56 results on '"Malta, TM"'
Search Results
2. Longitudinal molecular trajectories of diffuse glioma in adults
- Author
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Barthel, FP, Johnson, KC, Varn, FS, Moskalik, AD, Tanner, G, Kocakavuk, E, Anderson, KJ, Abiola, O, Aldape, K, Alfaro, KD, Alpar, D, Amin, SB, Ashley, DM, Bandopadhayay, P, Barnholtz-Sloan, JS, Beroukhim, R, Bock, C, Brastianos, PK, Brat, DJ, Brodbelt, AR, Bruns, AF, Bulsara, KR, Chakrabarty, A, Chakravarti, A, Chuang, JH, Claus, EB, Cochran, EJ, Connelly, J, Costello, JF, Finocchiaro, G, Fletcher, MN, French, PJ, Gan, HK, Gilbert, MR, Gould, PV, Grimmer, MR, Iavarone, A, Ismail, A, Jenkinson, MD, Khasraw, M, Kim, H, Kouwenhoven, MCM, LaViolette, PS, Li, M, Lichter, P, Ligon, KL, Lowman, AK, Malta, TM, Mazor, T, McDonald, KL, Molinaro, AM, Do-Hyun, N, Nayyar, N, Ng, HK, Ngan, CY, Niclou, SP, Niers, JM, Noushmehr, H, Noorbakhsh, J, Ormond, DR, Park, C-K, Poisson, LM, Rabadan, R, Radlwimmer, B, Rao, G, Reifenberger, G, Sa, JK, Schuster, M, Shaw, BL, Short, SC, Smitt, PAS, Sloan, AE, Smits, M, Suzuki, H, Tabatabai, G, Van Meir, EG, Watts, C, Weller, M, Wesseling, P, Westerman, BA, Widhalm, G, Woehrer, A, Yung, WKA, Zadeh, G, Huse, JT, De Groot, JF, Stead, LF, Verhaak, RGW, Barthel, FP, Johnson, KC, Varn, FS, Moskalik, AD, Tanner, G, Kocakavuk, E, Anderson, KJ, Abiola, O, Aldape, K, Alfaro, KD, Alpar, D, Amin, SB, Ashley, DM, Bandopadhayay, P, Barnholtz-Sloan, JS, Beroukhim, R, Bock, C, Brastianos, PK, Brat, DJ, Brodbelt, AR, Bruns, AF, Bulsara, KR, Chakrabarty, A, Chakravarti, A, Chuang, JH, Claus, EB, Cochran, EJ, Connelly, J, Costello, JF, Finocchiaro, G, Fletcher, MN, French, PJ, Gan, HK, Gilbert, MR, Gould, PV, Grimmer, MR, Iavarone, A, Ismail, A, Jenkinson, MD, Khasraw, M, Kim, H, Kouwenhoven, MCM, LaViolette, PS, Li, M, Lichter, P, Ligon, KL, Lowman, AK, Malta, TM, Mazor, T, McDonald, KL, Molinaro, AM, Do-Hyun, N, Nayyar, N, Ng, HK, Ngan, CY, Niclou, SP, Niers, JM, Noushmehr, H, Noorbakhsh, J, Ormond, DR, Park, C-K, Poisson, LM, Rabadan, R, Radlwimmer, B, Rao, G, Reifenberger, G, Sa, JK, Schuster, M, Shaw, BL, Short, SC, Smitt, PAS, Sloan, AE, Smits, M, Suzuki, H, Tabatabai, G, Van Meir, EG, Watts, C, Weller, M, Wesseling, P, Westerman, BA, Widhalm, G, Woehrer, A, Yung, WKA, Zadeh, G, Huse, JT, De Groot, JF, Stead, LF, and Verhaak, RGW
- Abstract
The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.
- Published
- 2019
3. Detection of glioma and prognostic subtypes by non-invasive circulating cell-free DNA methylation markers
- Author
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Noushmehr, H, primary, Sabedot, TS, additional, Malta, TM, additional, Nelson, K, additional, Snyder, J, additional, Wells, M, additional, deCarvalho, A, additional, Mukherjee, A, additional, Chitale, D, additional, Mosella, M, additional, Asmaro, K, additional, Robin, A, additional, Rosenblum, M, additional, Mikkelsen, T, additional, Rock, J, additional, Poisson, LM, additional, Lee, I, additional, Walbert, T, additional, Kalkanis, S, additional, and Castro, AV, additional
- Published
- 2019
- Full Text
- View/download PDF
4. Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer
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Hoadley, KA, Yau, C, Hinoue, T, Wolf, DM, Lazar, AJ, Drill, E, Shen, R, Taylor, AM, Cherniack, AD, Thorsson, V, Akbani, R, Bowlby, R, Wong, CK, Wiznerowicz, M, Sanchez-Vega, F, Robertson, AG, Schneider, BG, Lawrence, MS, Noushmehr, H, Malta, TM, Stuart, JM, Benz, CC, Laird, PW, Hoadley, KA, Yau, C, Hinoue, T, Wolf, DM, Lazar, AJ, Drill, E, Shen, R, Taylor, AM, Cherniack, AD, Thorsson, V, Akbani, R, Bowlby, R, Wong, CK, Wiznerowicz, M, Sanchez-Vega, F, Robertson, AG, Schneider, BG, Lawrence, MS, Noushmehr, H, Malta, TM, Stuart, JM, Benz, CC, and Laird, PW
- Abstract
We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.
- Published
- 2018
5. TCGAbiolinks: An R/Bioconductor package for integrative analysis of TCGA data
- Author
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Colaprico, A, Silva, T, Olsen, C, Garofano, L, Cava, C, Garolini, D, Sabedot, T, Malta, T, Pagnotta, S, Castiglioni, I, Ceccarelli, M, Bontempi, G, Noushmehr, H, Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, Sabedot TS, Malta TM, Pagnotta SM, CASTIGLIONI I, Ceccarelli M, Bontempi G, Noushmehr H, Colaprico, A, Silva, T, Olsen, C, Garofano, L, Cava, C, Garolini, D, Sabedot, T, Malta, T, Pagnotta, S, Castiglioni, I, Ceccarelli, M, Bontempi, G, Noushmehr, H, Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, Sabedot TS, Malta TM, Pagnotta SM, CASTIGLIONI I, Ceccarelli M, Bontempi G, and Noushmehr H
- Abstract
The Cancer Genome Atlas (TCGA) research network has made public a large collection of clinical and molecular phenotypes of more than 10 000 tumor patients across 33 different tumor types. Using this cohort, TCGA has published over 20 marker papers detailing the genomic and epigenomic alterations associated with these tumor types. Although many important discoveries have been made by TCGA's research network, opportunities still exist to implement novel methods, thereby elucidating new biological pathways and diagnostic markers. However, mining the TCGA data presents several bioinformatics challenges, such as data retrieval and integration with clinical data and other molecular data types (e.g. RNA and DNA methylation). We developed an R/Bioconductor package called TCGAbiolinks to address these challenges and offer bioinformatics solutions by using a guided workflow to allow users to query, download and perform integrative analyses of TCGA data. We combined methods from computer science and statistics into the pipeline and incorporated methodologies developed in previous TCGA marker studies and in our own group. Using four different TCGA tumor types (Kidney, Brain, Breast and Colon) as examples, we provide case studies to illustrate examples of reproducibility, integrative analysis and utilization of different Bioconductor packages to advance and accelerate novel discoveries.
- Published
- 2016
6. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma
- Author
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Michele Ceccarelli, Floris P. Barthel, Tathiane M. Malta, Thais S. Sabedot, Sofie R. Salama, Bradley A. Murray, Olena Morozova, Yulia Newton, Amie Radenbaugh, Stefano M. Pagnotta, Samreen Anjum, Jiguang Wang, Ganiraju Manyam, Pietro Zoppoli, Shiyun Ling, Arjun A. Rao, Mia Grifford, Andrew D. Cherniack, Hailei Zhang, Laila Poisson, Carlos Gilberto Carlotti, Daniela Pretti da Cunha Tirapelli, Arvind Rao, Tom Mikkelsen, Ching C. Lau, W.K. Alfred Yung, Raul Rabadan, Jason Huse, Daniel J. Brat, Norman L. Lehman, Jill S. Barnholtz-Sloan, Siyuan Zheng, Kenneth Hess, Ganesh Rao, Matthew Meyerson, Rameen Beroukhim, Lee Cooper, Rehan Akbani, Margaret Wrensch, David Haussler, Kenneth D. Aldape, Peter W. Laird, David H. Gutmann, Houtan Noushmehr, Antonio Iavarone, Roel G.W. Verhaak, Harindra Arachchi, J. Todd Auman, Miruna Balasundaram, Saianand Balu, Gene Barnett, Stephen Baylin, Sue Bell, Christopher Benz, Natalie Bir, Keith L. Black, Tom Bodenheimer, Lori Boice, Moiz S. Bootwalla, Jay Bowen, Christopher A. Bristow, Yaron S.N. Butterfield, Qing-Rong Chen, Lynda Chin, Juok Cho, Eric Chuah, Sudha Chudamani, Simon G. Coetzee, Mark L. Cohen, Howard Colman, Marta Couce, Fulvio D’Angelo, Tanja Davidsen, Amy Davis, John A. Demchok, Karen Devine, Li Ding, Rebecca Duell, J. Bradley Elder, Jennifer M. Eschbacher, Ashley Fehrenbach, Martin Ferguson, Scott Frazer, Gregory Fuller, Jordonna Fulop, Stacey B. Gabriel, Luciano Garofano, Julie M. Gastier-Foster, Nils Gehlenborg, Mark Gerken, Gad Getz, Caterina Giannini, William J. Gibson, Angela Hadjipanayis, D. Neil Hayes, David I. Heiman, Beth Hermes, Joe Hilty, Katherine A. Hoadley, Alan P. Hoyle, Mei Huang, Stuart R. Jefferys, Corbin D. Jones, Steven J.M. Jones, Zhenlin Ju, Alison Kastl, Ady Kendler, Jaegil Kim, Raju Kucherlapati, Phillip H. Lai, Michael S. Lawrence, Semin Lee, Kristen M. Leraas, Tara M. Lichtenberg, Pei Lin, Yuexin Liu, Jia Liu, Julia Y. Ljubimova, Yiling Lu, Yussanne Ma, Dennis T. Maglinte, Harshad S. Mahadeshwar, Marco A. Marra, Mary McGraw, Christopher McPherson, Shaowu Meng, Piotr A. Mieczkowski, C. Ryan Miller, Gordon B. Mills, Richard A. Moore, Lisle E. Mose, Andrew J. Mungall, Rashi Naresh, Theresa Naska, Luciano Neder, Michael S. Noble, Ardene Noss, Brian Patrick O’Neill, Quinn T. Ostrom, Cheryl Palmer, Angeliki Pantazi, Michael Parfenov, Peter J. Park, Joel S. Parker, Charles M. Perou, Christopher R. Pierson, Todd Pihl, Alexei Protopopov, Nilsa C. Ramirez, W. Kimryn Rathmell, Xiaojia Ren, Jeffrey Roach, A. Gordon Robertson, Gordon Saksena, Jacqueline E. Schein, Steven E. Schumacher, Jonathan Seidman, Kelly Senecal, Sahil Seth, Hui Shen, Yan Shi, Juliann Shih, Kristen Shimmel, Hugues Sicotte, Suzanne Sifri, Tiago Silva, Janae V. Simons, Rosy Singh, Tara Skelly, Andrew E. Sloan, Heidi J. Sofia, Matthew G. Soloway, Xingzhi Song, Carrie Sougnez, Camila Souza, Susan M. Staugaitis, Huandong Sun, Charlie Sun, Donghui Tan, Jiabin Tang, Yufang Tang, Leigh Thorne, Felipe Amstalden Trevisan, Timothy Triche, David J. Van Den Berg, Umadevi Veluvolu, Doug Voet, Yunhu Wan, Zhining Wang, Ronald Warnick, John N. Weinstein, Daniel J. Weisenberger, Matthew D. Wilkerson, Felicia Williams, Lisa Wise, Yingli Wolinsky, Junyuan Wu, Andrew W. Xu, Lixing Yang, Liming Yang, Travis I. Zack, Jean C. Zenklusen, Jianhua Zhang, Wei Zhang, Jiashan Zhang, Erik Zmuda, Ceccarelli, M, Barthel, Fp, Malta, Tm, Sabedot, T, Salama, Sr, Murray, Ba, Morozova, O, Newton, Y, Radenbaugh, A, Pagnotta, Sm, Anjum, S, Wang, Jg, Manyam, G, Zoppoli, P, Ling, S, Rao, Aa, Grifford, M, Cherniack, Ad, Zhang, Hl, Poisson, L, Carlotti, Cg, Tirapelli, Dpd, Rao, A, Mikkelsen, T, Lau, Cc, Yung, Wka, Rabadan, R, Huse, J, Brat, Dj, Lehman, Nl, Barnholtz-Sloan, J, Zheng, S, Hess, K, Rao, G, Meyerson, M, Beroukhim, R, Cooper, L, Akbani, R, Wrensch, M, Haussler, D, Aldape, Kd, Laird, Pw, Gutmann, Dh, Noushmehr, H, Iavarone, A, Verhaak, Rgw, and Neurosurgery
- Subjects
0301 basic medicine ,Adult ,X-linked Nuclear Protein ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Epigenesis, Genetic ,Transcriptome ,03 medical and health sciences ,Diffuse Glioma ,Glioma ,medicine ,Cluster Analysis ,Humans ,Promoter Regions, Genetic ,Gene ,Telomerase ,ATRX ,Cell Proliferation ,Pilocytic astrocytoma ,Biochemistry, Genetics and Molecular Biology(all) ,Brain Neoplasms ,MUTAÇÃO GENÉTICA ,DNA Helicases ,Nuclear Proteins ,DNA Methylation ,Middle Aged ,Telomere ,medicine.disease ,Isocitrate Dehydrogenase ,3. Good health ,030104 developmental biology ,DNA demethylation ,DNA methylation ,Mutation ,Cancer research ,Signal Transduction - 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
