Luciano Garofano, Fulvio D’Angelo, Ryan D. Najac, Alberto Picca, Franck Bielle, Anna Luisa Di Stefano, Julie Lerond, Jann N. Sarkaria, Michele Ceccarelli, Marc Sanson, Anna Lasorella, Antonio Iavarone, Migliozzi, Simona, Oh, Young Taek, Hasanain, Mohammad, Garofano, Luciano, D'Angelo, Fulvio, Najac, Ryan D, Picca, Alberto, Bielle, Franck, Di Stefano, Anna Luisa, Lerond, Julie, Sarkaria, Jann N, Ceccarelli, Michele, Sanson, Marc, Lasorella, Anna, and Iavarone, Antonio

Subjects
Cancer Research, Oncology
Abstract

Despite producing a panoply of potential cancer-specific targets, the proteogenomic characterization of human tumors has yet to demonstrate value for precision cancer medicine. Integrative multi-omics using a machine-learning network identified master kinases responsible for effecting phenotypic hallmarks of functional glioblastoma subtypes. In subtype-matched patient-derived models, we validated PKCδ and DNA-PK as master kinases of glycolytic/plurimetabolic and proliferative/progenitor subtypes, respectively, and qualified the kinases as potent and actionable glioblastoma subtype-specific therapeutic targets. Glioblastoma subtypes were associated with clinical and radiomics features, orthogonally validated by proteomics, phospho-proteomics, metabolomics, lipidomics and acetylomics analyses, and recapitulated in pediatric glioma, breast and lung squamous cell carcinoma, including subtype specificity of PKCδ and DNA-PK activity. We developed a probabilistic classification tool that performs optimally with RNA from frozen and paraffin-embedded tissues, which can be used to evaluate the association of therapeutic response with glioblastoma subtypes and to inform patient selection in prospective clinical trials.

Published
2023

42. Dysregulation of Principal Cell miRNAs Facilitates Epigenetic Regulation of AQP2 and Results in Nephrogenic Diabetes Insipidus

Author

Michele Caraglia, Francesco Trepiccione, Anna Iervolino, Sabina Jelen, Mariavittoria D'Acierno, Robert A. Fenton, Lei Cheng, Giovambattista Capasso, Qi Wu, Fulvio D'Angelo, Vincenzo Costanzo, Maria Cristina Mazzarella, Alfonso De Falco, Michele Ceccarelli, Federica Petrillo, Ilaria Guerriero, Tiziana Angrisano, Petrillo, Federica, Iervolino, Anna, Angrisano, Tiziana, Jelen, Sabina, Costanzo, Vincenzo, D'Acierno, Mariavittoria, Cheng, Lei, Wu, Qi, Guerriero, Ilaria, Mazzarella, Maria Cristina, De Falco, Alfonso, D'Angelo, Fulvio, Ceccarelli, Michele, Caraglia, Michele, Capasso, Giovambattista, Fenton, Robert A, Trepiccione, Francesco, Petrillo, F., Iervolino, A., Angrisano, T., Jelen, S., Costanzo, V., D'Acierno, M., Cheng, L., Wu, Q., Guerriero, I., Mazzarella, M. C., de Falco, A., D'Angelo, F., Ceccarelli, M., Caraglia, M., Capasso, G., Fenton, R. A., and Trepiccione, F.

