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48 results on '"Chun, Hye-Jung"'

1. ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis

Author

Zipeto, Maria Anna, Court, Angela C, Sadarangani, Anil, Santos, Nathaniel P Delos, Balaian, Larisa, Chun, Hye-Jung, Pineda, Gabriel, Morris, Sheldon R, Mason, Cayla N, Geron, Ifat, Barrett, Christian, Goff, Daniel J, Wall, Russell, Pellecchia, Maurizio, Minden, Mark, Frazer, Kelly A, Marra, Marco A, Crews, Leslie A, Jiang, Qingfei, and Jamieson, Catriona HM

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Hematology, Biotechnology, Stem Cell Research - Nonembryonic - Human, Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, Cancer, Genetics, Rare Diseases, Adenosine Deaminase, Animals, Base Sequence, Cell Self Renewal, Fusion Proteins, bcr-abl, Gene Expression Regulation, Leukemic, Janus Kinase 2, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, MicroRNAs, Neoplastic Stem Cells, RNA Editing, RNA-Binding Proteins, Signal Transduction, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Post-transcriptional adenosine-to-inosine RNA editing mediated by adenosine deaminase acting on RNA1 (ADAR1) promotes cancer progression and therapeutic resistance. However, ADAR1 editase-dependent mechanisms governing leukemia stem cell (LSC) generation have not been elucidated. In blast crisis chronic myeloid leukemia (BC CML), we show that increased JAK2 signaling and BCR-ABL1 amplification activate ADAR1. In a humanized BC CML mouse model, combined JAK2 and BCR-ABL1 inhibition prevents LSC self-renewal commensurate with ADAR1 downregulation. Lentiviral ADAR1 wild-type, but not an editing-defective ADAR1(E912A) mutant, induces self-renewal gene expression and impairs biogenesis of stem cell regulatory let-7 microRNAs. Combined RNA sequencing, qRT-PCR, CLIP-ADAR1, and pri-let-7 mutagenesis data suggest that ADAR1 promotes LSC generation via let-7 pri-microRNA editing and LIN28B upregulation. A small-molecule tool compound antagonizes ADAR1's effect on LSC self-renewal in stromal co-cultures and restores let-7 biogenesis. Thus, ADAR1 activation represents a unique therapeutic vulnerability in LSCs with active JAK2 signaling.

Published
2016

2. Reversion to an embryonic alternative splicing program enhances leukemia stem cell self-renewal

Author

Holm, Frida, Hellqvist, Eva, Mason, Cayla N, Ali, Shawn A, Delos-Santos, Nathaniel, Barrett, Christian L, Chun, Hye-Jung, Minden, Mark D, Moore, Richard A, Marra, Marco A, Runza, Valeria, Frazer, Kelly A, Sadarangani, Anil, and Jamieson, Catriona HM

Subjects
Medical Biotechnology, Biological Sciences, Biomedical and Clinical Sciences, Clinical Research, Hematology, Rare Diseases, Genetics, Stem Cell Research - Nonembryonic - Non-Human, Cancer, Stem Cell Research, Biotechnology, Adult, Alternative Splicing, Animals, Apoptosis, Blast Crisis, Bone Marrow, Cell Adhesion Molecules, Cell Proliferation, Cell Self Renewal, Cell Survival, Cellular Reprogramming, Female, Fusion Proteins, bcr-abl, Gene Expression Regulation, Leukemic, Gene Knockdown Techniques, Hematopoiesis, Human Embryonic Stem Cells, Humans, Hyaluronan Receptors, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Ligands, Male, Mice, Middle Aged, Neoplasm Transplantation, Neoplastic Stem Cells, Pluripotent Stem Cells, Proto-Oncogene Mas, CD44v3, MBNL3, RNA splicing, self-renewal, adhesion molecules
Abstract

Formative research suggests that a human embryonic stem cell-specific alternative splicing gene regulatory network, which is repressed by Muscleblind-like (MBNL) RNA binding proteins, is involved in cell reprogramming. In this study, RNA sequencing, splice isoform-specific quantitative RT-PCR, lentiviral transduction, and in vivo humanized mouse model studies demonstrated that malignant reprogramming of progenitors into self-renewing blast crisis chronic myeloid leukemia stem cells (BC LSCs) was partially driven by decreased MBNL3. Lentiviral knockdown of MBNL3 resulted in reversion to an embryonic alternative splice isoform program typified by overexpression of CD44 transcript variant 3, containing variant exons 8-10, and BC LSC proliferation. Although isoform-specific lentiviral CD44v3 overexpression enhanced chronic phase chronic myeloid leukemia (CML) progenitor replating capacity, lentiviral shRNA knockdown abrogated these effects. Combined treatment with a humanized pan-CD44 monoclonal antibody and a breakpoint cluster region - ABL proto-oncogene 1, nonreceptor tyrosine kinase (BCR-ABL1) antagonist inhibited LSC maintenance in a niche-dependent manner. In summary, MBNL3 down-regulation-related reversion to an embryonic alternative splicing program, typified by CD44v3 overexpression, represents a previously unidentified mechanism governing malignant progenitor reprogramming in malignant microenvironments and provides a pivotal opportunity for selective BC LSC detection and therapeutic elimination.