7. Network-Based Transcriptome Analysis Reveals FAM3C as a Novel Potential Biomarker for Glioblastoma.
- Author
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Chagas PS, Chagas HIS, Naeini SE, Bhandari B, Gouron J, Malta TM, Salles ÉL, Wang LP, Yu JC, and Baban B
- Subjects
- Humans, Protein Interaction Maps, Prognosis, Transcriptome, Gene Regulatory Networks, Computational Biology methods, Survival Rate, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Neoplasm Proteins biosynthesis, Cytokines, Glioblastoma genetics, Glioblastoma metabolism, Glioblastoma mortality, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Gene Expression Regulation, Neoplastic, Brain Neoplasms genetics, Brain Neoplasms metabolism, Brain Neoplasms pathology, Gene Expression Profiling
- Abstract
Glioblastoma (GBM) is the most common form of malignant primary brain tumor with a high mortality rate. The aim of the present study was to investigate the clinical significance of Family with Sequence Similarity 3, Member C, FAM3C, in GBM using bioinformatic-integrated analysis. First, we performed the transcriptomic integration analysis to assess the expression profile of FAM3C in GBM using several data sets (RNA-sequencing and scRNA-sequencing), which were obtained from TCGA and GEO databases. By using the STRING platform, we investigated FAM3C-coregulated genes to construct the protein-protein interaction network. Next, Metascape, Enrichr, and CIBERSORT databases were used. We found FAM3C high expression in GBM with poor survival rates. Further, we observed, via FAM3C coexpression network analysis, that FAM3C plays key roles in several hallmarks of cancer. Surprisingly, we also highlighted five FAM3C‑coregulated genes overexpressed in GBM. Specifically, we demonstrated the association between the high expression of FAM3C and the abundance of the different immune cells, which may markedly worsen GBM prognosis. For the first time, our findings suggest that FAM3C not only can be a new emerging biomarker with promising therapeutic values to GBM patients but also gave a new insight into a potential resource for future GBM studies., (© 2024 Wiley Periodicals LLC.)
- Published
- 2024
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8. The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen.
- Author
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Malta TM, Sabedot TS, Morosini NS, Datta I, Garofano L, Vallentgoed W, Varn FS, Aldape K, D'Angelo F, Bakas S, Barnholtz-Sloan JS, Gan HK, Hasanain M, Hau AC, Johnson KC, Cazacu S, deCarvalho AC, Khasraw M, Kocakavuk E, Kouwenhoven MCM, Migliozzi S, Niclou SP, Niers JM, Ormond DR, Paek SH, Reifenberger G, Sillevis Smitt PA, Smits M, Stead LF, van den Bent MJ, Van Meir EG, Walenkamp A, Weiss T, Weller M, Westerman BA, Ylstra B, Wesseling P, Lasorella A, French PJ, Poisson LM, Verhaak RGW, Iavarone A, and Noushmehr H
- Subjects
- Humans, Epigenesis, Genetic, Epigenomics, Mutation, Neoplasm Recurrence, Local genetics, Tumor Microenvironment, Brain Neoplasms pathology, Glioma pathology, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism
- Abstract
Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype., Significance: Standard treatments are related to loss of DNA methylation in IDHmut glioma, resulting in epigenetic activation of genes associated with tumor progression and alterations in the microenvironment that resemble treatment-naïve IDHwt glioma., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
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9. Machine learning determines stemness associated with simple and basal-like canine mammary carcinomas.
- Author
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Xavier PLP, Marção M, Simões RLS, Job MEG, de Francisco Strefezzi R, Fukumasu H, and Malta TM
- Abstract
Simple and complex carcinomas are the most common type of malignant Canine Mammary Tumors (CMTs), with simple carcinomas exhibiting aggressive behavior and poorer prognostic. Stemness is an ability associated with cancer initiation, malignancy, and therapeutic resistance, but is still few elucidated in canine mammary tumor subtypes. Here, we first validated, using CMT samples, a previously published canine one-class logistic regression machine learning algorithm (OCLR) to predict stemness (mRNAsi) in canine cancer cells. Then, using the canine mRNAsi, we observed that simple carcinomas exhibit higher stemness than complex carcinomas and other histological subtypes. Also, we confirmed that stemness is higher and associated with basal-like CMTs and with NMF2 metagene signature, a tumor-specific DNA-repair metagene signature. Using correlation analysis, we selected the top 50 genes correlated with higher stemness, and the top 50 genes correlated with lower stemness and further performed a gene set enrichment analysis to observe the biological processes enriched for these genes. Finally, we suggested two promise stemness-associated targets in CMTs, POLA2 and APEX1 , especially in simple carcinomas. Thus, our work elucidates stemness as a potential mechanism behind the aggressiveness and development of canine mammary tumors, especially in simple carcinomas, describing evidence of a promising strategy to target this disease., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)
- Published
- 2024
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10. Accumulation of sphingosine kinase 2 protein induces malignant transformation in oral keratinocytes associated with stemness, autophagy, senescence, and proliferation.
- Author
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Fugio LB, Silva G, Ferraz CL, Trevisan GL, Coeli-Lacchini FB, Garcia CB, Sousa LO, Malta TM, Gil CD, and Leopoldino AM
- Subjects
- Humans, Autophagy, Carcinogenesis genetics, Cell Proliferation, Cell Transformation, Neoplastic genetics, Keratinocytes, Squamous Cell Carcinoma of Head and Neck, Carcinoma, Squamous Cell genetics, Head and Neck Neoplasms, Mouth Neoplasms genetics
- Abstract
Sphingosine-1-phosphate (S1P) signaling has been widely explored as a therapeutic target in cancer. Sphingosine kinase 2 (SK2), one of the kinases that phosphorylate sphingosine, has a cell type and cell location-dependent mechanism of action, so the ability of SK2 to induce cell cycle arrest, apoptosis, proliferation, and survival is strongly influenced by the cell-context. In contrast to SK1, which is widely studied in different types of cancer, including head and neck cancer, the role of SK2 in the development and progression of oral cancer is still poorly understood. In order to elucidate SK2 role in oral cancer, we performed the overexpression of SK2 in non-tumor oral keratinocyte cell (NOK SK2) and in oral squamous cell carcinoma (HN12 SK2), and RNA interference for SK2 in another oral squamous cell carcinoma (HN13 shSK2). In our study we demonstrate for the first time that accumulation of SK2 can be a starting point for oncogenesis and transforms a non-tumor oral keratinocyte (NOK-SI) into highly aggressive tumor cells, even acting on cell plasticity. Furthermore, in oral metastatic cell line (HN12), SK2 contributed even more to the tumorigenesis, inducing proliferation and tumor growth. Our work reveals the intriguing role of SK2 as an oral tumor promoter and regulator of different pathways and cellular processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)
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- 2024
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11. A machine learning one-class logistic regression model to predict stemness for single cell transcriptomics and spatial omics.
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Dezem FS, Marção M, Ben-Cheikh B, Nikulina N, Omotoso A, Burnett D, Coelho P, Hurley J, Gomez C, Phan-Everson T, Ong G, Martelotto L, Lewis ZR, George S, Braubach O, Malta TM, and Plummer J
- Subjects
- Logistic Models, Gene Expression Profiling, Machine Learning, Transcriptome, Proteomics
- Abstract
Cell annotation is a crucial methodological component to interpreting single cell and spatial omics data. These approaches were developed for single cell analysis but are often biased, manually curated and yet unproven in spatial omics. Here we apply a stemness model for assessing oncogenic states to single cell and spatial omic cancer datasets. This one-class logistic regression machine learning algorithm is used to extract transcriptomic features from non-transformed stem cells to identify dedifferentiated cell states in tumors. We found this method identifies single cell states in metastatic tumor cell populations without the requirement of cell annotation. This machine learning model identified stem-like cell populations not identified in single cell or spatial transcriptomic analysis using existing methods. For the first time, we demonstrate the application of a ML tool across five emerging spatial transcriptomic and proteomic technologies to identify oncogenic stem-like cell types in the tumor microenvironment., (© 2023. The Author(s).)
- Published
- 2023
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12. Detection of diagnostic and prognostic methylation-based signatures in liquid biopsy specimens from patients with meningiomas.
- Author
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Herrgott GA, Snyder JM, She R, Malta TM, Sabedot TS, Lee IY, Pawloski J, Podolsky-Gondim GG, Asmaro KP, Zhang J, Cannella CE, Nelson K, Thomas B, deCarvalho AC, Hasselbach LA, Tundo KM, Newaz R, Transou A, Morosini N, Francisco V, Poisson LM, Chitale D, Mukherjee A, Mosella MS, Robin AM, Walbert T, Rosenblum M, Mikkelsen T, Kalkanis S, Tirapelli DPC, Weisenberger DJ, Carlotti CG Jr, Rock J, Castro AV, and Noushmehr H
- Subjects
- Humans, Prognosis, Artificial Intelligence, DNA Methylation, Liquid Biopsy, Meningioma diagnosis, Meningioma genetics, Meningeal Neoplasms diagnosis, Meningeal Neoplasms genetics
- Abstract
Recurrence of meningiomas is unpredictable by current invasive methods based on surgically removed specimens. Identification of patients likely to recur using noninvasive approaches could inform treatment strategy, whether intervention or monitoring. In this study, we analyze the DNA methylation levels in blood (serum and plasma) and tissue samples from 155 meningioma patients, compared to other central nervous system tumor and non-tumor entities. We discover DNA methylation markers unique to meningiomas and use artificial intelligence to create accurate and universal models for identifying and predicting meningioma recurrence, using either blood or tissue samples. Here we show that liquid biopsy is a potential noninvasive and reliable tool for diagnosing and predicting outcomes in meningioma patients. This approach can improve personalized management strategies for these patients., (© 2023. Springer Nature Limited.)
- Published
- 2023
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13. Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas.
