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2. Comprehensive Analysis of Hypermutation in Human Cancer

Author

Campbell, Brittany B, Light, Nicholas, Fabrizio, David, Zatzman, Matthew, Fuligni, Fabio, de Borja, Richard, Davidson, Scott, Edwards, Melissa, Elvin, Julia A, Hodel, Karl P, Zahurancik, Walter J, Suo, Zucai, Lipman, Tatiana, Wimmer, Katharina, Kratz, Christian P, Bowers, Daniel C, Laetsch, Theodore W, Dunn, Gavin P, Johanns, Tanner M, Grimmer, Matthew R, Smirnov, Ivan V, Larouche, Valérie, Samuel, David, Bronsema, Annika, Osborn, Michael, Stearns, Duncan, Raman, Pichai, Cole, Kristina A, Storm, Phillip B, Yalon, Michal, Opocher, Enrico, Mason, Gary, Thomas, Gregory A, Sabel, Magnus, George, Ben, Ziegler, David S, Lindhorst, Scott, Issai, Vanan Magimairajan, Constantini, Shlomi, Toledano, Helen, Elhasid, Ronit, Farah, Roula, Dvir, Rina, Dirks, Peter, Huang, Annie, Galati, Melissa A, Chung, Jiil, Ramaswamy, Vijay, Irwin, Meredith S, Aronson, Melyssa, Durno, Carol, Taylor, Michael D, Rechavi, Gideon, Maris, John M, Bouffet, Eric, Hawkins, Cynthia, Costello, Joseph F, Meyn, M Stephen, Pursell, Zachary F, Malkin, David, Tabori, Uri, and Shlien, Adam

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Human Genome, Cancer, Rare Diseases, Cancer Genomics, 2.1 Biological and endogenous factors, Good Health and Well Being, Adult, Child, Cluster Analysis, DNA Polymerase II, DNA Polymerase III, DNA Replication, Humans, Mutation, Neoplasms, Poly-ADP-Ribose Binding Proteins, DNA repair, DNA replication, cancer genomics, cancer predisposition, hypermutation, immune checkpoint inhibitors, mismatch repair, mutator, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.

Published
2017

4. DNA hypermethylation within TERT promoter upregulates TERT expression in cancer

Author

Lee, Donghyun D., Leao, Ricardo, Komosa, Martin, Gallo, Marco, Zhang, Cindy H., Lipman, Tatiana, Remke, Marc, Heidari, Abolfazl, Nunes, Nuno Miguel, Apolonio, Joana D., Price, Aryeh J., De Mello, Ramon Andrade, Dias, Joao S., Huntsman, David, Hermanns, Thomas, Wild, Peter J., Vanner, Robert, Zadeh, Gelareh, Karamchandani, Jason, Das, Sunit, Taylor, Michael D., Hawkins, Cynthia E., Wasserman, Jonathan D., Figueiredo, Arnaldo, Hamilton, Robert J., Minden, Mark D., Wani, Khalida, Diplas, Bill, Yan, Hai, Aldape, Kenneth, Akbari, Mohammad R., Danesh, Arnavaz, Pugh, Trevor J., Dirks, Peter B., Castelo-Branco, Pedro, and Tabori, Uri

Subjects
Cancer -- Genetic aspects -- Research, Gene mutation -- Research, Methylation -- Genetic aspects, Telomeres -- Research, Health care industry
Abstract

Replicative immortality is a hallmark of cancer cells governed by telomere maintenance. Approximately 90% of human cancers maintain their telomeres by activating telomerase, driven by the transcriptional upregulation of telomerase reverse transcriptase (TERT). Although TERT promoter mutations (TPMs) are a major cancer-associated genetic mechanism of TERT upregulation, many cancers exhibit TERT upregulation without TPMs. In this study, we describe the TERT hypermethylated oncological region (THOR), a 433-bp genomic region encompassing 52 CpG sites located immediately upstream of the TERT core promoter, as a cancer-associated epigenetic mechanism of TERT upregulation. Unmethylated THOR repressed TERT promoter activity regardless of TPM status, and hypermethylation of THOR counteracted this repressive function. THOR methylation analysis in 1,352 human tumors revealed frequent (>45%) cancer-associated DNA hypermethylation in 9 of 11 (82%) tumor types screened. Additionally, THOR hypermethylation, either independently or along with TPMs, accounted for how approximately 90% of human cancers can aberrantly activate telomerase. Thus, we propose that THOR hypermethylation is a prevalent telomerase-activating mechanism in cancer that can act independently of or in conjunction with TPMs, further supporting the utility of THOR hypermethylation as a prognostic biomarker., IntroductionReplicative immortality is an attribute of cancer cells governed by telomere maintenance (1). Telomeres are repetitive nucleoprotein structures that protect chromosomal ends and shorten after each replicative cycle, playing important [...]