Published
2015

3. GLI2 inhibition abrogates human leukemia stem cell dormancy

Author

Sadarangani, Anil, Pineda, Gabriel, Lennon, Kathleen M, Chun, Hye-Jung, Shih, Alice, Schairer, Annelie E, Court, Angela C, Goff, Daniel J, Prashad, Sacha L, Geron, Ifat, Wall, Russell, McPherson, John D, Moore, Richard A, Pu, Minya, Bao, Lei, Jackson-Fisher, Amy, Munchhof, Michael, VanArsdale, Todd, Reya, Tannishtha, Morris, Sheldon R, Minden, Mark D, Messer, Karen, Mikkola, Hanna KA, Marra, Marco A, Hudson, Thomas J, and Jamieson, Catriona HM

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Hematology, Genetics, Stem Cell Research - Nonembryonic - Human, Biotechnology, Rare Diseases, Stem Cell Research - Nonembryonic - Non-Human, Clinical Research, Human Genome, Stem Cell Research, Cancer, Animals, Base Sequence, Coculture Techniques, DNA Primers, Fetal Blood, Hedgehog Proteins, Humans, Kruppel-Like Transcription Factors, Leukemia, Mice, Mice, Knockout, Neoplastic Stem Cells, Nuclear Proteins, Reverse Transcriptase Polymerase Chain Reaction, Transcriptome, Zinc Finger Protein Gli2, Leukemia stem cells, Cell cycle, PF-04449913, Sonic hedgehog, Smoothened SMO, GLI2, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundDormant leukemia stem cells (LSC) promote therapeutic resistance and leukemic progression as a result of unbridled activation of stem cell gene expression programs. Thus, we hypothesized that 1) deregulation of the hedgehog (Hh) stem cell self-renewal and cell cycle regulatory pathway would promote dormant human LSC generation and 2) that PF-04449913, a clinical antagonist of the GLI2 transcriptional activator, smoothened (SMO), would enhance dormant human LSC eradication.MethodsTo test these postulates, whole transcriptome RNA sequencing (RNA-seq), microarray, qRT-PCR, stromal co-culture, confocal fluorescence microscopic, nanoproteomic, serial transplantation and cell cycle analyses were performed on FACS purified normal, chronic phase (CP) chronic myeloid leukemia (CML), blast crisis (BC) phase CML progenitors with or without PF-04449913 treatment.ResultsNotably, RNA-seq analyses revealed that Hh pathway and cell cycle regulatory gene overexpression correlated with leukemic progression. While lentivirally enforced GLI2 expression enhanced leukemic progenitor dormancy in stromal co-cultures, this was not observed with a mutant GLI2 lacking a transactivation domain, suggesting that GLI2 expression prevented cell cycle transit. Selective SMO inhibition with PF-04449913 in humanized stromal co-cultures and LSC xenografts reduced downstream GLI2 protein and cell cycle regulatory gene expression. Moreover, SMO inhibition enhanced cell cycle transit and sensitized BC LSC to tyrosine kinase inhibition in vivo at doses that spare normal HSC.ConclusionIn summary, while GLI2, forms part of a core HH pathway transcriptional regulatory network that promotes human myeloid leukemic progression and dormant LSC generation, selective inhibition with PF-04449913 reduces the dormant LSC burden thereby providing a strong rationale for clinical trials predicated on SMO inhibition in combination with TKIs or chemotherapeutic agents with the ultimate aim of obviating leukemic therapeutic resistance, persistence and progression.

Published
2015

4. Clinical response to nivolumab in an INI1-deficient pediatric chordoma correlates with immunogenic recognition of brachyury

Author

Williamson, Laura M., Rive, Craig M., Di Francesco, Daniela, Titmuss, Emma, Chun, Hye-Jung E., Brown, Scott D., Milne, Katy, Pleasance, Erin, Lee, Anna F., Yip, Stephen, Rosenbaum, Daniel G., Hasselblatt, Martin, Johann, Pascal D., Kool, Marcel, Harvey, Melissa, Dix, David, Renouf, Daniel J., Holt, Robert A., Nelson, Brad H., Hirst, Martin, Jones, Steven J. M., Laskin, Janessa, Rassekh, Shahrad R., Deyell, Rebecca J., and Marra, Marco A.