- Author
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Bredel M, Espinosa L, Kim H, Scholtens DM, McElroy JP, Rajbhandari R, Meng W, Kollmeyer TM, Malta TM, Quezada MA, Harsh GR, Lobo-Jarne T, Solé L, Merati A, Nagaraja S, Nair S, White JJ, Thudi NK, Fleming JL, Webb A, Natsume A, Ogawa S, Weber RG, Bertran J, Haque SJ, Hentschel B, Miller CR, Furnari FB, Chan TA, Grosu AL, Weller M, Barnholtz-Sloan JS, Monje M, Noushmehr H, Jenkins RB, Rogers CL, MacDonald DR, Pugh SL, and Chakravarti A
- Subjects
- Child, Humans, Epigenome, Haploinsufficiency genetics, Mutation genetics, NF-KappaB Inhibitor alpha genetics, Isocitrate Dehydrogenase, Brain Neoplasms genetics, Glioma genetics, Glioma pathology
- Abstract
Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas., Competing Interests: Declaration of interests M.B.: NIH/NINDS grant R01NS117641, advisory board membership and grant (Varian Medical Systems), consulting (MRIMath). L.E.: Instituto de Salud Carlos III grant PI22/00069. T.L.-J.: an Asociación Española Contra el Cáncer grant. G.R.H.: NIH/NIBIB grant (P41-EB032840-01). J.S.B.-S.: NIH/NCI grants to Case Western Reserve University School of Medicine. J.P.M.: MOU between OSU Radiation Oncology and OSU Center for Biostatistics. R.B.J.: NIH grants. A.W.: MOU between OSU Radiation Oncology and OSU Biomedical Informatics. T.A.C.: grants (PGDX, Pfizer, AstraZeneca, Illumina, NysnoBio); royalties (PGDX); consulting (Illumina, NysnoBio, Pfizer, BMS, Merck, LG Chem); patents (TMB as predictor of immunotherapy response); stock (Griststone Bio, Nysno Bio). A.N.: consulting (Daiichi-Sankyo, NGK, SparkPlug) to his institution; $2,000 as honoraria. M.W.: grants (Apogenix, Merck, Sharp & Dohme, Merck [EMD], Philogen, Quercis); consulting (Adastra, Medac, Merck [EMD], Nerviano Medical Sciences, Novartis); honoraria (Bristol Meyer Squibb, Medac, Merck, Sharp & Dohme); Data Safety Monitoring Board or Advisory Board (Orbus and Philogen); leadership (EORTC). R.G.W.: grant 70-3163-Wi 3 (German Cancer Aid). S.O.: grant (Cordia Therapeutics, Dainippon-Sumitomo, Pharmaceuticals, Otsuka Assay Inc.); royalties (ASAHI Genomics, Qiagen); consulting (Cordia Therapeutics, Kan Research Institute, Novartis Pharmaceuticals); honoraria (MSD Japan, Kyowa Hakko Kirin, Pfizer); stocks (ASAHI Genomics, Cordia Therapeutics, Rebirthell). M.M.: NIH grants (R01NS092597, DP1NS111132, P50CA165962), grants from Kleberg Foundation Cancer Research, Ludwig Fund for Cancer Research; consulting (Cygnal Therapeutics); honoraria for lectures. C.R.M. and F.B.F.: NIH grant (R01CA258248). F.B.F.: NIH grant (R01NS080939). D.R.M.: clinical trials support (INTELLANCE-1 study [M13-813], CCTG CE.8 [EORTC-1709-BTG], INDIGO study [AG-881], Abbvie, Celgene, Agios [now Servier])., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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14. Epigenomic integrative analysis pinpoint master regulator transcription factors associated with tumorigenesis in squamous cell carcinoma of oral tongue.
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Okano LM, Fonseca LMMD, Erthal ID, and Malta TM
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Head and Neck Cancer (HNC) is a heterogeneous group of cancers, which includes cancers arising in the oral cavity, nasopharynx, oropharynx, hypopharynx, and larynx. Epidemiological studies have revealed that several factors such as tobacco and alcohol use, exposure to environmental pollutants, viral infection, and genetic factors are risk factors for developing HNC. The squamous cell carcinoma of oral tongue (SCCOT), which is significantly more aggressive than the other forms of oral squamous cell carcinoma, presents a propensity for rapid local invasion and spread, and a high recurrence rate. Dysregulation in the epigenetic machinery of cancer cells might help uncover the mechanisms of SCOOT tumorigenesis. Here, we used DNA methylation changes to identify cancer-specific enhancers that were enriched for specific transcription factor binding sites (TFBS), and potential master regulator transcription factors (MRTF) associated with SCCOT. We identified the activation of MRTFs associated with increased invasiveness, metastasis, epithelial-to-mesenchymal transition, poor prognosis, and stemness. On the other hand, we found the downregulation of MRTFs associated with tumor suppression. The identified MRTFs should be further investigated to clarify their role in oral cancer tumorigenesis and for their potential use as biological markers.
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- 2023
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15. Advances in Central Nervous System Tumor Classification.
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Malta TM, Snyder J, Noushmehr H, and Castro AV
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- Humans, Central Nervous System, Histological Techniques, Meningioma diagnosis, Meningioma genetics, Central Nervous System Neoplasms diagnosis, Central Nervous System Neoplasms genetics, Meningeal Neoplasms genetics
- Abstract
Historically, the classification of tumors of the central nervous system (CNS) relies on the histologic appearance of cells under a microscope; however, the molecular era of medicine has resulted in new diagnostic paradigms anchored in the intrinsic biology of disease. The 2021 World Health Organization (WHO) reformulated the classification of CNS tumors to incorporate molecular parameters, in addition to histology, to define many tumor types. A contemporary classification system with integrated molecular features aims to provide an unbiased tool to define tumor subtype, the risk of tumor progression, and even the response to certain therapeutic agents. Meningiomas are heterogeneous tumors as depicted by the current 15 distinct variants defined by histology in the 2021 WHO classification, which also incorporated the first moelcular critiera for meningioma grading: homozygous loss of CDKN2A/B and TERT promoter mutation as criteria for a WHO grade 3 meningioma. The proper classification and clinical management of meningioma patients requires a multidisciplinary approach, which in addition to the information on microscopic (histology) and macroscopic (Simpson grade and imaging), should also include molecular alterations. In this chapter, we present the most up-to-date knowledge in CNS tumor classification, particularly in meningioma, in the molecular era and how it could affect their future classification and clinical management of patients with these diseases., (© 2023. Springer Nature Switzerland AG.)
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- 2023
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16. Molecular landscape of IDH-wild type, pTERT-wild type adult glioblastomas.
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Liu EM, Shi ZF, Li KK, Malta TM, Chung NY, Chen H, Chan JY, Poon MF, Kwan JS, Chan DT, Noushmehr H, Mao Y, and Ng HK
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- Humans, Isocitrate Dehydrogenase genetics, Homozygote, In Situ Hybridization, Fluorescence, Sequence Deletion, Mutation genetics, ErbB Receptors genetics, Biomarkers, Prognosis, Glioblastoma genetics, Glioblastoma pathology, Brain Neoplasms pathology, Telomerase genetics
- Abstract
Telomerase reverse transcriptase (TERT) promoter (pTERT) mutation has often been described as a late event in gliomagenesis and it has been suggested as a prognostic biomarker in gliomas other than 1p19q codeleted tumors. However, the characteristics of isocitrate dehydrogenase (IDH) wild type (wt) (IDHwt), pTERTwt glioblastomas are not well known. We recruited 72 adult IDHwt, pTERTwt glioblastomas and performed methylation profiling, targeted sequencing, and fluorescence in situ hybridization (FISH) for TERT structural rearrangement and ALT (alternative lengthening of telomeres). There was no significant difference in overall survival (OS) between our cohort and a the Cancer Genome Atlas (TCGA) cohort of IDHwt, pTERT mutant (mut) glioblastomas, suggesting that pTERT mutation on its own is not a prognostic factor among IDHwt glioblastomas. Epigenetically, the tumors clustered into classic-like (11%), mesenchymal-like (32%), and LGm6-glioblastoma (GBM) (57%), the latter far exceeding the corresponding proportion seen in the TCGA cohort of IDHwt, pTERTmut glioblastomas. LGm6-GBM-clustered tumors were enriched for platelet derived growth factor receptor alpha (PDGFRA) amplification or mutation (p = 0.008), and contained far fewer epidermal growth factor receptor (EGFR) amplification (p < 0.01), 10p loss (p = 0.001) and 10q loss (p < 0.001) compared with cases not clustered to this group. LGm6-GBM cases predominantly showed ALT (p = 0.038). In the whole cohort, only 35% cases showed EGFR amplification and no case showed combined chromosome +7/-10. Since the cases were already pTERTwt, so the three molecular properties of EGFR amplification, +7/-10, and pTERT mutation may not cover all IDHwt glioblastomas. Instead, EGFR and PDGFRA amplifications covered 67% and together with their mutations covered 71% of cases of this cohort. Homozygous deletion of cyclin dependent kinase inhibitor 2A (CDKN2A)/B was associated with a worse OS (p = 0.031) and was an independent prognosticator in multivariate analysis (p = 0.032). In conclusion, adult IDHwt, pTERTwt glioblastomas show epigenetic clustering different from IDHwt, pTERTmut glioblastomas, and IDHwt glioblastomas which are pTERTwt may however not show EGFR amplification or +7/-10 in a significant proportion of cases. CDKN2A/B deletion is a poor prognostic biomarker in this group., (© 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)
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- 2022
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17. Mast cell-T cell axis alters development of colitis-dependent and colitis-independent colorectal tumours: potential for therapeutically targeting via mast cell inhibition.
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Sakita JY, Elias-Oliveira J, Carlos D, de Souza Santos E, Almeida LY, Malta TM, Brunaldi MO, Albuquerque S, Araújo Silva CL, Andrade MV, Bonato VLD, Garcia SB, Cunha FQ, Cebinelli GCM, Martins RB, Matthews J, Colli L, Martin FL, Uyemura SA, and Kannen V
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- Animals, Fluorouracil, Humans, Mast Cells, Mice, Colitis, Colorectal Neoplasms
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Background: Colorectal cancer (CRC) has a high mortality rate and can develop in either colitis-dependent (colitis-associated (CA)-CRC) or colitis-independent (sporadic (s)CRC) manner. There has been a significant debate about whether mast cells (MCs) promote or inhibit the development of CRC. Herein we investigated MC activity throughout the multistepped development of CRC in both human patients and animal models., Methods: We analyzed human patient matched samples of healthy colon vs CRC tissue alongside conducting a The Cancer Genome Atlas-based immunogenomic analysis and multiple experiments employing genetically engineered mouse (GEM) models., Results: Analyzing human CRC samples revealed that MCs can be active or inactive in this disease. An activated MC population decreased the number of tumor-residing CD8 T cells. In mice, MC deficiency decreased the development of CA-CRC lesions, while it increased the density of tumor-based CD8 infiltration. Furthermore, co-culture experiments revealed that tumor-primed MCs promote apoptosis in CRC cells. In MC-deficient mice, we found that MCs inhibited the development of sCRC lesions. Further exploration of this with several GEM models confirmed that different immune responses alter and are altered by MC activity, which directly alters colon tumorigenesis. Since rescuing MC activity with bone marrow transplantation in MC-deficient mice or pharmacologically inhibiting MC effects impacts the development of sCRC lesions, we explored its therapeutic potential against CRC. MC activity promoted CRC cell engraftment by inhibiting CD8+ cell infiltration in tumors, pharmacologically blocking it inhibits the ability of allograft tumors to develop. This therapeutic strategy potentiated the cytotoxic activity of fluorouracil chemotherapy., Conclusion: Therefore, we suggest that MCs have a dual role throughout CRC development and are potential druggable targets against this disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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18. Detection of tumor-specific DNA methylation markers in the blood of patients with pituitary neuroendocrine tumors.