Published
2019
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6. CCR Translation for This Article from Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition

Author

Castelo-Branco, Pedro, primary, Zhang, Cindy, primary, Lipman, Tatiana, primary, Fujitani, Mayumi, primary, Hansford, Loen, primary, Clarke, Ian, primary, Harley, Calvin B., primary, Tressler, Robert, primary, Malkin, David, primary, Walker, Erin, primary, Kaplan, David R., primary, Dirks, Peter, primary, and Tabori, Uri, primary

Published
2023
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7. Supplementary Data from Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition

Author

Castelo-Branco, Pedro, primary, Zhang, Cindy, primary, Lipman, Tatiana, primary, Fujitani, Mayumi, primary, Hansford, Loen, primary, Clarke, Ian, primary, Harley, Calvin B., primary, Tressler, Robert, primary, Malkin, David, primary, Walker, Erin, primary, Kaplan, David R., primary, Dirks, Peter, primary, and Tabori, Uri, primary

Published
2023
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8. Additional file 13 of THOR is a targetable epigenetic biomarker with clinical implications in breast cancer

Author

Apolónio, Joana Dias, Dias, João S., Fernandes, Mónica Teotónio, Komosa, Martin, Lipman, Tatiana, Zhang, Cindy H., Leão, Ricardo, Lee, Donghyun, Nunes, Nuno Miguel, Maia, Ana-Teresa, Morera, José L., Vicioso, Luis, Tabori, Uri, and Castelo-Branco, Pedro

Abstract

Additional file 13: File S2. DNA sequences of plasmids used in the second targeted THOR demethylation approach.

Published
2023
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9. Methylation of the TERT promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study

Author

Castelo-Branco, Pedro, Choufani, Sanaa, Mack, Stephen, Gallagher, Denis, Zhang, Cindy, Lipman, Tatiana, Zhukova, Nataliya, Walker, Erin J, Martin, Dianna, Merino, Diana, Wasserman, Jonathan D, Elizabeth, Cynthia, Alon, Noa, Zhang, Libo, Hovestadt, Volker, Kool, Marcel, Jones, David TW, Zadeh, Gelareh, Croul, Sidney, Hawkins, Cynthia, Hitzler, Johann, Wang, Jean CY, Baruchel, Sylvain, Dirks, Peter B, Malkin, David, Pfister, Stefan, Taylor, Michael D, Weksberg, Rosanna, and Tabori, Uri

Published
2013
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11. MODL-25. REPLICATION REPAIR DEFICIENT MOUSE MODELS PROVIDE INSIGHT ON HYPERMUTANT BRAIN TUMOURS, MECHANISMS OF IMMUNE EVASION, AND COMBINATORIAL IMMUNOTHERAPY

Author

Galati, Melissa, primary, Li, Li, additional, Sudhaman, Sumedha, additional, Lipman, Tatiana, additional, Stengs, Lucie, additional, Elshaer, Dana, additional, Bridge, Taylor, additional, Semenova, Dar’ya, additional, Edwards, Melissa, additional, Hodel, Karl, additional, Forster, Victoria J, additional, Nunes, Nuno M, additional, Martin, Alberto, additional, Bouffet, Eric, additional, Pursell, Zachary, additional, Hawkins, Cynthia, additional, and Tabori, Uri, additional

Published
2020
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12. IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNE CHECKPOINT INHIBITION: AN INTERNATIONAL RRD CONSORTIUM REGISTRY STUDY