Published
2021
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5. Comprehensive molecular characterization of gastric adenocarcinoma

Author

Bass, Adam J, Thorsson, Vesteinn, Shmulevich, Ilya, Reynolds, Sheila M, Miller, Michael, Bernard, Brady, Hinoue, Toshinori, Laird, Peter W, Curtis, Christina, Shen, Hui, Weisenberger, Daniel J, Schultz, Nikolaus, Shen, Ronglai, Weinhold, Nils, Kelsen, David P, Bowlby, Reanne, Chu, Andy, Kasaian, Katayoon, Mungall, Andrew J, Robertson, A Gordon, Sipahimalani, Payal, Cherniack, Andrew, Getz, Gad, Liu, Yingchun, Noble, Michael S, Pedamallu, Chandra, Sougnez, Carrie, Taylor-Weiner, Amaro, Akbani, Rehan, Lee, Ju-Seog, Liu, Wenbin, Mills, Gordon B, Yang, Da, Zhang, Wei, Pantazi, Angeliki, Parfenov, Michael, Gulley, Margaret, Piazuelo, M Blanca, Schneider, Barbara G, Kim, Jihun, Boussioutas, Alex, Sheth, Margi, Demchok, John A, Rabkin, Charles S, Willis, Joseph E, Ng, Sam, Garman, Katherine, Beer, David G, Pennathur, Arjun, Raphael, Benjamin J, Wu, Hsin-Ta, Odze, Robert, Kim, Hark K, Bowen, Jay, Leraas, Kristen M, Lichtenberg, Tara M, Weaver, Stephanie, McLellan, Michael, Wiznerowicz, Maciej, Sakai, Ryo, Lawrence, Michael S, Cibulskis, Kristian, Lichtenstein, Lee, Fisher, Sheila, Gabriel, Stacey B, Lander, Eric S, Ding, Li, Niu, Beifang, Ally, Adrian, Balasundaram, Miruna, Birol, Inanc, Brooks, Denise, Butterfield, Yaron SN, Carlsen, Rebecca, Chu, Justin, Chuah, Eric, Chun, Hye-Jung E, Clarke, Amanda, Dhalla, Noreen, Guin, Ranabir, Holt, Robert A, Jones, Steven JM, Lee, Darlene, Li, Haiyan A, Lim, Emilia, Ma, Yussanne, Marra, Marco A, Mayo, Michael, Moore, Richard A, Mungall, Karen L, Ming Nip, Ka, and Schein, Jacqueline E

Subjects
Genetics, Digestive Diseases, Genetic Testing, Human Genome, Rare Diseases, Cancer, Good Health and Well Being, Adenocarcinoma, Female, Gene Expression Regulation, Neoplastic, Genome, Human, Herpesvirus 4, Human, Humans, Male, Mutation, Proteome, Stomach Neoplasms, Cancer Genome Atlas Research Network, General Science & Technology
Abstract

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.

Published
2014

6. The Cancer Genome Atlas Pan-Cancer analysis project

Author

Chang, Kyle, Creighton, Chad J, Davis, Caleb, Donehower, Lawrence, Drummond, Jennifer, Wheeler, David, Ally, Adrian, Balasundaram, Miruna, Birol, Inanc, Butterfield, Yaron SN, Chu, Andy, Chuah, Eric, Chun, Hye-Jung E, Dhalla, Noreen, Guin, Ranabir, Hirst, Martin, Hirst, Carrie, Holt, Robert A, Jones, Steven JM, Lee, Darlene, Li, Haiyan I, Marra, Marco A, Mayo, Michael, Moore, Richard A, Mungall, Andrew J, Robertson, A Gordon, Schein, Jacqueline E, Sipahimalani, Payal, Tam, Angela, Thiessen, Nina, Varhol, Richard J, Beroukhim, Rameen, Bhatt, Ami S, Brooks, Angela N, Cherniack, Andrew D, Freeman, Samuel S, Gabriel, Stacey B, Helman, Elena, Jung, Joonil, Meyerson, Matthew, Ojesina, Akinyemi I, Pedamallu, Chandra Sekhar, Saksena, Gordon, Schumacher, Steven E, Tabak, Barbara, Zack, Travis, Lander, Eric S, Bristow, Christopher A, Hadjipanayis, Angela, Haseley, Psalm, Kucherlapati, Raju, Lee, Semin, Lee, Eunjung, Luquette, Lovelace J, Mahadeshwar, Harshad S, Pantazi, Angeliki, Parfenov, Michael, Park, Peter J, Protopopov, Alexei, Ren, Xiaojia, Santoso, Netty, Seidman, Jonathan, Seth, Sahil, Song, Xingzhi, Tang, Jiabin, Xi, Ruibin, Xu, Andrew W, Yang, Lixing, Zeng, Dong, Auman, J Todd, Balu, Saianand, Buda, Elizabeth, Fan, Cheng, Hoadley, Katherine A, Jones, Corbin D, Meng, Shaowu, Mieczkowski, Piotr A, Parker, Joel S, Perou, Charles M, Roach, Jeffrey, Shi, Yan, Silva, Grace O, Tan, Donghui, Veluvolu, Umadevi, Waring, Scot, Wilkerson, Matthew D, Wu, Junyuan, Zhao, Wei, Bodenheimer, Tom, Hayes, D Neil, Hoyle, Alan P, Jeffreys, Stuart R, Mose, Lisle E, Simons, Janae V, Soloway, Mathew G, Baylin, Stephen B, Berman, Benjamin P, Bootwalla, Moiz S, Danilova, Ludmila, and Herman, James G

Subjects
Biological Sciences, Genetics, Cancer, Human Genome, Rare Diseases, Good Health and Well Being, Gene Expression Profiling, Genome, Humans, Neoplasms, Cancer Genome Atlas Research Network, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.