Subjects
Male, Ribonuclease III, Epithelial Sodium Channels/metabolism, GATA3 Transcription Factor/genetics, Proteome, MICRORNAS, AQUAPORIN-2, VASOPRESSIN, Diabetes Insipidus, Nephrogenic, urologic and male genital diseases, Epigenesis, Genetic, Mice, Gene expression, Transcriptional regulation, TRANSCRIPTION, RNA Processing, Post-Transcriptional, PHOSPHORYLATION, DNA METHYLATION, GENE-EXPRESSION, Aquaporin 2/genetics, Histone Demethylases, DNA methylation, Ribonuclease III/genetics, Epigenesis, Genetic/genetics, General Medicine, Kidney Tubules, Collecting/physiology, Cell biology, DNA-Binding Proteins, GATA2 Transcription Factor, Nephrology, Aquaporin 2, Female, epigenetic, Polyuria/genetics, ENaC, Transcription Factors/genetics, Down-Regulation, GATA3 Transcription Factor, Biology, Diabetes Insipidus, Nephrogenic/genetics, microRNA, medicine, LITHIUM, Animals, Epigenetics, Kidney Tubules, Collecting, Epithelial Sodium Channels, miRNA, Homeodomain Proteins, urogenital system, Polyuria, Sequence Analysis, RNA, Endoribonuclease Dicer, COLLECTING DUCT, AQP2, GATA2 Transcription Factor/genetics, Nephrogenic diabetes insipidus, medicine.disease, Renal Reabsorption, enzymes and coenzymes (carbohydrates), MicroRNAs/genetics, MicroRNAs, Basic Research, Gene Expression Regulation, biology.protein, Histone Demethylases/genetics, SYSTEMS-LEVEL ANALYSIS, Homeodomain Proteins/genetics, DNA-Binding Proteins/genetics, Dicer, Transcription Factors
Abstract

Water reabsorption along the collecting duct is dependent on the function of aquaporin 2 (AQP2). Currently, information on microRNA (miRNA)-mediated, post-transcriptional regulation of AQP2, which may influence water reabsorption, is limited. In mice, ablation of the Dicer enzyme (crucial for miRNA maturation) in AQP2-expressing cells induces nephrogenic diabetes insipidus (NDI) with dysregulation of the miRNA profile. A major finding is the identification of miRNAs associated with NDI through mediating epigenetic control of AQP2. This study offers novel targets for AQP2 regulation and potential treatment for governing renal water reabsorption.Background MicroRNAs (miRNAs), formed by cleavage of pre-microRNA by the endoribonuclease Dicer, are critical modulators of cell function by post-transcriptionally regulating gene expression.Methods Selective ablation of Dicer in AQP2-expressing cells (DicerAQP2Cre+ mice) was used to investigate the role of miRNAs in the kidney collecting duct of mice.Results The mice had severe polyuria and nephrogenic diabetes insipidus, potentially due to greatly reduced AQP2 and AQP4 levels. Although epithelial sodium channel levels were decreased in cortex and increased in inner medulla, amiloride-sensitive sodium reabsorption was equivalent in DicerAQP2Cre+ mice and controls. Small-RNA sequencing and proteomic analysis revealed 31 and 178 significantly regulated miRNAs and proteins, respectively. Integrated bioinformatic analysis of the miRNAome and proteome suggested alterations in the epigenetic machinery and various transcription factors regulating AQP2 expression in DicerAQP2Cre+ mice. The expression profile and function of three miRNAs (miR-7688-5p, miR-8114, and miR-409-3p) whose predicted targets were involved in epigenetic control (Phf2, Kdm5c, and Kdm4a) or transcriptional regulation (GATA3, GATA2, and ELF3) of AQP2 were validated. Luciferase assays could not demonstrate direct interaction of AQP2 or the three potential transcription factors with miR-7688-5p, miR-8114, and miR-409textendash3p. However, transfection of respective miRNA mimics reduced AQP2 expression. Chromatin immunoprecipitation assays demonstrated decreased Phf2 and significantly increased Kdm5c interactions at the Aqp2 gene promoter in DicerAQP2Cre+ mice, resulting in decreased RNA Pol II association.Conclusions Novel evidence indicates miRNA-mediated epigenetic regulation of AQP2 expression.