Author

Bouffet, Eric, primary, Sudhaman, Sumedha, additional, Chung, Jiil, additional, Kelly, Jacalyn, additional, Coblentz, Ailish, additional, Edwards, Melissa, additional, Lipman, Tatiana, additional, Zhang, Cindy, additional, Ercan, Ayse Bahar, additional, Sambira, Lauren, additional, Bendel, Anne, additional, Bielack, Stefan, additional, Koustenis, Elisabeth, additional, Blumenthal, Deborah, additional, Bowers, Daniel, additional, Broniscer, Alberto, additional, Bronsema, Annika, additional, Carroll, Sara, additional, Chiaravalli, Stefano, additional, Cole, Kristina, additional, Constantini, Shlomi, additional, De Mola, Rebecca Loret, additional, Dunn, Gavin, additional, Fröjd, Charlotta, additional, Gass, David, additional, Gauvain, Karen, additional, George, Ben, additional, Hijiya, Nobuko, additional, Hoffman, Lindsey, additional, Knipstein, Jeffrey, additional, Laetsch, Ted, additional, Larouche, Valérie, additional, Lassaletta, Alvaro, additional, Lindhorst, Scott, additional, Lossos, Alexander, additional, Luna-Fineman, Sandra, additional, Magimairajan, Vanan, additional, Mason, Gary, additional, Mason, Warren, additional, Massimino, Maura, additional, Mordechai, Oz, additional, Opocher, Enrico, additional, Oren, Michal, additional, Osborn, Michael, additional, Reddy, Alyssa, additional, Remke, Mark, additional, Roy, Sumita, additional, Sabel, Magnus, additional, Samuel, David, additional, Schneider, Kami, additional, Sen, Santanu, additional, Stearns, Duncan, additional, Sumerauer, David, additional, Thomas, Gregory, additional, Tomboc, Patrick, additional, Van Damme, An, additional, Wierman, Margaret, additional, Winer, Ira, additional, Yen, Lee Yi, additional, Zapotocky, Michal, additional, Ziegler, David, additional, Zimmermann, Stefanie, additional, Dvir, Rina, additional, Rechavi, Gidi, additional, Durno, Carol, additional, Aronson, Melyssa, additional, Taylor, Michael, additional, Dirks, Peter, additional, Pugh, Trevor, additional, Shlien, Adam, additional, Hawkins, Cynthia, additional, Morgenstern, Daniel, additional, and Tabori, Uri, additional

Published
2020
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13. Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behaviour of bladder cancer

Author

Leão, Ricardo, Lee, Donghyun, Figueiredo, Arnaldo, Hermanns, Thomas, Wild, Peter, Komosa, Martin, Lau, Irene, Mistry, Mathew, Nunes, Nuno Miguel, Price, Aryeh J, Zhang, Cindy, Lipman, Tatiana, Poyet, Cédric, Valtcheva, Nadejda, Oehl, Kathrin, et al, and University of Zurich

Subjects
10062 Urological Clinic, 10049 Institute of Pathology and Molecular Pathology, 610 Medicine & health, 2730 Oncology, 1306 Cancer Research
Published
2019

14. Unexpected difficulty in performance of a monocyte monolayer assay when using RBCs from a patient with sickle cell disease.

Author

Lipman, Tatiana, Bienz, Marc Nicolas, Pendergrast, Jacob, Cserti‐Gazdewich, Christine, and Branch, Donald R.

Subjects
*SICKLE cell anemia, *MONOMOLECULAR films, *MONONUCLEAR leukocytes
Abstract

This article discusses the challenges encountered when performing a monocyte monolayer assay (MMA) using red blood cells (RBCs) from a patient with sickle cell disease (SCD). The MMA is used to identify RBC units that are least likely to induce immune-mediated clearance. However, in this particular case, the density gradient separation method resulted in an unusual distribution of RBCs, making it difficult to isolate peripheral blood mononuclear cells (PBMCs) without RBC contamination. Despite attempts to eliminate the contaminating RBCs, they remained on the slides, making it challenging to assess the monocytes accurately. As a result, an allogeneic MMA was used to evaluate the donors for transfusion in this patient. The article emphasizes the importance of using an allogeneic MMA when contaminating RBCs cannot be eliminated. [Extracted from the article]

Published
2024
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16. IMMU-20. IMMUNE AND TUMOR BIOMARKERS OF OUTCOME IN REPLICATION REPAIR DEFICIENT BRAIN TUMORS TREATED WITH IMMUNE CHECKPOINT INHIBITORS: UPDATES FROM THE INTERNATIONAL REPLICATION REPAIR DEFICIENCY CONSORTIUM