Published
2013

7. Integrated genomic characterization of endometrial carcinoma

Author

Getz, Gad, Gabriel, Stacey B, Cibulskis, Kristian, Lander, Eric, Sivachenko, Andrey, Sougnez, Carrie, Lawrence, Mike, Kandoth, Cyriac, Dooling, David, Fulton, Robert, Fulton, Lucinda, Kalicki-Veizer, Joelle, McLellan, Michael D, O’Laughlin, Michelle, Schmidt, Heather, Wilson, Richard K, Ye, Kai, Ding, Li, Mardis, Elaine R, Ally, Adrian, Balasundaram, Miruna, Birol, Inanc, Butterfield, Yaron SN, Carlsen, Rebecca, Carter, Candace, Chu, Andy, Chuah, Eric, Chun, Hye-Jung E, Dhalla, Noreen, Guin, Ranabir, Hirst, Carrie, Holt, Robert A, Jones, Steven JM, Lee, Darlene, Li, Haiyan I, Marra, Marco A, Mayo, Michael, Moore, Richard A, Mungall, Andrew J, Plettner, Patrick, Schein, Jacqueline E, Sipahimalani, Payal, Tam, Angela, Varhol, Richard J, Gordon Robertson, A, Cherniack, Andrew D, Pashtan, Itai, Saksena, Gordon, Onofrio, Robert C, Schumacher, Steven E, Tabak, Barbara, Carter, Scott L, Hernandez, Bryan, Gentry, Jeff, Salvesen, Helga B, Ardlie, Kristin, Winckler, Wendy, Beroukhim, Rameen, Meyerson, Matthew, Hadjipanayis, Angela, Lee, Semin, Mahadeshwar, Harshad S, Park, Peter, Protopopov, Alexei, Ren, Xiaojia, Seth, Sahil, Song, Xingzhi, Tang, Jiabin, Xi, Ruibin, Yang, Lixing, Zeng, Dong, Kucherlapati, Raju, Chin, Lynda, Zhang, Jianhua, Todd Auman, J, Balu, Saianand, Bodenheimer, Tom, Buda, Elizabeth, Neil Hayes, D, Hoyle, Alan P, Jefferys, Stuart R, Jones, Corbin D, Meng, Shaowu, Mieczkowski, Piotr A, Mose, Lisle E, Parker, Joel S, Perou, Charles M, Roach, Jeff, Shi, Yan, Simons, Janae V, Soloway, Mathew G, Tan, Donghui, Topal, Michael D, Waring, Scot, Wu, Junyuan, Hoadley, Katherine A, Baylin, Stephen B, and Bootwalla, Moiz S

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Reproductive Medicine, Human Genome, Cancer, Uterine Cancer, Biotechnology, Breast Neoplasms, Chromosome Aberrations, DNA Copy Number Variations, DNA Mutational Analysis, DNA Polymerase II, DNA-Binding Proteins, Endometrial Neoplasms, Exome, Female, Gene Expression Regulation, Neoplastic, Genome, Human, Genomics, Humans, Ovarian Neoplasms, Poly-ADP-Ribose Binding Proteins, Signal Transduction, Transcription Factors, Cancer Genome Atlas Research Network, General Science & Technology
Abstract