Published
2020

43. Exploring the Molecular Crosstalk between Pancreatic Bud and Mesenchyme in Embryogenesis: Novel Signals Involved

Author

Alessandro Sgambato, Maria De Angelis, Anna Nardelli, Mario De Felice, Rita Leveque, Geppino Falco, Eleonora Savignano, Simona Laurino, Michele Ceccarelli, Luca Roberto, Ilaria Guerriero, Giovanni Storto, Elena Amendola, Pellegrino Mazzone, Fulvio D'Angelo, Valeria Lucci, Guerriero, Ilaria, DE ANGELIS, MARIA TERESA, D’Angelo, Fulvio, Leveque, Rita, Savignano, Eleonora, DE LUCA, Roberto, Lucci, Valeria, Mazzone, Pellegrino, Laurino, Simona, Storto, Giovanni, Nardelli, Anna, Sgambato, Alessandro, Ceccarelli, Michele, De Felice, Mario, Amendola, Elena, and Falco, Geppino

Subjects
genetic structures, Mesenchyme, Organogenesis, Morphogenesis, Embryonic Development, In situ hybridization, [object Object], macromolecular substances, Biology, Catalysis, Article, Inorganic Chemistry, lcsh:Chemistry, Mesoderm, Mice, medicine, Pancrea, Animals, Physical and Theoretical Chemistry, Molecular Biology, lcsh:QH301-705.5, Pancreas, Spectroscopy, mesenchymal stem cell, Laser capture microdissection, Gene Expression Profiling, Organic Chemistry, pancreatic disorders, Computational Biology, Gene Expression Regulation, Developmental, General Medicine, progenitor cells, embryonic stem cells, Embryonic stem cell, bud, Computer Science Applications, Cell biology, omics, Crosstalk (biology), pancreatic stem cells, medicine.anatomical_structure, lcsh:Biology (General), lcsh:QD1-999, Pancreatic bud, biology.protein, Versican, laser microdissection, Signal Transduction
Abstract

Pancreatic organogenesis is a multistep process that requires the cooperation of several signaling pathways. In this context, the role of pancreatic mesenchyme is important to define the epithelium development, nevertheless, the precise space&ndash, temporal signaling activation still needs to be clarified. This study reports a dissection of the pancreatic embryogenesis, highlighting the molecular network surrounding the epithelium&ndash, mesenchyme interaction. To investigate this crosstalk, pancreatic epithelium and surrounding mesenchyme, at embryonic day 10.5, were collected through laser capture microdissection (LCM) and characterized based on their global gene expression. We performed a bioinformatic analysis to hypothesize crosstalk interactions, validating the most promising genes and verifying the precise localization of their expression in the compartments, by RNA in situ hybridization (ISH). Our analyses pointed out also the c-Met gene, a very well-known factor involved in stimulating motility, morphogenesis, and organ regeneration. We also highlighted the potential crosstalk between Versican (Vcan) and Syndecan4 (Sdc4) since these genes are involved in pancreatic tissue repair, strengthening the concept that the same signaling pathways required during pancreatic embryogenesis are also involved in tissue repair. This finding leads to novel strategies for obtaining functional pancreatic stem cells for cell replacement therapies.

Published
2019
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44. Transcriptional landscape of mouse-aged ovaries reveals a unique set of non-coding RNAs associated with physiological and environmental ovarian dysfunctions

Author

Annacristina Petriella, Fulvio D'Angelo, Maria N. D’Agostino, Danila Cuomo, David W. Threadgill, Massimo Mallardo, William T. Barrington, Immacolata Porreca, Michele Ceccarelli, Gilda Cobellis, Francesca De Stefano, Mario De Felice, Concetta Ambrosino, Cuomo, Danila, Porreca, Immacolata, Ceccarelli, Michele, Threadgill, David W, Barrington, William T, Petriella, Annacristina, D'Angelo, Fulvio, Cobellis, Gilda, De Stefano, Francesca, D'Agostino, Maria N, De Felice, Mario, Mallardo, Massimo, and Ambrosino, Concetta

Subjects
0301 basic medicine, Senescence, Cancer Research, Transcriptional landscape, RNAs, ovarian dysfunctions, Immunology, Ovary, Biology, Bioinformatics, lcsh:RC254-282, Article, Transcriptome, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Follicular phase, microRNA, medicine, lcsh:QH573-671, Ovarian reserve, 030219 obstetrics & reproductive medicine, lcsh:Cytology, Cell Biology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Follicular fluid, 030104 developmental biology, medicine.anatomical_structure, GAS5
Abstract