Author

Bouffet, Eric, primary, Sudhaman, Sumedha, additional, Chung, Jiil, additional, Campbell, Brittany, additional, Kelly, Jacalyn, additional, Coblentz, Ailish, additional, Edwards, Melissa, additional, Lipman, Tatiana, additional, Zhang, Cindy, additional, Ercan, Ayse Bahar, additional, Sambira, Lauren, additional, Bendel, Anne, additional, Bielack, Stefan, additional, Koustenis, Elisabeth, additional, Blumenthal, Deborah, additional, Bowers, Daniel, additional, Nichols, Kim, additional, Bronsema, Annika, additional, Carroll, Sara, additional, Chiaravalli, Stefano, additional, Cole, Kristina, additional, Constantini, Shlomi, additional, De Mola, Rebecca Loret, additional, Dunn, Gavin, additional, Fröjd, Charlotta, additional, Gass, David, additional, Gauvain, Karen, additional, George, Ben, additional, Hijiya, Nobuko, additional, Hoffman, Lindsey, additional, Knipstein, Jeffrey, additional, Laetsch, Ted, additional, Larouche, Valérie, additional, Lassaletta, Alvaro, additional, Lindhorst, Scott, additional, Lossos, Alexander, additional, Luna-Fineman, Sandra, additional, Magimairajan, Vanan, additional, Mason, Gary, additional, Mason, Warren, additional, Massimino, Maura, additional, Mordechai, Oz, additional, Opocher, Enrico, additional, Oren, Michal, additional, Osborn, Michael, additional, Reddy, Alyssa, additional, Remke, Mark, additional, Roy, Sumita, additional, Sabel, Magnus, additional, Samuel, David, additional, Schneider, Kami, additional, Sen, Santanu, additional, Stearns, Duncan, additional, Sumerauer, David, additional, Thomas, Gregory, additional, Tomboc, Patrick, additional, Damme, An Van, additional, Wierman, Margaret, additional, Winer, Ira, additional, Yen, Lee Yi, additional, Zapotocky, Michal, additional, Ziegler, David, additional, Zimmermann, Stefanie, additional, Dvir, Rina, additional, Rechavi, Gidi, additional, Durno, Carol, additional, Aronson, Melyssa, additional, Taylor, Michael, additional, Dirks, Peter, additional, Pugh, Trevor, additional, Shlien, Adam, additional, Hawkins, Cynthia, additional, Morgenstern, Daniel, additional, and Tabori, Uri, additional

Published
2019
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17. TMOD-10. REPLICATION REPAIR DEFICIENT MOUSE MODELS PROVIDE INSIGHT ON HYPERMUTANT BRAIN TUMOURS AND COMBINATIONAL IMMUNOTHERAPY

Author

Galati, Melissa, primary, Bridge, Taylor, additional, Sudhaman, Sumedha, additional, Elshaer, Dana, additional, Ercan, Ayse, additional, Joksimovic, Lazar, additional, Gams, Miki, additional, Hodel, Karl, additional, Lipman, Tatiana, additional, Siddiqui, Iram, additional, Borja, Richard de, additional, Forster, Victoria, additional, Martin, Alberto, additional, Bouffet, Eric, additional, Shlien, Adam, additional, Guidos, Cynthia, additional, Pursell, Zachary, additional, Hawkins, Cynthia, additional, and Tabori, Uri, additional

Published
2019
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18. Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancer

Author

Leão, Ricardo, primary, Lee, Donghyun, additional, Figueiredo, Arnaldo, additional, Hermanns, Thomas, additional, Wild, Peter, additional, Komosa, Martin, additional, Lau, Irene, additional, Mistry, Mathew, additional, Nunes, Nuno Miguel, additional, Price, Aryeh J., additional, Zhang, Cindy, additional, Lipman, Tatiana, additional, Poyet, Cédric, additional, Valtcheva, Nadejda, additional, Oehl, Kathrin, additional, Coelho, Hugo, additional, Sayyid, Rashid, additional, Gomes, Ana Melo, additional, Prado e Castro, Ligia, additional, Sweet, Joan, additional, Vinagre, João, additional, Apolónio, Joana, additional, Stephens, Derek, additional, Faleiro, Inês, additional, Fadaak, Kamel, additional, Richard, Patrick O., additional, Kulkarni, Girish, additional, Zlotta, Alexandre R., additional, Hamilton, Robert J., additional, Castelo‐Branco, Pedro, additional, and Tabori, Uri, additional

Published
2018
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19. DNA hypermethylation within TERT promoter upregulates TERT expression in cancer