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Herrgott GA, Asmaro KP, Wells M, Sabedot TS, Malta TM, Mosella MS, Nelson K, Scarpace L, Barnholtz-Sloan JS, Sloan AE, Selman WR, deCarvalho AC, Poisson LM, Mukherjee A, Robin AM, Lee IY, Snyder J, Walbert T, Rosenblum M, Mikkelsen T, Bhan A, Craig J, Kalkanis S, Rock J, Noushmehr H, and Castro AV
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- Biomarkers, Tumor genetics, DNA Methylation, Humans, Cell-Free Nucleic Acids, Neuroendocrine Tumors diagnosis, Neuroendocrine Tumors genetics, Neuroendocrine Tumors pathology, Pituitary Neoplasms diagnosis, Pituitary Neoplasms genetics, Pituitary Neoplasms pathology
- Abstract
Background: DNA methylation abnormalities are pervasive in pituitary neuroendocrine tumors (PitNETs). The feasibility to detect methylome alterations in circulating cell-free DNA (cfDNA) has been reported for several central nervous system (CNS) tumors but not across PitNETs. The aim of the study was to use the liquid biopsy (LB) approach to detect PitNET-specific methylation signatures to differentiate these tumors from other sellar diseases., Methods: We profiled the cfDNA methylome (EPIC array) of 59 serum and 41 plasma LB specimens from patients with PitNETs and other CNS diseases (sellar tumors and other pituitary non-neoplastic diseases, lower-grade gliomas, and skull-base meningiomas) or nontumor conditions, grouped as non-PitNET., Results: Our results indicated that despite quantitative and qualitative differences between serum and plasma cfDNA composition, both sources of LB showed that patients with PitNETs presented a distinct methylome landscape compared to non-PitNETs. In addition, LB methylomes captured epigenetic features reported in PitNET tissue and provided information about cell-type composition. Using LB-derived PitNETs-specific signatures as input to develop machine-learning predictive models, we generated scores that distinguished PitNETs from non-PitNETs conditions, including sellar tumor and non-neoplastic pituitary diseases, with accuracies above ~93% in independent cohort sets., Conclusions: Our results underpin the potential application of methylation-based LB profiling as a noninvasive approach to identify clinically relevant epigenetic markers to diagnose and potentially impact the prognostication and management of patients with PitNETs., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
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- 2022
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19. Glioma progression is shaped by genetic evolution and microenvironment interactions.
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Varn FS, Johnson KC, Martinek J, Huse JT, Nasrallah MP, Wesseling P, Cooper LAD, Malta TM, Wade TE, Sabedot TS, Brat D, Gould PV, Wöehrer A, Aldape K, Ismail A, Sivajothi SK, Barthel FP, Kim H, Kocakavuk E, Ahmed N, White K, Datta I, Moon HE, Pollock S, Goldfarb C, Lee GH, Garofano L, Anderson KJ, Nehar-Belaid D, Barnholtz-Sloan JS, Bakas S, Byrne AT, D'Angelo F, Gan HK, Khasraw M, Migliozzi S, Ormond DR, Paek SH, Van Meir EG, Walenkamp AME, Watts C, Weiss T, Weller M, Palucka K, Stead LF, Poisson LM, Noushmehr H, Iavarone A, and Verhaak RGW
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- Adult, Evolution, Molecular, Genes, p16, Humans, Isocitrate Dehydrogenase genetics, Mutation, Neoplasm Recurrence, Local, Brain Neoplasms genetics, Brain Neoplasms pathology, Glioma genetics, Glioma pathology, Tumor Microenvironment
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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., Competing Interests: Declaration of interests R.G.W.V. is a co-founder of Boundless Bio and a consultant for Stellanova Therapeutics. M.K. has received research funding from AbbVie and Bristol Myers Squibb, and he is on the advisory board for Janssen; he has received honoraria from the Jackson Laboratory. D.R.O. has received funding from Integra and Agios. F.P.B. has performed consulting for Bristol Myers Squibb. M.W. has received research grants from AbbVie, Adastra, Apogenix, Merck, Sharp & Dohme, Novocure, and Quercis and honoraria for lectures or advisory board participation or consulting from AbbVie, Adastra, Basilea, Bristol Meyer Squibb, Celgene, Medac, Merck, Sharp & Dohme, Merck, Nerviano Medical Sciences, Novartis, Orbus, Philogen, Roche, Tocagen, and yMabs. A.M.E.W. reported receiving institutional financial support for an advisory role from Polyphor, IPSEN, Karyopharm, and Novartis; unrestricted research grants from IPSEN and Novartis; and study budgets from AbbVie, BMS, Genzyme, Karyopharm Therapeutics, and Roche, all outside the submitted work. H.K.G. has performed consulting for AbbVie, and he is a member of the speaker bureau for AbbVie and Igynta. K.P. is a scientific advisory board member and owns stock in Cue BioPharma., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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20. Evaluation of psychological symptoms in patients before and after simultaneous pancreas-kidney transplantation: a single-center cross-sectional study.
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Romano TM, Linhares MM, Posegger KR, Rangel ÉB, Gonzalez AM, Salzedas-Netto AA, Mucci S, Silva-Junior HT, Lopes Filho GJ, and Medina-Pestana JO
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- Cross-Sectional Studies, Female, Humans, Male, Pancreas, Kidney Failure, Chronic surgery, Kidney Transplantation adverse effects, Kidney Transplantation methods, Pancreas Transplantation adverse effects, Pancreas Transplantation methods
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Purpose: Simultaneous pancreas-kidney transplantation (SPKT) brings several benefits for insulin-dependent type-1 diabetic patients associated with end-stage renal disease (ESRD). However, data on psychological outcomes for the waiting list and the transplanted patients are still lacking., Methods: Using the psychological Beck inventories of anxiety (BAI) and depression (BDI), 39 patients on the waiting list were compared to 88 post-transplanted patients who had undergone SPKT., Results: Significant differences were found regarding depression (p = 0.003) but not anxiety (p = 0.161), being the pretransplant patients more vulnerable to psychological disorders. Remarkable differences were observed relative to the feeling of punishment (p < 0.001) and suicidal thoughts (p = 0.008) between the groups. It was observed that patients who waited a longer period for the transplant showed more post-transplant anxiety symptoms due to the long treatment burden (p = 0.002)., Conclusions: These results demonstrated the positive impact of SPKT on psychological aspects related to depression when comparing the groups. The high number of stressors in the pretransplant stage impacts more severely the psychosocial condition of the patient.
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- 2022
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21. Predicting master transcription factors from pan-cancer expression data.
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Reddy J, Fonseca MAS, Corona RI, Nameki R, Segato Dezem F, Klein IA, Chang H, Chaves-Moreira D, Afeyan LK, Malta TM, Lin X, Abbasi F, Font-Tello A, Sabedot T, Cejas P, Rodríguez-Malavé N, Seo JH, Lin DC, Matulonis U, Karlan BY, Gayther SA, Pasaniuc B, Gusev A, Noushmehr H, Long H, Freedman ML, Drapkin R, Young RA, Abraham BJ, and Lawrenson K
- Abstract
Critical developmental “master transcription factors” (MTFs) can be subverted during tumorigenesis to control oncogenic transcriptional programs. Current approaches to identifying MTFs rely on ChIP-seq data, which is unavailable for many cancers. We developed the CaCTS (Cancer Core Transcription factor Specificity) algorithm to prioritize candidate MTFs using pan-cancer RNA sequencing data. CaCTS identified candidate MTFs across 34 tumor types and 140 subtypes including predictions for cancer types/subtypes for which MTFs are unknown, including e.g. PAX8, SOX17, and MECOM as candidates in ovarian cancer (OvCa). In OvCa cells, consistent with known MTF properties, these factors are required for viability, lie proximal to superenhancers, co-occupy regulatory elements globally, co-bind loci encoding OvCa biomarkers, and are sensitive to pharmacologic inhibition of transcription. Our predictions of MTFs, especially for tumor types with limited understanding of transcriptional drivers, pave the way to therapeutic targeting of MTFs in a broad spectrum of cancers.
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- 2021
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22. A serum-based DNA methylation assay provides accurate detection of glioma.
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Sabedot TS, Malta TM, Snyder J, Nelson K, Wells M, deCarvalho AC, Mukherjee A, Chitale DA, Mosella MS, Sokolov A, Asmaro KP, Robin A, Rosenblum ML, Mikkelsen T, Rock J, Poisson LM, Lee I, Walbert T, Kalkanis S, Iavarone A, Castro AV, and Noushmehr H
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- Biomarkers, Tumor genetics, DNA Methylation, Epigenomics, Humans, Liquid Biopsy, Brain Neoplasms diagnosis, Brain Neoplasms genetics, Glioma diagnosis, Glioma genetics
- Abstract
Background: The detection of somatic mutations in cell-free DNA (cfDNA) from liquid biopsy has emerged as a noninvasive tool to monitor the follow-up of cancer patients. However, the significance of cfDNA clinical utility remains uncertain in patients with brain tumors, primarily because of the limited sensitivity cfDNA has to detect real tumor-specific somatic mutations. This unresolved challenge has prevented accurate follow-up of glioma patients with noninvasive approaches., Methods: Genome-wide DNA methylation profiling of tumor tissue and serum cfDNA of glioma patients., Results: Here, we developed a noninvasive approach to profile the DNA methylation status in the serum of patients with gliomas and identified a cfDNA-derived methylation signature that is associated with the presence of gliomas and related immune features. By testing the signature in an independent discovery and validation cohorts, we developed and verified a score metric (the "glioma-epigenetic liquid biopsy score" or GeLB) that optimally distinguished patients with or without glioma (sensitivity: 100%, specificity: 97.78%). Furthermore, we found that changes in GeLB score reflected clinicopathological changes during surveillance (eg, progression, pseudoprogression, and response to standard or experimental treatment)., Conclusions: Our results suggest that the GeLB score can be used as a complementary approach to diagnose and follow up patients with glioma., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2021
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23. DNA methylation-based signatures classify sporadic pituitary tumors according to clinicopathological features.
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Mosella MS, Sabedot TS, Silva TC, Malta TM, Dezem FS, Asmaro KP, Wells M, Mukherjee A, Poisson LM, Snyder J, deCarvalho AC, Walbert T, Aho T, Kalkanis S, Elias PC, Antonini SR, Rock J, Noushmehr H, Castro M, and Castro AV
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- Cohort Studies, DNA Methylation, Humans, Prognosis, Neuroendocrine Tumors genetics, Pituitary Neoplasms genetics
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Background: Distinct genome-wide methylation patterns cluster pituitary neuroendocrine tumors (PitNETs) into molecular groups associated with specific clinicopathological features. Here we aim to identify, characterize, and validate methylation signatures that objectively classify PitNET into clinicopathological groups., Methods: Combining in-house and publicly available data, we conducted an analysis of the methylome profile of a comprehensive cohort of 177 tumors (Panpit cohort) and 20 nontumor specimens from the pituitary gland. We also retrieved methylome data from an independent PitNET cohort (N = 86) to validate our findings., Results: We identified three methylation clusters associated with adenohypophyseal cell lineages and functional status using an unsupervised approach. Differentially methylated probes (DMP) significantly distinguished the Panpit clusters and accurately assigned the samples of the validation cohort to their corresponding lineage and functional subtypes memberships. The DMPs were annotated in regulatory regions enriched with enhancer elements, associated with pathways and genes involved in pituitary cell identity, function, tumorigenesis, and invasiveness. Some DMPs correlated with genes with prognostic and therapeutic values in other intra- or extracranial tumors., Conclusions: We identified and validated methylation signatures, mainly annotated in enhancer regions that distinguished PitNETs by distinct adenohypophyseal cell lineages and functional status. These signatures provide the groundwork to develop an unbiased approach to classifying PitNETs according to the most recent classification recommended by the 2017 WHO and to explore their biological and clinical relevance in these tumors., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2021
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24. Molecular landscape of IDH-mutant primary astrocytoma Grade IV/glioblastomas.