The progressive and physiological decline in ovarian function depends on the rate of follicular loss by atresia, contributing to the reduction in ovarian reserve. Genetics and environmental factors play important roles in ovarian senescence and in the onset of ovarian dysfunctions such as diminished ovarian reserve. A better understanding of the mechanisms underlying ovarian aging and their regulation by genetic and environmental factors is needed to evaluate ovarian reserve and to predict fertility potential by identification of more accurate and less invasive markers. We report transcriptomic data (i) implicating novel (e.g. EIF2 signalling) and well-known pathways (e.g. TGFβ signalling), and (ii) defining a unique set of non-coding RNA (ncRNA), both associated with ovarian function. The latter includes miRNAs (e.g. Mir143 and Mir145), snoRNAs (e.g. Snord16a and Snora34), and one lncRNA (Gas5), which are differentially expressed in middle-aged ovaries (12 months) vs young-aged (3 months) from CD1 mice. Experimental analysis confirms that ovary lifespan varies across genetic backgrounds in mice and, genetics influences the response to environmental perturbations such as diet. Moreover, the identified ncRNAs were verified in a model of reproductive dysfunction promoted by the environmental toxicant ethylenthiourea. We also report the increase of miRNA143 and miRNA145 in follicular fluid of women with diminished ovarian reserve. Their levels inversely correlate with the hormonal profile and with the number of the oocytes recruited upon hormonal stimulation. Overall, we report a transcriptomic signature for ovarian dysfunction in vivo that provides a valuable resource for translational research in human reproductive aging.

Published
2018

45. The molecular landscape of glioma in patients with Neurofibromatosis 1

Author

Dominique Vidaud, Mariona Suñol, Tala, Francesco DiMeco, John de Groot, Gaetano Finocchiaro, Fulvio D'Angelo, Luc Bauchet, Marica Eoli, Véronique Lorgis, David Meyronet, Kristin Alfaro, Luciano Garofano, John M. Slopis, Laurent Capelle, Pascale Varlet, Giulia Berzero, Mario Cangiano, Veronica Saletti, Romuald Seizeur, Jing Zhang, Carlo Efisio Marras, Veronique Frattini, Walid Farah, Cinzia Lavarino, David Cachia, Genevieve Lewis, Michele Ceccarelli, Seung-Ki Kim, David E. Reuss, Hugues Loiseau, Carlos Kamiya-Matsuoka, Do-Hyun Nam, Krishna P. Bhat, Stéphane Goutagny, Karima Mokhtari, François Ducray, Anna Lasorella, Colin Watts, Francesca Pia Caruso, Hector Salvador, Antonio Iavarone, F. Vandenbos, Ian E. McCutcheon, Susanna Ronchi, Viviane Tabar, Marc Sanson, D'Angelo, Fulvio, Ceccarelli, Michele, Tala, Garofano, Luciano, Zhang, Jing, Frattini, Veronique, Caruso, Francesca P., Lewis, Genevieve, Alfaro, Kristin D., Bauchet, Luc, Berzero, Giulia, Cachia, David, Cangiano, Mario, Capelle, Laurent, de Groot, John, Dimeco, Francesco, Ducray, Francoi, Farah, Walid, Finocchiaro, Gaetano, Goutagny, Stephane, Kamiya-Matsuoka, Carlo, Lavarino, Cinzia, Loiseau, Hugue, Lorgis, Veronique, Marras, Carlo E., Mccutcheon, Ian, Nam, Do-Hyun, Ronchi, Susanna, Saletti, Veronica, Seizeur, Romuald, Slopis, John, Sunol, Mariona, Vandenbos, Fanny, Varlet, Pascale, Vidaud, Dominique, Watts, Colin, Tabar, Viviane, Reuss, David E., Kim, Seung-Ki, Meyronet, David, Mokhtari, Karima, Salvador, Hector, Bhat, Krishna P., Eoli, Marica, Sanson, Marc, Lasorella, Anna, Iavarone, Antonio, D'Angelo, F., Ceccarelli, M., Garofano, L., Zhang, J., Frattini, V., Caruso, F. P., Lewis, G., Alfaro, K. D., Bauchet, L., Berzero, G., Cachia, D., Cangiano, M., Capelle, L., de Groot, J., Dimeco, F., Ducray, F., Farah, W., Finocchiaro, G., Goutagny, S., Kamiya-Matsuoka, C., Lavarino, C., Loiseau, H., Lorgis, V., Marras, C. E., Mccutcheon, I., Nam, D. -H., Ronchi, S., Saletti, V., Seizeur, R., Slopis, J., Sunol, M., Vandenbos, F., Varlet, P., Vidaud, D., Watts, C., Tabar, V., Reuss, D. E., Kim, S. -K., Meyronet, D., Mokhtari, K., Salvador, H., Bhat, K. P., Eoli, M., Sanson, M., Lasorella, A., Iavarone, A., Columbia University Medical Center (CUMC), Columbia University [New York], University of Sannio [Benevento], The University of Texas M.D. Anderson Cancer Center [Houston], CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Medical University of South Carolina [Charleston] (MUSC), Service de Neurochirurgie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Milan, Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Bordeaux [Bordeaux], Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Sungkyunkwan University [Suwon] (SKKU), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Pasteur [Nice] (CHU), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Sainte Anne [Paris], Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], University of Birmingham [Birmingham], Memorial Sloane Kettering Cancer Center [New York], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Heidelberg University, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Beaujon, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), and CHU Cochin [AP-HP]