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

Published
2013

8. Comprehensive genomic characterization of squamous cell lung cancers

Author

Hammerman, Peter S, Lawrence, Michael S, Voet, Douglas, Jing, Rui, Cibulskis, Kristian, Sivachenko, Andrey, Stojanov, Petar, McKenna, Aaron, Lander, Eric S, Gabriel, Stacey, Getz, Gad, Sougnez, Carrie, Imielinski, Marcin, Helman, Elena, Hernandez, Bryan, Pho, Nam H, Meyerson, Matthew, Chu, Andy, Chun, Hye-Jung E, Mungall, Andrew J, Pleasance, Erin, Gordon Robertson, A, Sipahimalani, Payal, Stoll, Dominik, Balasundaram, Miruna, Birol, Inanc, Butterfield, Yaron SN, Chuah, Eric, Coope, Robin JN, Corbett, Richard, Dhalla, Noreen, Guin, Ranabir, He, An, Hirst, Carrie, Hirst, Martin, Holt, Robert A, Lee, Darlene, Li, Haiyan I, Mayo, Michael, Moore, Richard A, Mungall, Karen, Ming Nip, Ka, Olshen, Adam, Schein, Jacqueline E, Slobodan, Jared R, Tam, Angela, Thiessen, Nina, Varhol, Richard, Zeng, Thomas, Zhao, Yongjun, Jones, Steven JM, Marra, Marco A, Saksena, Gordon, Cherniack, Andrew D, Schumacher, Stephen E, Tabak, Barbara, Carter, Scott L, Nguyen, Huy, Onofrio, Robert C, Crenshaw, Andrew, Ardlie, Kristin, Beroukhim, Rameen, Winckler, Wendy, Protopopov, Alexei, Zhang, Jianhua, Hadjipanayis, Angela, Lee, Semin, Xi, Ruibin, Yang, Lixing, Ren, Xiaojia, Zhang, Hailei, Shukla, Sachet, Chen, Peng-Chieh, Haseley, Psalm, Lee, Eunjung, Chin, Lynda, Park, Peter J, Kucherlapati, Raju, Socci, Nicholas D, Liang, Yupu, Schultz, Nikolaus, Borsu, Laetitia, Lash, Alex E, Viale, Agnes, Sander, Chris, Ladanyi, Marc, Todd Auman, J, Hoadley, Katherine A, Wilkerson, Matthew D, Shi, Yan, Liquori, Christina, Meng, Shaowu, Li, Ling, Turman, Yidi J, Topal, Michael D, and Tan, Donghui

Subjects
Human Genome, Biotechnology, Genetics, Rare Diseases, Cancer, Lung Cancer, Lung, Aetiology, 2.1 Biological and endogenous factors, Adenocarcinoma, Adenocarcinoma of Lung, Carcinoma, Squamous Cell, DNA Mutational Analysis, Gene Deletion, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genes, p16, Genes, p53, Genome, Human, Genomics, Humans, Lung Neoplasms, Molecular Targeted Therapy, Mutation, Mutation Rate, Phosphatidylinositol 3-Kinases, Signal Transduction, Cancer Genome Atlas Research Network, General Science & Technology
Abstract

Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers.

Published
2012

9. ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia

Author

Jiang, Qingfei, Crews, Leslie A., Barrett, Christian L., Chun, Hye-Jung, Court, Angela C., Isquith, Jane M., Zipeto, Maria A., Goff, Daniel J., Minden, Mark, Sadarangani, Anil, Rusert, Jessica M., Dao, Kim-Hien T., Morris, Sheldon R., Goldstein, Lawrence S. B., Marra, Marco A., Frazer, Kelly A., and Jamieson, Catriona H. M.

Published
2013

11. List of Contributors

Author

Anderson, Kenneth C., primary, Aparicio, Samuel A., additional, Arceci, Robert J., additional, Berlin, Alejandro, additional, Berman, Jason N., additional, Borrello, Maria Grazia, additional, Bristow, Robert G., additional, Bydoun, Moamen, additional, Calin, George A., additional, Chiu, Priscilla P.L., additional, Chun, Hye-Jung E., additional, Cottini, Francesca, additional, Dancey, Janet E., additional, Dellaire, Graham, additional, EL-Naggar, Amal M., additional, Fernandez, Conrad V., additional, Fraser, Michael, additional, Gaston, Daniel, additional, Giacomantonio, Carman, additional, Greco, Angela, additional, Hedlund, Erin, additional, Herder, Matthew, additional, Hohenstein, Peter, additional, Irwin, Meredith S., additional, Jones, Steven J.M., additional, Kasaian, Katayoon, additional, Khan, Javed, additional, Khattra, Jaswinder, additional, Krzywinski, Martin, additional, Le Page, Cécile, additional, Leprivier, Gabriel, additional, Li, Yvonne Y., additional, Ling, Hui, additional, Magliocco, Anthony M., additional, Malkin, David, additional, Manoranjan, Branavan, additional, Marcato, Paola, additional, Marra, Marco A., additional, Mes-Masson, Anne-Marie, additional, Meshinchi, Soheil, additional, Miranda, Claudia, additional, Montgomery, Stephen B., additional, Morgenstern, Daniel A., additional, Morin, Ryan D., additional, Ouellet, Veronique, additional, Parker, Louise, additional, Parker, Matthew, additional, Perlman, Elizabeth J., additional, Pierotti, Marco A., additional, Rassekh, Shahrad Rod, additional, Ross, Colin J.D., additional, Saad, Fred, additional, Singh, Sheila K., additional, Sorensen, Poul H., additional, Tonon, Giovanni, additional, Venugopal, Chitra, additional, Vora, Parvez, additional, Wei, Jun S., additional, Xu, Zhaolin, additional, Zhang, Jinghui, additional, and Zhang, Shile, additional

Published
2014
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13. Molecular characterization of rhabdoid tumours from multiple anatomical sites