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Wong QH, Li KK, Wang WW, Malta TM, Noushmehr H, Grabovska Y, Jones C, Chan AK, Kwan JS, Huang QJ, Wong GC, Li WC, Liu XZ, Chen H, Chan DT, Mao Y, Zhang ZY, Shi ZF, and Ng HK
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- Adult, Astrocytoma mortality, Astrocytoma pathology, Brain Neoplasms mortality, Brain Neoplasms pathology, DNA Mutational Analysis, Female, Glioblastoma mortality, Glioblastoma pathology, Humans, Isocitrate Dehydrogenase genetics, Male, Middle Aged, Mutation, Prognosis, Astrocytoma genetics, Brain Neoplasms genetics, Glioblastoma genetics
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WHO 2016 classified glioblastomas into IDH-mutant and IDH-wildtype with the former having a better prognosis but there was no study on IDH-mutant primary glioblastomas only, as previous series included secondary glioblastomas. We recruited a series of 67 IDH-mutant primary glioblastomas/astrocytoma IV without a prior low-grade astrocytoma and examined them using DNA-methylation profiling, targeted sequencing, RNA sequencing and TERT promoter sequencing, and correlated the molecular findings with clinical parameters. The median OS of 39.4 months of 64 cases and PFS of 25.9 months of 57 cases were better than the survival data of IDH-wildtype glioblastomas and IDH-mutant secondary glioblastomas retrieved from datasets. The molecular features often seen in glioblastomas, such as EGFR amplification, combined +7/-10, and TERT promoter mutations were only observed in 6/53 (11.3%), 4/53 (7.5%), and 2/67 (3.0%) cases, respectively, and gene fusions were found only in two cases. The main mechanism for telomere maintenance appeared to be alternative lengthening of telomeres as ATRX mutation was found in 34/53 (64.2%) cases. In t-SNE analyses of DNA-methylation profiles, with an exceptional of one case, a majority of our cases clustered to IDH-mutant high-grade astrocytoma subclass (40/53; 75.5%) and the rest to IDH-mutant astrocytoma subclass (12/53; 22.6%). The latter was also enriched with G-CIMP high cases (12/12; 100%). G-CIMP-high status and MGMT promoter methylation were independent good prognosticators for OS (p = 0.022 and p = 0.002, respectively) and TP53 mutation was an independent poor prognosticator (p = 0.013) when correlated with other clinical parameters. Homozygous deletion of CDKN2A/B was not correlated with OS (p = 0.197) and PFS (p = 0.278). PDGFRA amplification or mutation was found in 16/59 (27.1%) of cases and was correlated with G-CIMP-low status (p = 0.010). Aside from the three well-known pathways of pathogenesis in glioblastomas, chromatin modifying and mismatch repair pathways were common aberrations (88.7% and 20.8%, respectively), the former due to high frequency of ATRX involvement. We conclude that IDH-mutant primary glioblastomas have better prognosis than secondary glioblastomas and have major molecular differences from other commoner glioblastomas. G-CIMP subgroups, MGMT promoter methylation, and TP53 mutation are useful prognostic adjuncts.
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- 2021
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25. Correction to: Molecular landscape of IDH-mutant primary astrocytoma Grade IV/Glioblastomas.
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Wong QH, Li KK, Wang WW, Malta TM, Noushmehr H, Grabovska Y, Jones C, Chan AK, Kwan JS, Huang QJ, Wong GC, Li WC, Liu XZ, Chen H, Chan DT, Mao Y, Zhang ZY, Shi ZF, and Ng HK
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- 2021
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26. Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology.
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Golebiewska A, Hau AC, Oudin A, Stieber D, Yabo YA, Baus V, Barthelemy V, Klein E, Bougnaud S, Keunen O, Wantz M, Michelucci A, Neirinckx V, Muller A, Kaoma T, Nazarov PV, Azuaje F, De Falco A, Flies B, Richart L, Poovathingal S, Arns T, Grzyb K, Mock A, Herold-Mende C, Steino A, Brown D, May P, Miletic H, Malta TM, Noushmehr H, Kwon YJ, Jahn W, Klink B, Tanner G, Stead LF, Mittelbronn M, Skupin A, Hertel F, Bjerkvig R, and Niclou SP
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- Animals, Brain Neoplasms genetics, Glioblastoma drug therapy, Glioblastoma genetics, Glioma genetics, Heterografts drug effects, Humans, Mice, Neoplasm Recurrence, Local genetics, Organoids immunology, Precision Medicine methods, Rats, Brain Neoplasms drug therapy, Glioma drug therapy, Heterografts immunology, Organoids pathology, Temozolomide therapeutic use
- Abstract
Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.
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- 2020
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27. Generation of induced pluripotent stem cells from large domestic animals.
- Author
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Bressan FF, Bassanezze V, de Figueiredo Pessôa LV, Sacramento CB, Malta TM, Kashima S, Fantinato Neto P, Strefezzi RF, Pieri NCG, Krieger JE, Covas DT, and Meirelles FV
- Subjects
- Animals, Animals, Domestic, Cattle, Cell Differentiation, Cellular Reprogramming, Embryonic Stem Cells, Fibroblasts, Horses, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors genetics, Mice, Octamer Transcription Factor-3 genetics, SOXB1 Transcription Factors genetics, Induced Pluripotent Stem Cells
- Abstract
Background: Induced pluripotent stem cells (iPSCs) have enormous potential in developmental biology studies and in cellular therapies. Although extensively studied and characterized in human and murine models, iPSCs from animals other than mice lack reproducible results., Methods: Herein, we describe the generation of robust iPSCs from equine and bovine cells through lentiviral transduction of murine or human transcription factors Oct4, Sox2, Klf4, and c-Myc and from human and murine cells using similar protocols, even when different supplementations were used. The iPSCs were analyzed regarding morphology, gene and protein expression of pluripotency factors, alkaline phosphatase detection, and spontaneous and induced differentiation., Results: Although embryonic-derived stem cells are yet not well characterized in domestic animals, generation of iPS cells from these species is possible through similar protocols used for mouse or human cells, enabling the use of pluripotent cells from large animals for basic or applied purposes. Herein, we also infer that bovine iPS (biPSCs) exhibit similarity to mouse iPSCs (miPSCs), whereas equine iPSs (eiPSCs) to human (hiPSCs)., Conclusions: The generation of reproducible protocols in different animal species will provide an informative tool for producing in vitro autologous pluripotent cells from domestic animals. These cells will create new opportunities in animal breeding through transgenic technology and will support a new era of translational medicine with large animal models.
- Published
- 2020
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28. Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling.
- Author
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Chen J, Mitra A, Li S, Song S, Nguyen BN, Chen JS, Shin JH, Gough NR, Lin P, Obias V, He AR, Yao Z, Malta TM, Noushmehr H, Latham PS, Su X, Rashid A, Mishra B, Wu RC, and Mishra L
- Subjects
- Animals, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Cell Line, Tumor, Cell Proliferation drug effects, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Down-Regulation, Gene Deletion, Gene Expression Regulation, Gene Knockdown Techniques, Gene Silencing, Heterografts, Humans, Liver Neoplasms genetics, Liver Neoplasms pathology, Mice, Mice, Nude, Neoplastic Stem Cells, Oleanolic Acid analogs & derivatives, Oleanolic Acid pharmacology, Phosphorylation, RNA, Small Interfering, Smad Proteins metabolism, Smad2 Protein metabolism, Smad3 Protein deficiency, Smad3 Protein genetics, Spectrin genetics, Spectrin metabolism, Stem Cells pathology, Transforming Growth Factor beta genetics, Transforming Growth Factor beta1 metabolism, Ubiquitin-Protein Ligases antagonists & inhibitors, Ubiquitin-Protein Ligases genetics, Ubiquitination, Up-Regulation, Exome Sequencing, Carcinoma, Hepatocellular metabolism, Liver Neoplasms metabolism, Smad3 Protein metabolism, Transforming Growth Factor beta metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFβ/SMAD signaling. SMAD3 and its adaptors, such as β2SP, are important mediators of TGFβ signaling and regulate gene expression to suppress stem cell-like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC). Here, PJA1, an E3 ligase, promoted ubiquitination and degradation of phosphorylated SMAD3 and impaired a SMAD3/β2SP-dependent tumor-suppressing pathway in multiple HCC cell lines. In mice deficient for SMAD3 ( Smad3
+/- ), PJA1 overexpression promoted the transformation of liver stem cells. Analysis of genes regulated by PJA1 knockdown and TGFβ1 signaling revealed 1,584 co-upregulated genes and 1,280 co-downregulated genes, including many implicated in cancer. The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and reduced growth of HCC cells in culture and xenografts of HCC tumors, suggesting that inhibition of PJA1 may be beneficial in treating HCC or preventing HCC development in at-risk patients. Significance: These findings provide a novel mechanism regulating the tumor suppressor function of TGFβ in liver carcinogenesis., (©2020 American Association for Cancer Research.)- Published
- 2020
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29. Metabolic reprogramming associated with aggressiveness occurs in the G-CIMP-high molecular subtypes of IDH1mut lower grade gliomas.
- Author
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Ruiz-Rodado V, Malta TM, Seki T, Lita A, Dowdy T, Celiku O, Cavazos-Saldana A, Li A, Liu Y, Han S, Zhang W, Song H, Davis D, Lee S, Trepel JB, Sabedot TS, Munasinghe J, Yang C, Herold-Mende C, Gilbert MR, Cherukuri MK, Noushmehr H, and Larion M
- Subjects
- DNA Methylation, Guanine, Humans, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Mutation, Phenotype, Brain Neoplasms genetics, Glioma genetics
- Abstract
Background: Early detection of increased aggressiveness of brain tumors is a major challenge in the field of neuro-oncology because of the inability of traditional imaging to uncover it. Isocitrate dehydrogenase (IDH)-mutant gliomas represent an ideal model system to study the molecular mechanisms associated with tumorigenicity because they appear indolent and non-glycolytic initially, but eventually a subset progresses toward secondary glioblastoma with a Warburg-like phenotype. The mechanisms and molecular features associated with this transformation are poorly understood., Methods: We employed model systems for IDH1 mutant (IDH1mut) gliomas with different growth and proliferation rates in vivo and in vitro. We described the metabolome, transcriptome, and epigenome of these models in order to understand the link between their metabolism and the tumor biology. To verify whether this metabolic reprogramming occurs in the clinic, we analyzed data from The Cancer Genome Atlas., Results: We reveal that the aggressive glioma models have lost DNA methylation in the promoters of glycolytic enzymes, especially lactate dehydrogenase A (LDHA), and have increased mRNA and metabolite levels compared with the indolent model. We find that the acquisition of the high glycolytic phenotype occurs at the glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP)-high molecular subtype in patients and is associated with the worst outcome., Conclusion: We propose very early monitoring of lactate levels as a biomarker of metabolic reprogramming and tumor aggressiveness., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
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30. The quality of life in type I diabetic patients with end-stage kidney disease before and after simultaneous pancreas-kidney transplantation: a single-center prospective study.
- Author
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Posegger KR, Linhares MM, Mucci S, Romano TM, Gonzalez AM, Salzedas Netto AA, Rangel ÉB, Lopes Filho GJ, Silva-Junior HT, and Medina-Pestana J
- Subjects
- Humans, Pancreas, Prospective Studies, Quality of Life, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 1 surgery, Kidney Failure, Chronic surgery, Kidney Transplantation, Pancreas Transplantation
- Abstract
Simultaneous pancreas-kidney transplantation (SPKT) aimed at increasing the life expectancy for diabetic patients with end-stage kidney disease (ESKD). However, the risks of surgery complications and immunosuppression therapy make it unclear if the SPKT positively impacts patient's quality of life (QoL). Using the Kidney Disease Quality of Life-Short-Form Health Survey (KDQOL-SF36) and Problems Areas in Diabetes (PAID) measurement tools, we compared the QoL of 57 patients on the pretransplant waiting list with that of 103 patients who had undergone SPKT. Posttransplantation patients were assessed within different time intervals (<1, 1-3, and >3 years). Mean KDQOL-SF36 scores were better among posttransplantation patients in the SF36 and KDQOL domains. It was also observed patients' stress reduction in PAID mean score (P = 0.011) after SPKT. We concluded that patients receiving SPKT had a better perception of QoL than did patients on the waiting list, and this positive perception remained almost entirely comparable over the three different intervals of the posttransplantation time. These positive results showed better outcomes when excluding patients that lost pancreas graft function. Further research is needed to compare diabetic patients with kidney transplant alone using specific measurement tools to evaluate patient's QoL., (© 2019 Steunstichting ESOT.)
- Published
- 2020
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31. Mutated CEACAMs Disrupt Transforming Growth Factor Beta Signaling and Alter the Intestinal Microbiome to Promote Colorectal Carcinogenesis.