Subjects
0301 basic medicine, Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, X-linked Nuclear Protein, Neurofibromatosis 1, Adolescent, [SDV]Life Sciences [q-bio], T-Lymphocytes, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Germline mutation, CDKN2A, Antigens, Neoplasm, Glioma, medicine, Humans, Epigenetics, Neurofibromatosis, 10. No inequality, Child, Gene, neoplasms, ATRX, Germ-Line Mutation, Cancer, Neurofibromin 1, Brain Neoplasms, Reproducibility of Results, General Medicine, DNA Methylation, Middle Aged, medicine.disease, 3. Good health, nervous system diseases, 030104 developmental biology, 030220 oncology & carcinogenesis, Child, Preschool, DNA methylation, Cancer research, Genomics, Bioinformatic, Female, Transcriptome
Abstract

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors. An integrated analysis of glioma samples from patients with neurofibromatosis 1 annotates their mutational, epigenetic, transcriptional, and immunological features and uncovers similitudes with a subset of sporadic gliomas.

Published
2018

46. Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Author

Lucia De Franceschi, Fulvio D'Angelo, Alessandro Weisz, Concetta Ambrosino, Achille Iolascon, Immacolata Porreca, Roberta Tarallo, Michele Ceccarelli, Maria Ravo, Massimo Mallardo, Marzia Scarfò, Mario De Felice, Alessandro Matte, Filomena Russo, Alberto Zamò, Porreca, Immacolata, D'Angelo, Fulvio, De Franceschi, Lucia, Mattè, Alessandro, Ceccarelli, Michele, Iolascon, Achille, Zamò, Alberto, Russo, Filomena, Ravo, Maria, Tarallo, Roberta, Scarfò, Marzia, Weisz, Alessandro, DE FELICE, Mario, Mallardo, Massimo, and Ambrosino, Concetta

Subjects
0301 basic medicine, Male, Thyroid Gland, Ethylenethiourea, Biology, Bioinformatics, Article, Transcriptome, 03 medical and health sciences, Mice, In vivo, Toxicity Tests, Animals, Humans, Pesticides, toxicogenomics, Gene, Cells, Cultured, Multidisciplinary, Gene Expression Profiling, In vitro, Cell biology, Hematopoiesis, Rats, Pesticide, Gene expression profiling, Haematopoiesis, 030104 developmental biology, Toxicity, Female, In vitro Omics analysis (i.e. transcriptome), Chlorpyrifos, Toxicogenomics
Abstract