Author

Chun, Hye-Jung Elizabeth

Abstract

Rhabdoid tumours (RTs) are highly aggressive paediatric cancers that predominantly affect infants, with an overall 4-year survival rate below 25% and no curative therapy established to date. Nearly all RTs exhibit pathognomonic loss of SMARCB1, a core subunit of the SWI/SNF complex that mobilizes nucleosomes and regulates gene expression and epigenetic reprogramming. RTs are broadly classified into cranial (atypical teratoid RTs / ATRTs) and extra-cranial RTs (malignant RTs / MRTs), yet the extent to which they are different or similar was not fully determined. Previous reports indicated some shared molecular features between the two entities, but there had been no direct comparison between ATRTs and MRTs. Furthermore, previous reports indicated clinical and histological heterogeneity within and across ATRTs and MRTs, yet the extent of molecular heterogeneity was unknown, particularly in MRTs for which genomic, transcriptomic and epigenomic data were lacking. To address these knowledge gaps, I hypothesized that multi-omic data analyses would identify novel mutations, and gene expression and epigenetic features in MRTs and that such analyses could identify potential molecular underpinnings of heterogeneity. To test these hypotheses, I analyzed whole genome, transcriptome, DNA methylome, histone H3K27me3 and H3K27ac modification profiles obtained from 40 MRT cases, and analyzed multi-omics datasets derived from 140 MRT and 161 ATRT cases. My whole genome analyses revealed recurrently altered genes that were previously undescribed in MRTs. Integration of gene expression and epigenetic data revealed the convergence in dysregulation of HOX genes, imprinted genes and other development-regulating genes such as those involved in neural crest development, indicating dysregulation of early human developmental processes in MRTs. I also identified five DNA methylation subgroups of RTs across different anatomical sites. Among these, subgroups containing MRTs and ATRTs expressing relatively high levels of MYC exhibited gene expression signatures and epigenetic modifications indicative of increased immunological activities. I analyzed immunohistochemistry data to confirm increased levels of immune cell infiltration and expression of immune checkpoint proteins in these subgroups. My findings implied the potential utility of immune checkpoint blockade treatments for RT patients despite the low prevalence of mutations in these cancers.

Published
2020
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14. Comprehensive molecular characterization of clear cell renal cell carcinoma