- Author
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Gu S, Zaidi S, Hassan MI, Mohammad T, Malta TM, Noushmehr H, Nguyen B, Crandall KA, Srivastav J, Obias V, Lin P, Nguyen BN, Yao M, Yao R, King CH, Mazumder R, Mishra B, Rao S, and Mishra L
- Subjects
- Animals, Bacteria genetics, Bacteria isolation & purification, Carcinoembryonic Antigen metabolism, Colorectal Neoplasms microbiology, Colorectal Neoplasms mortality, Disease Models, Animal, Feces microbiology, GPI-Linked Proteins genetics, GPI-Linked Proteins metabolism, Gain of Function Mutation, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Metagenomics, Mice, Mice, Transgenic, Protein Domains genetics, Receptor, Transforming Growth Factor-beta Type I metabolism, Smad4 Protein genetics, Smad4 Protein metabolism, Spheroids, Cellular, Survival Analysis, Transforming Growth Factor beta metabolism, Carcinoembryonic Antigen genetics, Carcinogenesis genetics, Colorectal Neoplasms genetics, Gastrointestinal Microbiome physiology, Signal Transduction genetics
- Abstract
Background & Aims: We studied interactions among proteins of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, which interact with microbes, and transforming growth factor beta (TGFB) signaling pathway, which is often altered in colorectal cancer cells. We investigated mechanisms by which CEACAM proteins inhibit TGFB signaling and alter the intestinal microbiome to promote colorectal carcinogenesis., Methods: We collected data on DNA sequences, messenger RNA expression levels, and patient survival times from 456 colorectal adenocarcinoma cases, and a separate set of 594 samples of colorectal adenocarcinomas, in The Cancer Genome Atlas. We performed shotgun metagenomic sequencing analyses of feces from wild-type mice and mice with defects in TGFB signaling (Sptbn1
+/- and Smad4+/- /Sptbn1+/- ) to identify changes in microbiota composition before development of colon tumors. CEACAM protein and its mutants were overexpressed in SW480 and HCT116 colorectal cancer cell lines, which were analyzed by immunoblotting and proliferation and colony formation assays., Results: In colorectal adenocarcinomas, high expression levels of genes encoding CEACAM proteins, especially CEACAM5, were associated with reduced survival times of patients. There was an inverse correlation between expression of CEACAM genes and expression of TGFB pathway genes (TGFBR1, TGFBR2, and SMAD3). In colorectal adenocarcinomas, we also found an inverse correlation between expression of genes in the TGFB signaling pathway and genes that regulate stem cell features of cells. We found mutations encoding L640I and A643T in the B3 domain of human CEACAM5 in colorectal adenocarcinomas; structural studies indicated that these mutations would alter the interaction between CEACAM5 and TGFBR1. Overexpression of these mutants in SW480 and HCT116 colorectal cancer cell lines increased their anchorage-independent growth and inhibited TGFB signaling to a greater extent than overexpression of wild-type CEACAM5, indicating that they are gain-of-function mutations. Compared with feces from wild-type mice, feces from mice with defects in TGFB signaling had increased abundance of bacterial species that have been associated with the development of colon tumors, including Clostridium septicum, and decreased amounts of beneficial bacteria, such as Bacteroides vulgatus and Parabacteroides distasonis., Conclusion: We found expression of CEACAMs and genes that regulate stem cell features of cells to be increased in colorectal adenocarcinomas and inversely correlated with expression of TGFB pathway genes. We found colorectal adenocarcinomas to express mutant forms of CEACAM5 that inhibit TGFB signaling and increase proliferation and colony formation. We propose that CEACAM proteins disrupt TGFB signaling, which alters the composition of the intestinal microbiome to promote colorectal carcinogenesis., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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32. Longitudinal molecular trajectories of diffuse glioma in adults.
- Author
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Barthel FP, Johnson KC, Varn FS, Moskalik AD, Tanner G, Kocakavuk E, Anderson KJ, Abiola O, Aldape K, Alfaro KD, Alpar D, Amin SB, Ashley DM, Bandopadhayay P, Barnholtz-Sloan JS, Beroukhim R, Bock C, Brastianos PK, Brat DJ, Brodbelt AR, Bruns AF, Bulsara KR, Chakrabarty A, Chakravarti A, Chuang JH, Claus EB, Cochran EJ, Connelly J, Costello JF, Finocchiaro G, Fletcher MN, French PJ, Gan HK, Gilbert MR, Gould PV, Grimmer MR, Iavarone A, Ismail A, Jenkinson MD, Khasraw M, Kim H, Kouwenhoven MCM, LaViolette PS, Li M, Lichter P, Ligon KL, Lowman AK, Malta TM, Mazor T, McDonald KL, Molinaro AM, Nam DH, Nayyar N, Ng HK, Ngan CY, Niclou SP, Niers JM, Noushmehr H, Noorbakhsh J, Ormond DR, Park CK, Poisson LM, Rabadan R, Radlwimmer B, Rao G, Reifenberger G, Sa JK, Schuster M, Shaw BL, Short SC, Smitt PAS, Sloan AE, Smits M, Suzuki H, Tabatabai G, Van Meir EG, Watts C, Weller M, Wesseling P, Westerman BA, Widhalm G, Woehrer A, Yung WKA, Zadeh G, Huse JT, De Groot JF, Stead LF, and Verhaak RGW
- Subjects
- Adult, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 19, Disease Progression, Glioma pathology, Humans, Isocitrate Dehydrogenase genetics, Mutation, Polymorphism, Single Nucleotide, Recurrence, Glioma genetics
- Abstract
The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear
1,2 . Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.- Published
- 2019
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33. The Immune Landscape of Cancer.
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Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, Porta-Pardo E, Gao GF, Plaisier CL, Eddy JA, Ziv E, Culhane AC, Paull EO, Sivakumar IKA, Gentles AJ, Malhotra R, Farshidfar F, Colaprico A, Parker JS, Mose LE, Vo NS, Liu J, Liu Y, Rader J, Dhankani V, Reynolds SM, Bowlby R, Califano A, Cherniack AD, Anastassiou D, Bedognetti D, Mokrab Y, Newman AM, Rao A, Chen K, Krasnitz A, Hu H, Malta TM, Noushmehr H, Pedamallu CS, Bullman S, Ojesina AI, Lamb A, Zhou W, Shen H, Choueiri TK, Weinstein JN, Guinney J, Saltz J, Holt RA, Rabkin CS, Lazar AJ, Serody JS, Demicco EG, Disis ML, Vincent BG, and Shmulevich I
- Published
- 2019
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34. Identification of subsets of IDH -mutant glioblastomas with distinct epigenetic and copy number alterations and stratified clinical risks.
- Author
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Li KK, Shi ZF, Malta TM, Chan AK, Cheng S, Kwan JSH, Yang RR, Poon WS, Mao Y, Noushmehr H, Chen H, and Ng HK
- Abstract
Background: IDH -mutant glioblastoma is classified by the 2016 CNS WHO as a group with good prognosis. However, the actual number of cases examined in the literature is relatively small. We hypothesize that IDH -mutant glioblastoma is not a uniform group and should be further stratified., Methods: We conducted methylation profiles and estimated copy number variations of 57 IDH- mutant glioblastomas., Results: Our results showed that 59.6% and 40.4% of tumors belonged to glioma-CpG island methylator phenotype (G-CIMP)-high and G-CIMP-low methylation subgroups, respectively. G-CIMP-low subgroup was associated with significantly worse overall survival (OS) as compared to G-CIMP-high ( P = .005). CDKN2A deletion (42.1%) was the most common gene copy number variation, and was significantly associated with G-CIMP-low subgroup ( P = .004). Other frequent copy number changes included mesenchymal-epithelial transition ( MET ) (5.3%), CCND2 (19.3%), PDGFRA (14.0%), CDK4 (12.3%), and EGFR (12.3%) amplification. Both CDKN2A deletion ( P = .036) and MET amplification ( P < .001) were associated with poor OS in IDH -mutant glioblastomas. Combined epigenetic signature and gene copy number variations separated IDH -mutant glioblastomas into Group 1 (G-CIMP-high), Group 2 (G-CIMP-low without CDKN2A nor MET alteration), and Group 3 (G-CIMP-low with CDKN2A and/or MET alteration). Survival analysis revealed Groups 1 and 2 exhibited a favorable OS (median survival: 619 d [20.6 mo] and 655 d [21.8 mo], respectively). Group 3 exhibited a significant shorter OS (median survival: 252 d [8.4 mo]). Multivariable analysis confirmed the independent prognostic significance of our Groups., Conclusions: IDH -mutant glioblastomas should be stratified for risk with combined epigenetic signature and CDKN2A/MET status and some cases have poor outcome., (© The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
- Published
- 2019
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35. Endothelial cells from different anatomical origin have distinct responses during SNAIL/TGF-β2-mediated endothelial-mesenchymal transition.
- Author
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Pinto MT, Ferreira Melo FU, Malta TM, Rodrigues ES, Plaça JR, Silva WA Jr, Panepucci RA, Covas DT, de Oliveira Rodrigues C, and Kashima S
- Abstract
Background: Endothelial-mesenchymal transition (EndMT) is a complex process whereby differentiated endothelial cells undergo phenotypic transition to mesenchymal cells. EndMT can be stimulated by several factors and the most common are the transforming growth factor-beta (TGF-β) and SNAIL transcription factor. Given the diversity of the vascular system, it is unclear whether endothelial cells lining different vessels are able to undergo EndMT through the same mechanisms. Here we evaluate the molecular and functional changes that occur in different types of endothelial cells following induction of EndMT by overexpression of SNAIL and TGF-β2., Results: We found that responses to induction by SNAIL are determined by cell origin and marker expression. Human coronary endothelial cells (HCAECs) showed the greatest EndMT responses evidenced by significant reciprocal changes in the expression of mesenchymal and endothelial markers, effects that were potentiated by a combination of SNAIL and TGF-β2. Key molecular events associated with EndMT driven by SNAIL/TGF-β2 involved extracellular-matrix remodeling and inflammation (IL-8, IL-12, IGF-1, and TREM-1 signaling). Notch signaling pathway members DLL4, NOTCH3 and NOTCH4 as well as members of the Wnt signaling pathway FZD2, FZD9, and WNT5B were altered in the combination treatment strategy, implicating Notch and Wnt signaling pathways in the induction process., Conclusion: Our results provide a foundation for understanding the roles of specific signaling pathways in mediating EndMT in endothelial cells from different anatomical origins., Competing Interests: None.
- Published
- 2018
36. The Immune Landscape of Cancer.
- Author
-
Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, Porta-Pardo E, Gao GF, Plaisier CL, Eddy JA, Ziv E, Culhane AC, Paull EO, Sivakumar IKA, Gentles AJ, Malhotra R, Farshidfar F, Colaprico A, Parker JS, Mose LE, Vo NS, Liu J, Liu Y, Rader J, Dhankani V, Reynolds SM, Bowlby R, Califano A, Cherniack AD, Anastassiou D, Bedognetti D, Mokrab Y, Newman AM, Rao A, Chen K, Krasnitz A, Hu H, Malta TM, Noushmehr H, Pedamallu CS, Bullman S, Ojesina AI, Lamb A, Zhou W, Shen H, Choueiri TK, Weinstein JN, Guinney J, Saltz J, Holt RA, Rabkin CS, Lazar AJ, Serody JS, Demicco EG, Disis ML, Vincent BG, and Shmulevich I
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Humans, Interferon-gamma genetics, Interferon-gamma immunology, Macrophages immunology, Male, Middle Aged, Prognosis, Th1-Th2 Balance physiology, Transforming Growth Factor beta genetics, Transforming Growth Factor beta immunology, Wound Healing genetics, Wound Healing immunology, Young Adult, Genomics methods, Neoplasms classification, Neoplasms genetics, Neoplasms immunology
- Abstract
We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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37. A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence.