In vitro Omics analysis (i.e. transcriptome) is suggested to predict in vivo toxicity and adverse effects in humans, although the causal link between high-throughput data and effects in vivo is not easily established. Indeed, the chemical-organism interaction can involve processes, such as adaptation, not established in cell cultures. Starting from this consideration we investigate the transcriptomic response of immortalized thyrocytes to ethylenthiourea and chlorpyrifos. In vitro data revealed specific and common genes/mechanisms of toxicity, controlling the proliferation/survival of the thyrocytes and unrelated hematopoietic cell lineages. These results were phenotypically confirmed in vivo by the reduction of circulating T4 hormone and the development of pancytopenia after long exposure. Our data imply that in vitro toxicogenomics is a powerful tool in predicting adverse effects in vivo, experimentally confirming the vision described as Tox21c (Toxicity Testing in the 21st century) although not fully recapitulating the biocomplexity of a living animal.

Published
2016

47. 'Stockpile' of Slight Transcriptomic Changes Determines the Indirect Genotoxicity of Low-Dose BPA in Thyroid Cells

Author

Concetta Ambrosino, Danila Cuomo, Immacolata Porreca, Massimo Mallardo, Mario De Felice, Luisa Ulloa Severino, Michele Ceccarelli, Angela Nebbioso, Elena Amendola, Lucia Altucci, Fulvio D'Angelo, Porreca, I, Ulloa Severino, L, D'Angelo, F, Cuomo, D, Ceccarelli, M, Altucci, L, Amendola, E, Nebbioso, A, Mallardo, M, De Felice, M, Ambrosino, C., Porreca, Immacolata, ULLOA SEVERINO, Luisa, D'Angelo, Fulvio, Cuomo, Danila, Ceccarelli, Michele, Altucci, Lucia, Amendola, Elena, Nebbioso, Angela, Mallardo, Massimo, De Felice, Mario, Ambrosino, Concetta, and Ulloa Severino, Luisa

Subjects
0301 basic medicine, Genetics and Molecular Biology (all), Time Factors, Light, Benzhydryl Compounds, Cell Line, DNA Damage, DNA Replication, Dose-Response Relationship, Drug, Gene Expression, Humans, Phenols, Thyroid Gland, Transcriptome, Medicine (all), Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), Microarrays, DNA rapair, lcsh:Medicine, 010501 environmental sciences, medicine.disease_cause, 01 natural sciences, Biochemistry, Medicine and Health Sciences, lcsh:Science, Benzhydryl Compound, Thyroid, Multidisciplinary, Physics, Genomics, Cell biology, Nucleic acids, Chemistry, Bioassays and Physiological Analysis, Toxicity, Physical Sciences, DNA microarray, Drug, Anatomy, Transcriptome Analysis, hormones, hormone substitutes, and hormone antagonists, Human, Research Article, Ultraviolet radiation, Programmed cell death, endocrine system, Pollutants, Time Factor, DNA repair, DNA damage, DNA recombination, Endocrine System, Biology, Research and Analysis Methods, Dose-Response Relationship, 03 medical and health sciences, Electromagnetic radiation, medicine, Genetics, Environmental Chemistry, 0105 earth and related environmental sciences, Phenol, Biology and life sciences, urogenital system, lcsh:R, Ecology and Environmental Sciences, Computational Biology, DNA Repair Pathway, DNA, Genome Analysis, Molecular biology, 030104 developmental biology, lcsh:Q, Ultraviolet C, Genotoxicity
Abstract