Author

Creighton, Chad J., Morgan, Margaret, Gunaratne, Preethi H., Wheeler, David A., Gibbs, Richard A., Robertson, Gordon A., Chu, Andy, Beroukhim, Rameen, Cibulskis, Kristian, Signoretti, Sabina, Hsin-Ta Wu, Fabio Vandin, Raphael, Benjamin J., Verhaak, Roel G. W., Tamboli, Pheroze, Torres-Garcia, Wandaliz, Akbani, Rehan, Weinstein, John N., Reuter, Victor, Hsieh, James J., Brannon, Rose A., Ari Hakimi, A., Jacobsen, Anders, Ciriello, Giovanni, Reva, Boris, Ricketts, Christopher J., Linehan, Marston W., Stuart, Joshua M., Rathmell, Kimryn W., Shen, Hui, Laird, Peter W., Muzny, Donna, Davis, Caleb, Xi, Liu, Chang, Kyle, Kakkar, Nipun, Treviño, Lisa R., Benton, Susan, Reid, Jeffrey G., Morton, Donna, Doddapaneni, Harsha, Han, Yi, Lewis, Lora, Dinh, Huyen, Kovar, Christie, Zhu, Yiming, Santibanez, Jireh, Wang, Min, Hale, Walker, Kalra, Divya, Getz, Gad, Lawrence, Michael S., Sougnez, Carrie, Carter, Scott L., Sivachenko, Andrey, Lichtenstein, Lee, Stewart, Chip, Voet, Doug, Fisher, Sheila, Gabriel, Stacey B., Lander, Eric, Schumacher, Steve E., Tabak, Barbara, Saksena, Gordon, Onofrio, Robert C., Cherniack, Andrew D., Gentry, Jeff, Ardlie, Kristin, Meyerson, Matthew, Chun, Hye-Jung E., Mungall, Andrew J., Sipahimalani, Payal, Stoll, Dominik, Ally, Adrian, Balasundaram, Miruna, Butterfield, Yaron S. N., Carlsen, Rebecca, Carter, Candace, Chuah, Eric, Coope, Robin J. N., Dhalla, Noreen, Gorski, Sharon, Guin, Ranabir, Hirst, Carrie, Hirst, Martin, Holt, Robert A., Lebovitz, Chandra, Lee, Darlene, Li, Haiyan I., Mayo, Michael, Moore, Richard A., Pleasance, Erin, Plettner, Patrick, Schein, Jacqueline E., Shafiei, Arash, Slobodan, Jared R., Tam, Angela, Thiessen, Nina, Varhol, Richard J., Wye, Natasja, Zhao, Yongjun, Birol, Inanc, Jones, Steven J. M., Marra, Marco A., Auman, Todd J., Tan, Donghui, Jones, Corbin D., Hoadley, Katherine A., Mieczkowski, Piotr A., Mose, Lisle E., Jefferys, Stuart R., Topal, Michael D., Liquori, Christina, Turman, Yidi J., Shi, Yan, Waring, Scot, Buda, Elizabeth, Walsh, Jesse, Wu, Junyuan, Bodenheimer, Tom, Hoyle, Alan P., Simons, Janae V., Soloway, Mathew G., Balu, Saianand, Parker, Joel S., Hayes, Neil D., Perou, Charles M., Kucherlapati, Raju, Park, Peter, Triche, Timothy, Jr, Weisenberger, Daniel J., Lai, Phillip H., Bootwalla, Moiz S., Maglinte, Dennis T., Mahurkar, Swapna, Berman, Benjamin P., Van Den Berg, David J., Cope, Leslie, Baylin, Stephen B., Noble, Michael S., DiCara, Daniel, Zhang, Hailei, Cho, Juok, Heiman, David I., Gehlenborg, Nils, Mallard, William, Lin, Pei, Frazer, Scott, Stojanov, Petar, Liu, Yingchun, Zhou, Lihua, Kim, Jaegil, Chin, Lynda, Vandin, Fabio, Wu, Hsin-Ta, Benz, Christopher, Yau, Christina, Reynolds, Sheila M., Shmulevich, Ilya, Verhaak, Roel G.W., Vegesna, Rahul, Kim, Hoon, Zhang, Wei, Cogdell, David, Jonasch, Eric, Ding, Zhiyong, Lu, Yiling, Zhang, Nianxiang, Unruh, Anna K., Casasent, Tod D., Wakefield, Chris, Tsavachidou, Dimitra, Mills, Gordon B., Schultz, Nikolaus, Antipin, Yevgeniy, Gao, Jianjiong, Cerami, Ethan, Gross, Benjamin, Aksoy, Arman B., Sinha, Rileen, Weinhold, Nils, Sumer, Onur S., Taylor, Barry S., Shen, Ronglai, Ostrovnaya, Irina, Berger, Michael F., Ladanyi, Marc, Sander, Chris, Fei, Suzanne S., Stout, Andrew, Spellman, Paul T., Rubin, Daniel L., Liu, Tiffany T., Ng, Sam, Paull, Evan O., Carlin, Daniel, Goldstein, Theodore, Waltman, Peter, Ellrott, Kyle, Zhu, Jing, Haussler, David, Xiao, Weimin, Shelton, Candace, Gardner, Johanna, Penny, Robert, Sherman, Mark, Mallery, David, Morris, Scott, Paulauskis, Joseph, Burnett, Ken, Shelton, Troy, Kaelin, William G., Choueiri, Toni, Atkins, Michael B., Curley, Erin, Tickoo, Satish, Thorne, Leigh, Boice, Lori, Huang, Mei, Fisher, Jennifer C., Vocke, Cathy D., Peterson, James, Worrell, Robert, Merino, Maria J., Schmidt, Laura S., Czerniak, Bogdan A., Aldape, Kenneth D., Wood, Christopher G., Boyd, Jeff, Weaver, JoEllen, Iacocca, Mary V., Petrelli, Nicholas, Witkin, Gary, Brown, Jennifer, Czerwinski, Christine, Huelsenbeck-Dill, Lori, Rabeno, Brenda, Myers, Jerome, Morrison, Carl, Bergsten, Julie, Eckman, John, Harr, Jodi, Smith, Christine, Tucker, Kelinda, Zach, Leigh Anne, Bshara, Wiam, Gaudioso, Carmelo, Dhir, Rajiv, Maranchie, Jodi, Nelson, Joel, Parwani, Anil, Potapova, Olga, Fedosenko, Konstantin, Cheville, John C., Thompson, Houston R., Mosquera, Juan M., Rubin, Mark A., Blute, Michael L., Pihl, Todd, Jensen, Mark, Sfeir, Robert, Kahn, Ari, Chu, Anna, Kothiyal, Prachi, Snyder, Eric, Pontius, Joan, Ayala, Brenda, Backus, Mark, Walton, Jessica, Baboud, Julien, Berton, Dominique, Nicholls, Matthew, Srinivasan, Deepak, Raman, Rohini, Girshik, Stanley, Kigonya, Peter, Alonso, Shelley, Sanbhadti, Rashmi, Barletta, Sean, Pot, David, Sheth, Margi, Demchok, John A., Davidsen, Tanja, Wang, Zhining, Yang, Liming, Tarnuzzer, Roy W., Zhang, Jiashan, Eley, Greg, Ferguson, Martin L., Mills Shaw, Kenna R., Guyer, Mark S., Ozenberger, Bradley A., and Sofia, Heidi J.