Author

Lee, Donghyun D., primary, Leão, Ricardo, additional, Komosa, Martin, additional, Gallo, Marco, additional, Zhang, Cindy H., additional, Lipman, Tatiana, additional, Remke, Marc, additional, Heidari, Abolfazl, additional, Nunes, Nuno Miguel, additional, Apolónio, Joana D., additional, Price, Aryeh J., additional, De Mello, Ramon Andrade, additional, Dias, João S., additional, Huntsman, David, additional, Hermanns, Thomas, additional, Wild, Peter J., additional, Vanner, Robert, additional, Zadeh, Gelareh, additional, Karamchandani, Jason, additional, Das, Sunit, additional, Taylor, Michael D., additional, Hawkins, Cynthia E., additional, Wasserman, Jonathan D., additional, Figueiredo, Arnaldo, additional, Hamilton, Robert J., additional, Minden, Mark D., additional, Wani, Khalida, additional, Diplas, Bill, additional, Yan, Hai, additional, Aldape, Kenneth, additional, Akbari, Mohammad R., additional, Danesh, Arnavaz, additional, Pugh, Trevor J., additional, Dirks, Peter B., additional, Castelo-Branco, Pedro, additional, and Tabori, Uri, additional

Published
2018
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21. A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: A retrospective cohort study

Author

Castelo-Branco, Pedro, Leao, Ricardo, Lipman, Tatiana, Campbell, Brittany, Lee, Donghyun, Price, Aryeh, Zhang, Cindy, Heidari, Abolfazl, Stephens, Derek, Boerno, Stefan, Coelho, Hugo, Gomes, Ana, Domingos, Celia, Apolonio, Joana D., Schaefer, Georg, Bristow, Robert G., Schweiger, Michal R., Hamilton, Robert, Zlotta, Alexandre, Figueiredo, Arnaldo, Klocker, Helmut, Sueltmann, Holger, Tabori, Uri, Castelo-Branco, Pedro, Leao, Ricardo, Lipman, Tatiana, Campbell, Brittany, Lee, Donghyun, Price, Aryeh, Zhang, Cindy, Heidari, Abolfazl, Stephens, Derek, Boerno, Stefan, Coelho, Hugo, Gomes, Ana, Domingos, Celia, Apolonio, Joana D., Schaefer, Georg, Bristow, Robert G., Schweiger, Michal R., Hamilton, Robert, Zlotta, Alexandre, Figueiredo, Arnaldo, Klocker, Helmut, Sueltmann, Holger, and Tabori, Uri

Abstract

The identification of new biomarkers to differentiate between indolent and aggressive prostate tumors is an important unmet need. We examined the role of THOR (TERT Hypermethylated Oncological Region) as a diagnostic and prognostic biomarker in prostate cancer (PCa). We analyzed THOR in common cancers using genome-wide methylation arrays. Methylation status of the whole TERT gene in benign and malignant prostate samples was determined by MeDIP-Seq. The prognostic role of THOR in PCa was assessed by pyrosequencing on discovery and validation cohorts from patients who underwent radical prostatectomy with long-term follow-up data. Most cancers (n = 3056) including PCa (n = 300) exhibited hypermethylation of THOR. THOR was the only region within the TERT gene that is differentially methylated between normal and malignant prostate tissue (p < 0.0001). Also, THOR was significantly hypermethylated in PCa when compared to paired benign tissues (n = 164, p < 0.0001). THOR hypermethylation correlated with Gleason scores and was associated with tumor invasiveness (p = 0.0147). Five years biochemical progression free survival (BPFS) for PCa patients in the discovery cohort was 87% (95% CI 73-100) and 65% (95% CI 52-78) for THOR non-hypermethylated and hypermethylated cancers respectively (p = 0.01). Similar differences in BPFS were noted in the validation cohort (p = 0.03). Importantly, THOR was able to predict outcome in the challenging (Gleason 6 and 7 (3 + 4)) PCa (p = 0.007). For this group, THOR was an independent risk factor for BPFS with a hazard-ratio of 3.685 (p = 0.0247). Finally, THOR hypermethylation more than doubled the risk of recurrence across all PSA levels (OR 2.5, p = 0.02).