- Author
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de Souza CF, Sabedot TS, Malta TM, Stetson L, Morozova O, Sokolov A, Laird PW, Wiznerowicz M, Iavarone A, Snyder J, deCarvalho A, Sanborn Z, McDonald KL, Friedman WA, Tirapelli D, Poisson L, Mikkelsen T, Carlotti CG Jr, Kalkanis S, Zenklusen J, Salama SR, Barnholtz-Sloan JS, and Noushmehr H
- Subjects
- Adult, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Brain Neoplasms genetics, Brain Neoplasms mortality, Brain Neoplasms therapy, CpG Islands, Female, Genomic Instability, Glioma genetics, Glioma mortality, Glioma therapy, Humans, Isocitrate Dehydrogenase genetics, Kaplan-Meier Estimate, Longitudinal Studies, Male, Middle Aged, Mutation, Neoplasm Grading, Neoplastic Stem Cells cytology, Neoplastic Stem Cells metabolism, Phenotype, Prognosis, Brain Neoplasms pathology, DNA Methylation, Glioma pathology, Neoplasm Recurrence, Local genetics
- Abstract
Glioma diagnosis is based on histomorphology and grading; however, such classification does not have predictive clinical outcome after glioblastomas have developed. To date, no bona fide biomarkers that significantly translate into a survival benefit to glioblastoma patients have been identified. We previously reported that the IDH mutant G-CIMP-high subtype would be a predecessor to the G-CIMP-low subtype. Here, we performed a comprehensive DNA methylation longitudinal analysis of diffuse gliomas from 77 patients (200 tumors) to enlighten the epigenome-based malignant transformation of initially lower-grade gliomas. Intra-subtype heterogeneity among G-CIMP-high primary tumors allowed us to identify predictive biomarkers for assessing the risk of malignant recurrence at early stages of disease. G-CIMP-low recurrence appeared in 9.5% of all gliomas, and these resembled IDH-wild-type primary glioblastoma. G-CIMP-low recurrence can be characterized by distinct epigenetic changes at candidate functional tissue enhancers with AP-1/SOX binding elements, mesenchymal stem cell-like epigenomic phenotype, and genomic instability. Molecular abnormalities of longitudinal G-CIMP offer possibilities to defy glioblastoma progression., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
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38. Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications.
- Author
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Malta TM, de Souza CF, Sabedot TS, Silva TC, Mosella MS, Kalkanis SN, Snyder J, Castro AVB, and Noushmehr H
- Subjects
- Glioma pathology, Humans, Mutation, Phenotype, CpG Islands, DNA Methylation, Epigenomics, Genome, Human, Glioma genetics
- Abstract
Gliomas are a heterogeneous group of brain tumors with distinct biological and clinical properties. Despite advances in surgical techniques and clinical regimens, treatment of high-grade glioma remains challenging and carries dismal rates of therapeutic success and overall survival. Challenges include the molecular complexity of gliomas, as well as inconsistencies in histopathological grading, resulting in an inaccurate prediction of disease progression and failure in the use of standard therapy. The updated 2016 World Health Organization (WHO) classification of tumors of the central nervous system reflects a refinement of tumor diagnostics by integrating the genotypic and phenotypic features, thereby narrowing the defined subgroups. The new classification recommends molecular diagnosis of isocitrate dehydrogenase (IDH) mutational status in gliomas. IDH-mutant gliomas manifest the cytosine-phosphate-guanine (CpG) island methylator phenotype (G-CIMP). Notably, the recent identification of clinically relevant subsets of G-CIMP tumors (G-CIMP-high and G-CIMP-low) provides a further refinement in glioma classification that is independent of grade and histology. This scheme may be useful for predicting patient outcome and may be translated into effective therapeutic strategies tailored to each patient. In this review, we highlight the evolution of our understanding of the G-CIMP subsets and how recent advances in characterizing the genome and epigenome of gliomas may influence future basic and translational research.
- Published
- 2018
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39. Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer.
- Author
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Hoadley KA, Yau C, Hinoue T, Wolf DM, Lazar AJ, Drill E, Shen R, Taylor AM, Cherniack AD, Thorsson V, Akbani R, Bowlby R, Wong CK, Wiznerowicz M, Sanchez-Vega F, Robertson AG, Schneider BG, Lawrence MS, Noushmehr H, Malta TM, Stuart JM, Benz CC, and Laird PW
- Subjects
- Aneuploidy, Chromosomes genetics, Cluster Analysis, CpG Islands, DNA Methylation, Databases, Factual, Humans, MicroRNAs metabolism, Mutation, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Neoplasms genetics, RNA, Messenger metabolism, Neoplasms pathology
- Abstract
We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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40. Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation.
- Author
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Malta TM, Sokolov A, Gentles AJ, Burzykowski T, Poisson L, Weinstein JN, Kamińska B, Huelsken J, Omberg L, Gevaert O, Colaprico A, Czerwińska P, Mazurek S, Mishra L, Heyn H, Krasnitz A, Godwin AK, Lazar AJ, Stuart JM, Hoadley KA, Laird PW, Noushmehr H, and Wiznerowicz M
- Subjects
- Carcinogenesis, DNA Methylation, Databases, Genetic, Epigenesis, Genetic, Humans, MicroRNAs metabolism, Neoplasm Metastasis, Neoplasms genetics, Stem Cells cytology, Stem Cells metabolism, Transcriptome, Tumor Microenvironment, Cell Dedifferentiation genetics, Machine Learning, Neoplasms pathology
- Abstract
Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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41. Mesenchymal Stem Cells and Pericytes: To What Extent Are They Related?
- Author
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de Souza LE, Malta TM, Kashima Haddad S, and Covas DT
- Subjects
- Animals, Bone and Bones cytology, Epithelial-Mesenchymal Transition, Humans, Mesenchymal Stem Cells cytology, Pericytes cytology
- Abstract
Mesenchymal stem cells (MSCs) were initially identified as progenitors of skeletal tissues within mammalian bone marrow and cells with similar properties were also obtained from other tissues such as adipose and dental pulp. Although MSCs have been extensively investigated, their native behavior and in vivo identity remain poorly defined. Uncovering the in vivo identity of MSCs has been challenging due to the lack of exclusive cell markers, cellular alterations caused by culture methods, and extensive focus on in vitro properties for characterization. Although MSC site of origin influences their functional properties, these mesenchymal progenitors can be found in the perivascular space in virtually all organs from where they were obtained. However, the precise identity of MSCs within the vascular wall is highly controversial. The recurrent concept that MSCs correspond to pericytes in vivo has been supported mainly by their perivascular localization and expression of some molecular markers. However, this view has been a subject of controversy, in part, due to the application of loose criteria to define pericytes and due to the lack of a marker able to unequivocally identify these cells. Furthermore, recent evidences indicate that subpopulations of MSCs can be found at extravascular sites such as the endosteum. In this opinion review, we bring together the advances and pitfalls on the search for the in vivo identity of MSCs and highlight the recent evidences that suggest that perivascular MSCs are adventitial cells, acting as precursors of pericytes and other stromal cells during tissue homeostasis.
- Published
- 2016
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42. The gene expression profile of non-cultured, highly purified human adipose tissue pericytes: Transcriptomic evidence that pericytes are stem cells in human adipose tissue.
- Author
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da Silva Meirelles L, de Deus Wagatsuma VM, Malta TM, Bonini Palma PV, Araújo AG, Panepucci RA, Silva WA, Kashima S, and Covas DT
- Subjects
- Cell Differentiation physiology, Cells, Cultured, Female, Humans, Adipose Tissue cytology, Cell Differentiation genetics, Mesenchymal Stem Cells metabolism, Pericytes cytology, Stem Cells cytology, Transcriptome genetics
- Abstract
Pericytes (PCs) are a subset of perivascular cells that can give rise to mesenchymal stromal cells (MSCs) when culture-expanded, and are postulated to give rise to MSC-like cells during tissue repair in vivo. PCs have been suggested to behave as stem cells (SCs) in situ in animal models, although evidence for this role in humans is lacking. Here, we analyzed the transcriptomes of highly purified, non-cultured adipose tissue (AT)-derived PCs (ATPCs) to detect gene expression changes that occur as they acquire MSC characteristics in vitro, and evaluated the hypothesis that human ATPCs exhibit a gene expression profile compatible with an AT SC phenotype. The results showed ATPCs are non-proliferative and express genes characteristic not only of PCs, but also of AT stem/progenitor cells. Additional analyses defined a gene expression signature for ATPCs, and revealed putative novel ATPC markers. Almost all AT stem/progenitor cell genes differentially expressed by ATPCs were not expressed by ATMSCs or culture-expanded ATPCs. Genes expressed by ATMSCs but not by ATPCs were also identified. These findings strengthen the hypothesis that PCs are SCs in vascularized tissues, highlight gene expression changes they undergo as they assume an MSC phenotype, and provide new insights into PC biology., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
43. TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data.
- Author
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Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, Sabedot TS, Malta TM, Pagnotta SM, Castiglioni I, Ceccarelli M, Bontempi G, and Noushmehr H
- Subjects
- BRCA1 Protein genetics, BRCA2 Protein genetics, Biomarkers, Tumor genetics, DNA Methylation genetics, Humans, Neoplasms classification, Statistics as Topic methods, Computational Biology methods, Data Mining methods, Databases, Genetic, Genome, Human genetics, Genomics methods, Neoplasms genetics
- Abstract
The Cancer Genome Atlas (TCGA) research network has made public a large collection of clinical and molecular phenotypes of more than 10 000 tumor patients across 33 different tumor types. Using this cohort, TCGA has published over 20 marker papers detailing the genomic and epigenomic alterations associated with these tumor types. Although many important discoveries have been made by TCGA's research network, opportunities still exist to implement novel methods, thereby elucidating new biological pathways and diagnostic markers. However, mining the TCGA data presents several bioinformatics challenges, such as data retrieval and integration with clinical data and other molecular data types (e.g. RNA and DNA methylation). We developed an R/Bioconductor package called TCGAbiolinks to address these challenges and offer bioinformatics solutions by using a guided workflow to allow users to query, download and perform integrative analyses of TCGA data. We combined methods from computer science and statistics into the pipeline and incorporated methodologies developed in previous TCGA marker studies and in our own group. Using four different TCGA tumor types (Kidney, Brain, Breast and Colon) as examples, we provide case studies to illustrate examples of reproducibility, integrative analysis and utilization of different Bioconductor packages to advance and accelerate novel discoveries., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2016
- Full Text
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44. Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma.
- Author
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Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, Morozova O, Newton Y, Radenbaugh A, Pagnotta SM, Anjum S, Wang J, Manyam G, Zoppoli P, Ling S, Rao AA, Grifford M, Cherniack AD, Zhang H, Poisson L, Carlotti CG Jr, Tirapelli DP, Rao A, Mikkelsen T, Lau CC, Yung WK, Rabadan R, Huse J, Brat DJ, Lehman NL, Barnholtz-Sloan JS, Zheng S, Hess K, Rao G, Meyerson M, Beroukhim R, Cooper L, Akbani R, Wrensch M, Haussler D, Aldape KD, Laird PW, Gutmann DH, Noushmehr H, Iavarone A, and Verhaak RG
- Subjects
- Adult, Brain Neoplasms metabolism, Cell Proliferation, Cluster Analysis, DNA Helicases genetics, DNA Methylation, Epigenesis, Genetic, Glioma metabolism, Humans, Isocitrate Dehydrogenase genetics, Middle Aged, Mutation, Nuclear Proteins genetics, Promoter Regions, Genetic, Signal Transduction, Telomerase genetics, Telomere, X-linked Nuclear Protein, Brain Neoplasms genetics, Brain Neoplasms pathology, Glioma genetics, Glioma pathology, Transcriptome
- 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., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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45. Cultured Human Adipose Tissue Pericytes and Mesenchymal Stromal Cells Display a Very Similar Gene Expression Profile.