Epidemiological and experimental data highlighted the thyroid-disrupting activity of bisphenol A (BPA). Although pivotal to identify the mechanisms of toxicity, direct low-dose BPA effects on thyrocytes have not been assessed. Here, we report the results of microarray experiments revealing that the transcriptome reacts dynamically to low-dose BPA exposure, adapting the changes in gene expression to the exposure duration. The response involves many genes, enriching specific pathways and biological functions mainly cell death/proliferation or DNA repair. Their expression is only slightly altered but, since they enrich specific pathways, this results in major effects as shown here for transcripts involved in the DNA repair pathway. Indeed, even though no phenotypic changes are induced by the treatment, we show that the exposure to BPA impairs the cell response to further stressors. We experimentally verify that prolonged exposure to low doses of BPA results in a delayed response to UV-C-induced DNA damage, due to impairment of p21-Tp53 axis, with the BPA-treated cells more prone to cell death and DNA damage accumulation. The present findings shed light on a possible mechanism by which BPA, not able to directly cause genetic damage at environmental dose, may exert an indirect genotoxic activity.

Published
2016

48. Cross-species toxicogenomic analyses and phenotypic anchoring in response to groundwater low-level pollution

Author

Immacolata Porreca, Michele Ceccarelli, Marzia Scarfò, Antonio Nardone, Francesca Pane, Daniela Gentilcore, Pasquale De Luca, Fulvio D'Angelo, Libera Esposito, Mario De Felice, Paolo Sordino, Massimo Mallardo, Concetta Ambrosino, Emanuele Carchia, Angela Amoresano, Sergio Maccarone, Francesco M. Guadagno, Andrea Affuso, Porreca, Immacolata, D'Angelo, Fulvio, Gentilcore, Daniela, Carchia, Emanuele, Amoresano, Angela, Affuso, Andrea, Ceccarelli, Michele, De Luca, Pasquale, Esposito, Libera, Guadagno, Francesco M., Mallardo, Massimo, Nardone, Antonio, Maccarone, Sergio, Pane, Francesca, Scarfò, Marzia, Sordino, Paolo, DE FELICE, Mario, and Ambrosino, Concetta

Subjects
Male, Time Factors, Microarray, ved/biology.organism_classification_rank.species, Gene Expression, 010501 environmental sciences, Bioinformatics, Toxicology, Toxicogenetics, 01 natural sciences, Mice, Liver Function Tests, Toxicity Tests, Chronic, Groundwater, Zebrafish, Groundwater pollution, 0303 health sciences, Liver Function Test, Environmental exposure, Toxicogenomics, 3. Good health, Animal models, Phenotype, Liver, Chemical mixture, Female, DNA microarray, Research Article, Biotechnology, Time Factor, Low-dose, Reproducibility of Result, Toxicogenomic, Computational biology, Biology, Toxicogenetic, 03 medical and health sciences, Species Specificity, Toxicity Tests, Acute, Genetics, Animals, Animal model, Model organism, 030304 developmental biology, 0105 earth and related environmental sciences, Animal, ved/biology, Microarray analysis techniques, Gene Expression Profiling, Water Pollution, Reproducibility of Results, Biomarker, Environmental Exposure, biology.organism_classification, Estrogen, Gene expression profiling, Biomarkers
Abstract

Background Comparison of toxicogenomic data facilitates the identification of deregulated gene patterns and maximizes health risk prediction in human. Results Here, we performed phenotypic anchoring on the effects of acute exposure to low-grade polluted groundwater using mouse and zebrafish. Also, we evaluated two windows of chronic exposure in mouse, starting in utero and at the end of lactation. Bioinformatic analysis of livers microarray data showed that the number of deregulated biofunctions and pathways is higher after acute exposure, compared to the chronic one. It also revealed specific profiles of altered gene expression in all treatments, pointing to stress response/mitochondrial pathways as major players of environmental toxicity. Of note, dysfunction of steroid hormones was also predicted by bioinformatic analysis and verified in both models by traditional approaches, serum estrogens measurement and vitellogenin mRNA determination in mice and zebrafish, respectively. Conclusions In our report, phenotypic anchoring in two vertebrate model organisms highlights the toxicity of low-grade pollution, with varying susceptibility based on exposure window. The overlay of zebrafish and mice deregulated pathways, more than single genes, is useful in risk identification from chemicals implicated in the observed effects. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-1067) contains supplementary material, which is available to authorized users.

Published
2014

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