Published
2016

22. A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: a retrospective cohort study

Author

Castelo-Branco, Pedro, primary, Leão, Ricardo, additional, Lipman, Tatiana, additional, Campbell, Brittany, additional, Lee, Donghyun, additional, Price, Aryeh, additional, Zhang, Cindy, additional, Heidari, Abolfazl, additional, Stephens, Derek, additional, Boerno, Stefan, additional, Coelho, Hugo, additional, Gomes, Ana, additional, Domingos, Celia, additional, Apolonio, Joana D., additional, Schäfer, Georg, additional, Bristow, Robert G., additional, Schweiger, Michal R., additional, Hamilton, Robert, additional, Zlotta, Alexandre, additional, Figueiredo, Arnaldo, additional, Klocker, Helmut, additional, Sültmann, Holger, additional, and Tabori, Uri, additional

Published
2016
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23. Abstract B09: DNA polymerase mutations trigger rapid onset of ultra-hypermutant malignant brain tumors in children with biallelic mismatch repair deficiency

Author

Shlien, Adam, primary, Campbell, Brittany B., additional, Borja, Richard de, additional, Alexandrov, Ludmil B., additional, Merico, Daniele, additional, Wedge, David, additional, Loo, Peter Van, additional, Tarpey, Patrick S., additional, Coupland, Paul, additional, Pollett, Aaron, additional, Lipman, Tatiana, additional, Heidari, Abolfazl, additional, Deshmukh, Shriya, additional, Gerstung, Moritz, additional, Merino, Diana, additional, Ramakrishna, Manasa, additional, Remke, Marc, additional, Arnold, Roland, additional, Panigrahi, Gagan B., additional, Afzal, Samina, additional, Larouche, Valerie, additional, Druker, Harriet, additional, Lerner-Ellis, Jordan, additional, Mistry, Matthew, additional, Dvir, Rina, additional, Grant, Ronald, additional, Elhasid, Ronit, additional, Farah, Roula, additional, Taylor, Glenn P., additional, Nathan, Paul C., additional, Alexander, Sarah, additional, Ben-Shachar, Shay, additional, Jabado, Nada, additional, Gallinger, Steven, additional, Constantini, Shlohmi, additional, Dirks, Peter, additional, Huang, Annie, additional, Scherer, Steven W., additional, Grundy, Richard G., additional, Durno, Carol, additional, Aronson, Melyssa, additional, Meyn, M Stephen, additional, Taylor, Michael D., additional, Pursell, Zachary F., additional, Pearson, Christopher E., additional, Malkin, David, additional, Futreal, P Andrew, additional, Hawkins, Cynthia, additional, Bouffet, Eric, additional, Campbell, Peter J., additional, and Tabori, Uri, additional

Published
2015
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24. Abstract A20: hTERT promoter hypermethylation is a cancer signature which predicts survival and response to targeted therapy in pediatric nervous system tumors

Author

castelo-branco, Pedro, primary, Choufani, Sanaa, additional, Mack, Stephen, additional, Gallagher, Denis, additional, Zhang, Cindy, additional, Lipman, Tatiana, additional, Zhukova, Nataliya, additional, Walker, Erin J., additional, Merino, Diana, additional, Jonathan, Jonathan D., additional, Elizabeth, Cynthia, additional, Alon, Noa, additional, Zhang, Libo, additional, Hovestadt, Volker, additional, Kool, Marcel, additional, Jones, David TW, additional, Croul, Sidney, additional, Hawkins, Cynthia, additional, Hitzler, Johann, additional, Wang, Jean C.Y., additional, Malkin, David, additional, Baruchel, Sylvain, additional, Dirks, Peter B., additional, Pfister, Stefan, additional, Taylor, Michael, additional, Weksberg, Rosanna, additional, and Tabori, Uri, additional

Published
2014
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25. Abstract LB-210: Abrogation of mutantTP53radiation resistance by lithium inducedCTNNB1(β-catenin) activation in medulloblastoma.

Author

Zhukova, Nataliya, primary, Martin, Dianna, additional, Lipman, Tatiana, additional, Castelo-Branco, Pedro, additional, Zhang, Cindy H., additional, Fraser, Michael, additional, Baskin, Berivan, additional, Ray, Peter, additional, Bouffet, Eric, additional, Bristow, Robert, additional, Alman, Benjamin A., additional, Taylor, Michael D., additional, Malkin, David, additional, Hawkins, Cynthia, additional, and Tabori, Uri, additional

Published
2012
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26. Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition

Author

Castelo-Branco, Pedro, primary, Zhang, Cindy, additional, Lipman, Tatiana, additional, Fujitani, Mayumi, additional, Hansford, Loen, additional, Clarke, Ian, additional, Harley, Calvin B., additional, Tressler, Robert, additional, Malkin, David, additional, Walker, Erin, additional, Kaplan, David R., additional, Dirks, Peter, additional, and Tabori, Uri, additional