- Author
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da Silva Meirelles L, Malta TM, de Deus Wagatsuma VM, Palma PV, Araújo AG, Ribeiro Malmegrim KC, Morato de Oliveira F, Panepucci RA, Silva WA Jr, Kashima Haddad S, and Covas DT
- Subjects
- Adolescent, Adult, Antigens, CD genetics, Antigens, CD metabolism, Cell Differentiation, Cells, Cultured, Female, Humans, Male, Mesenchymal Stem Cells cytology, Middle Aged, Pericytes cytology, Primary Cell Culture methods, Adipose Tissue cytology, Mesenchymal Stem Cells metabolism, Pericytes metabolism, Transcriptome
- Abstract
Mesenchymal stromal cells (MSCs) are cultured cells that can give rise to mature mesenchymal cells under appropriate conditions and secrete a number of biologically relevant molecules that may play an important role in regenerative medicine. Evidence indicates that pericytes (PCs) correspond to mesenchymal stem cells in vivo and can give rise to MSCs when cultured, but a comparison between the gene expression profiles of cultured PCs (cPCs) and MSCs is lacking. We have devised a novel methodology to isolate PCs from human adipose tissue and compared cPCs to MSCs obtained through traditional methods. Freshly isolated PCs expressed CD34, CD140b, and CD271 on their surface, but not CD146. Both MSCs and cPCs were able to differentiate along mesenchymal pathways in vitro, displayed an essentially identical surface immunophenotype, and exhibited the ability to suppress CD3(+) lymphocyte proliferation in vitro. Microarray expression data of cPCs and MSCs formed a single cluster among other cell types. Further analyses showed that the gene expression profiles of cPCs and MSCs are extremely similar, although MSCs differentially expressed endothelial cell (EC)-specific transcripts. These results confirm, using the power of transcriptomic analysis, that PCs give rise to MSCs and suggest that low levels of ECs may persist in MSC cultures established using traditional protocols.
- Published
- 2015
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46. Transcriptomic comparisons between cultured human adipose tissue-derived pericytes and mesenchymal stromal cells.
- Author
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da Silva Meirelles L, Malta TM, Panepucci RA, and da Silva WA Jr
- Abstract
Mesenchymal stromal cells (MSCs), sometimes called mesenchymal stem cells, are cultured cells able to give rise to mature mesenchymal cells such as adipocytes, osteoblasts, and chondrocytes, and to secrete a wide range of trophic and immunomodulatory molecules. Evidence indicates that pericytes, cells that surround and maintain physical connections with endothelial cells in blood vessels, can give rise to MSCs (da Silva Meirelles et al., 2008 [1]; Caplan and Correa, 2011 [2]). We have compared the transcriptomes of highly purified, human adipose tissue pericytes subjected to culture-expansion in pericyte medium or MSC medium, with that of human adipose tissue MSCs isolated with traditional methods to test the hypothesis that their transcriptomes are similar (da Silva Meirelles et al., 2015 [3]). Here, we provide further information and analyses of microarray data from three pericyte populations cultured in pericyte medium, three pericyte populations cultured in MSC medium, and three adipose tissue MSC populations deposited in the Gene Expression Omnibus under accession number GSE67747.
- Published
- 2015
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47. T cell receptor signaling pathway is overexpressed in CD4(+) T cells from HAM/TSP individuals.
- Author
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Pinto MT, Malta TM, Rodrigues ES, Takayanagui OM, Tanaka Y, Covas DT, and Kashima S
- Subjects
- Adult, Aged, CD3 Complex metabolism, CD4-Positive T-Lymphocytes enzymology, CD4-Positive T-Lymphocytes virology, Case-Control Studies, Female, Gene Expression, Humans, Male, Middle Aged, Paraparesis, Tropical Spastic genetics, Protein-Tyrosine Kinases metabolism, Proto-Oncogene Proteins c-vav metabolism, Real-Time Polymerase Chain Reaction, T-Lymphocytes metabolism, Viral Load, ZAP-70 Protein-Tyrosine Kinase metabolism, CD4-Positive T-Lymphocytes immunology, Gene Expression Profiling, Paraparesis, Tropical Spastic immunology, Receptors, Antigen, T-Cell immunology, Signal Transduction immunology
- Abstract
Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus related to the chronic neuroinflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). CD4(+) T cells activation appears to play a key role on HTLV-1 infection. Here we investigated the expression of genes associated to T cell activation CD3e molecule, epsilon (CD3ɛ), lymphocyte-specific protein tyrosine kinase (LCK), vav 1 guanine nucleotide exchange factor (VAV1), and zeta-chain (TCR) associated protein kinase 70kDa (ZAP70) on T lymphocytes of HTLV-1-infected individuals and compared to healthy uninfected individuals (CT). We observed that CD3ɛ, LCK, ZAP70, and VAV1 gene expression were increased in CD4(+) T cells from HAM/TSP group compared to HTLV-1 asymptomatic patients (HAC). Moreover, ZAP70 and VAV1 were also upregulated in HAM/TSP compared to CT group. We detected a positive correlation among all these genes. We also observed that CD3ɛ, LCK, and VAV1 genes had a positive correlation with the proviral load (PVL) and Tax expression. These results suggest that PVL and Tax protein could drive CD3ɛ, LCK, and VAV1 gene expression in CD4(+) T cells, and these genes function on a synchronized way on the CD4(+) T cell activation. The elucidation of the mechanisms underlying T cell receptor signaling pathway is of considerable interest and might lead to new insights into the mechanism of HAM/TSP., (Copyright © 2015 Elsevier Editora Ltda. All rights reserved.)
- Published
- 2015
- Full Text
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48. Novel polymorphisms in the promoter region of the perforin gene among distinct Brazilian populations and their functional impact.
- Author
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Garcia FB, Kashima S, Rodrigues ES, Silva IT, Malta TM, Nicolete LD, Haddad R, Moraes-Souza H, and Covas DT
- Subjects
- Alleles, Asian People, Base Sequence, Black People, Brazil, Gene Frequency, Genetics, Population, Haplotypes, Humans, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Molecular Sequence Data, Perforin, Pore Forming Cytotoxic Proteins immunology, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic metabolism, White People, Gene Expression immunology, Polymorphism, Single Nucleotide, Pore Forming Cytotoxic Proteins genetics, Promoter Regions, Genetic
- Abstract
Cytotoxic T lymphocytes and natural killer cells play a crucial role in eliminating tumour and virus-infected cells. The perforin is a key part of the arsenal that these cells use to destroy their targets. In this study, we characterized single-nucleotide polymorphisms (SNPs) located in the promoter region of the perforin gene among distinct Brazilian ethnic groups. The study was carried out by sequencing this region in three groups: European, African and Asian descents. We demonstrated for the first time the occurrence of three new polymorphisms in the promoter region of gene PRF1: 494A/G (rs78058707), 720G/A (rs75925789) and 1176C/T (rs75183511). Three other SNPs already described in the literature 63A/G (rs35401316), 112A/G (rs10999428) and 1012C/T (rs35069510) were also detected. The SNPs are distributed differently in the ethnic groups studied. The 112G allele was observed at high frequency, especially among Asian descents (48.1%). The 1012T allele was detected only among European descents, the 494G allele only among Asian descents and 1176T allele only in African descents. Based on the association between the polymorphisms described, ten new haplotypes were originated. In functional analysis, we noticed that SNPs present in most common haplotypes cannot induce significant differences in expression levels of perforin alone. In conclusion, this study demonstrates for the first time the existence of three new polymorphisms in perforin promoter and, contrary to what was stated, the presence of these SNPs does not alter the levels of protein expression., (© 2013 John Wiley & Sons Ltd.)
- Published
- 2014
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49. Genes related to antiviral activity, cell migration, and lysis are differentially expressed in CD4(+) T cells in human t cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis patients.
- Author
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Pinto MT, Malta TM, Rodrigues ES, Pinheiro DG, Panepucci RA, Malmegrim de Farias KC, Sousa Ade P, Takayanagui OM, Tanaka Y, Covas DT, and Kashima S
- Subjects
- Adult, Gene Expression Profiling, Humans, Male, Middle Aged, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes virology, Carrier State immunology, Genes, pX, HTLV-I Infections immunology
- Abstract
Human T cell leukemia virus type 1 (HTLV-1) preferentially infects CD4(+) T cells and these cells play a central role in HTLV-1 infection. In this study, we investigated the global gene expression profile of circulating CD4(+) T cells from the distinct clinical status of HTLV-1-infected individuals in regard to TAX expression levels. CD4(+) T cells were isolated from asymptomatic HTLV-1 carrier (HAC) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients in order to identify genes involved in HAM/TSP development using a microarray technique. Hierarchical clustering analysis showed that healthy control (CT) and HTLV-1-infected samples clustered separately. We also observed that the HAC and HAM/TSP groups clustered separately regardless of TAX expression. The gene expression profile of CD4(+) T cells was compared among the CT, HAC, and HAM/TSP groups. The paxillin (Pxn), chemokine (C-X-C motif ) receptor 4 (Cxcr4), interleukin 27 (IL27), and granzyme A (Gzma) genes were differentially expressed between the HAC and HAM/TSP groups, regardless of TAX expression. The perforin 1 (Prf1) and forkhead box P3 (Foxp3) genes were increased in the HAM/TSP group and presented a positive correlation to the expression of TAX and the proviral load (PVL). The frequency of CD4(+)FOXP3(+) regulatory T cells (Treg) was higher in HTLV-1-infected individuals. Foxp3 gene expression was positively correlated with cell lysis-related genes (Gzma, Gzmb, and Prf1). These findings suggest that CD4(+) T cell activity is distinct between the HAC and HAM/TSP groups.
- Published
- 2014
- Full Text
- View/download PDF
50. Altered expression of degranulation-related genes in CD8+ T cells in human T lymphotropic virus type I infection.
- Author
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Malta TM, Silva IT, Pinheiro DG, Santos AR, Pinto MT, Panepucci RA, Takayanagui OM, Tanaka Y, Covas DT, and Kashima S
- Subjects
- Adult, Aged, Asymptomatic Infections, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes physiology, Cytokines genetics, Cytokines metabolism, Female, Flow Cytometry, Gene Expression Profiling, Gene Expression Regulation, Viral genetics, Gene Expression Regulation, Viral physiology, Granzymes genetics, Granzymes metabolism, HTLV-I Infections virology, Humans, Male, Middle Aged, Paraparesis, Tropical Spastic immunology, Paraparesis, Tropical Spastic metabolism, Paxillin genetics, Paxillin metabolism, Perforin, Pore Forming Cytotoxic Proteins genetics, Pore Forming Cytotoxic Proteins metabolism, Real-Time Polymerase Chain Reaction, Young Adult, ZAP-70 Protein-Tyrosine Kinase genetics, ZAP-70 Protein-Tyrosine Kinase metabolism, CD8-Positive T-Lymphocytes virology, HTLV-I Infections immunology, Human T-lymphotropic virus 1 physiology, Paraparesis, Tropical Spastic virology
- Abstract
Human T lymphotropic virus type I (HTLV-1) is the etiological agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). CD8+ T cells may contribute to the protection or development of HAM/TSP. In this study we used SAGE methodology to screen for differentially expressed genes in CD8+ T cells isolated from HTLV-1 asymptomatic carriers (HAC) and from HAM/TSP patients to identify genes involved in HAM/TSP development. SAGE analysis was conducted by pooling samples according to clinical status. The comparison of gene expression profiles between HAC and HAM/TSP libraries identified 285 differentially expressed tags. We focus on cytotoxicity and cytokine-related genes due to their potential biological role in HTLV-1 infection. Our results showed that patients with HAM/TSP have high expression levels of degranulation-related genes, namely GZMH and PRF1, and of the cytoskeletal adaptor PXN. We found that GZMB and ZAP70 were overexpressed in HTLV-infected patients compared to the noninfected group. We also detected that CCL5 was higher in the HAM/TSP group compared to the HAC and CT groups. Our findings showed that CD8+ T cells of HAM/TSP patients have an inflammatory and active profile. PXN and ZAP70 overexpression in HTLV-1-infected patients was described for the first time here and reinforces this concept. However, although active and abundant, CD8+ T cells are not able to completely eliminate infected cells and prevent the development of HAM/TSP and, moreover, these cells might contribute to the pathogenesis of the disease by migrating to the central nervous system (CNS). These results should be further tested with biological functional assays to increase our understanding on the role of these molecules in the development of HTLV-1-related diseases.
- Published
- 2013
- Full Text
- View/download PDF
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