Published
2011
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27. Abstract 12: Metastatic neuroblastoma cancer stem cells display a mixed phenotype of tumor and niche origin required for survival

Author

Hansford, Loen M., primary, Morozova, Olena, additional, Lipman, Tatiana, additional, Blakely, Kim, additional, Ohira, Miki, additional, Marrano, Paula, additional, Angelini, Paola, additional, Moffat, Jason, additional, Thiele, Carol J., additional, Thorner, Paul, additional, Dick, John, additional, Nakagawara, Akira, additional, Irwin, Meredith, additional, Marra, Marco, additional, and Kaplan, David R., additional

Published
2010
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29. Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancer.

Author

Leão R, Lee D, Figueiredo A, Hermanns T, Wild P, Komosa M, Lau I, Mistry M, Nunes NM, Price AJ, Zhang C, Lipman T, Poyet C, Valtcheva N, Oehl K, Coelho H, Sayyid R, Gomes AM, Prado E Castro L, Sweet J, Vinagre J, Apolónio J, Stephens D, Faleiro I, Fadaak K, Richard PO, Kulkarni G, Zlotta AR, Hamilton RJ, Castelo-Branco P, and Tabori U

Subjects
Disease Progression, Epigenesis, Genetic, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, Prognosis, Promoter Regions, Genetic, Sequence Analysis, RNA, Up-Regulation, DNA Methylation, Mutation, Telomerase genetics, Urinary Bladder Neoplasms genetics
Abstract

In urothelial bladder cancer (UBC), risk stratification remains an important unmet need. Limitless self-renewal, governed by TERT expression and telomerase activation, is crucial for cancer progression. Thus, telomerase activation through the interplay of mutations (TERTp Mut ) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERTp Mut and the TERT Hypermethylated Oncological Region (THOR) status on telomerase activation and patient outcome in a UBC international cohort (n = 237). We verified that TERTp Mut were frequent (76.8%) and present in all stages and grades of UBC. Hypermethylation of THOR was associated with higher TERT expression and higher-risk disease in nonmuscle invasive bladder cancers (NMIBC). TERTp Mut alone predicted disease recurrence (HR: 3.18, 95%CI 1.84 to 5.51, p < 0.0001) but not progression in NMIBC. Combined THOR high /TERTp Mut increased the risk of disease recurrence (HR 5.12, p < 0.0001) and progression (HR 3.92, p = 0.025). Increased THOR hypermethylation doubled the risk of stage progression of both TERTp wt and TERTp Mut NMIBC. These results highlight that both mechanisms are common and coexist in bladder cancer and while TERTp Mut is an early event in bladder carcinogenesis THOR hypermethylation is a dynamic process that contributes to disease progression. While the absence of alterations comprises an extremely indolent phenotype, the combined genetic and epigenetic alterations of TERT bring additional prognostic value in NMIBC and provide a novel insight into telomere biology in cancer., (© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Published
2019
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30. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers.

Author

Shlien A, Campbell BB, de Borja R, Alexandrov LB, Merico D, Wedge D, Van Loo P, Tarpey PS, Coupland P, Behjati S, Pollett A, Lipman T, Heidari A, Deshmukh S, Avitzur N, Meier B, Gerstung M, Hong Y, Merino DM, Ramakrishna M, Remke M, Arnold R, Panigrahi GB, Thakkar NP, Hodel KP, Henninger EE, Göksenin AY, Bakry D, Charames GS, Druker H, Lerner-Ellis J, Mistry M, Dvir R, Grant R, Elhasid R, Farah R, Taylor GP, Nathan PC, Alexander S, Ben-Shachar S, Ling SC, Gallinger S, Constantini S, Dirks P, Huang A, Scherer SW, Grundy RG, Durno C, Aronson M, Gartner A, Meyn MS, Taylor MD, Pursell ZF, Pearson CE, Malkin D, Futreal PA, Stratton MR, Bouffet E, Hawkins C, Campbell PJ, and Tabori U

Subjects
DNA Repair, DNA-Directed DNA Polymerase genetics, Exons, Germ-Line Mutation, Humans, Microsatellite Instability, Base Pair Mismatch, Brain Neoplasms genetics, DNA Mismatch Repair, DNA Replication genetics
Abstract

DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10(-13)). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.

Published
2015
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