Published
2013
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15. Comprehensive molecular portraits of human breast tumours

Author

Koboldt, Daniel C., Fulton, Robert S., McLellan, Michael D., Schmidt, Heather, Kalicki-Veizer, Joelle, McMichael, Joshua F., Fulton, Lucinda L., Dooling, David J., Ding, Li, Mardis, Elaine R., Wilson, Richard K., Ally, Adrian, Balasundaram, Miruna, Butterfield, Yaron S. N., Carlsen, Rebecca, Carter, Candace, Chu, Andy, Chuah, Eric, Chun, Hye-Jung E., Coope, Robin J. N., Dhalla, Noreen, Guin, Ranabir, Hirst, Carrie, Hirst, Martin, Holt, Robert A., Lee, Darlene, Li, Haiyan I., Mayo, Michael, Moore, Richard A., Mungall, Andrew J., Pleasance, Erin, Gordon Robertson, A., Schein, Jacqueline E., Shafiei, Arash, Sipahimalani, Payal, Slobodan, Jared R., Stoll, Dominik, Tam, Angela, Thiessen, Nina, Varhol, Richard J., Wye, Natasja, Zeng, Thomas, Zhao, Yongjun, Birol, Inanc, Jones, Steven J. M., Marra, Marco A., Cherniack, Andrew D., Saksena, Gordon, Onofrio, Robert C., Pho, Nam H., Carter, Scott L., Schumacher, Steven E., Tabak, Barbara, Hernandez, Bryan, Gentry, Jeff, Nguyen, Huy, Crenshaw, Andrew, Ardlie, Kristin, Beroukhim, Rameen, Winckler, Wendy, Getz, Gad, Gabriel, Stacey B., Meyerson, Matthew, Chin, Lynda, Park, Peter J., Kucherlapati, Raju, Hoadley, Katherine A., Todd Auman, J., Fan, Cheng, Turman, Yidi J., Shi, Yan, Li, Ling, Topal, Michael D., He, Xiaping, Chao, Hann-Hsiang, Prat, Aleix, Silva, Grace O., Iglesia, Michael D., Zhao, Wei, Usary, Jerry, Berg, Jonathan S., Adams, Michael, Booker, Jessica, Wu, Junyuan, Gulabani, Anisha, Bodenheimer, Tom, Hoyle, Alan P., Simons, Janae V., Soloway, Matthew G., Mose, Lisle E., Jefferys, Stuart R., Balu, Saianand, Parker, Joel S., Neil Hayes, D., Perou, Charles M., Malik, Simeen, Mahurkar, Swapna, Shen, Hui, Weisenberger, Daniel J., Triche, Timothy, Jr, Lai, Phillip H., Bootwalla, Moiz S., Maglinte, Dennis T., Berman, Benjamin P., Van Den Berg, David J., Baylin, Stephen B., Laird, Peter W., Creighton, Chad J., Donehower, Lawrence A., Noble, Michael, Voet, Doug, Gehlenborg, Nils, DiCara, Daniel, Zhang, Juinhua, Zhang, Hailei, Wu, Chang-Jiun, Liu, Spring Yingchun, Lawrence, Michael S., Zou, Lihua, Sivachenko, Andrey, Lin, Pei, Stojanov, Petar, Jing, Rui, Cho, Juok, Sinha, Raktim, Park, Richard W., Nazaire, Marc-Danie, Robinson, Jim, Thorvaldsdottir, Helga, Mesirov, Jill, Reynolds, Sheila, Kreisberg, Richard B., Bernard, Brady, Bressler, Ryan, Erkkila, Timo, Lin, Jake, Thorsson, Vesteinn, Zhang, Wei, Shmulevich, Ilya, Ciriello, Giovanni, Weinhold, Nils, Schultz, Nikolaus, Gao, Jianjiong, Cerami, Ethan, Gross, Benjamin, Jacobsen, Anders, Sinha, Rileen, Arman Aksoy, B., Antipin, Yevgeniy, Reva, Boris, Shen, Ronglai, Taylor, Barry S., Ladanyi, Marc, Sander, Chris, Anur, Pavana, Spellman, Paul T., Lu, Yiling, Liu, Wenbin, Verhaak, Roel R. G., Mills, Gordon B., Akbani, Rehan, Zhang, Nianxiang, Broom, Bradley M., Casasent, Tod D., Wakefield, Chris, Unruh, Anna K., Baggerly, Keith, Coombes, Kevin, Weinstein, John N., Haussler, David, Benz, Christopher C., Stuart, Joshua M., Benz, Stephen C., Zhu, Jingchun, Szeto, Christopher C., Scott, Gary K., Yau, Christina, Paull, Evan O., Carlin, Daniel, Wong, Christopher, Sokolov, Artem, Thusberg, Janita, Mooney, Sean, Ng, Sam, Goldstein, Theodore C., Ellrott, Kyle, Grifford, Mia, Wilks, Christopher, Ma, Singer, Craft, Brian, Yan, Chunhua, Hu, Ying, Meerzaman, Daoud, Gastier-Foster, Julie M., Bowen, Jay, Ramirez, Nilsa C., Black, Aaron D., Pyatt, Robert E., White, Peter, Zmuda, Erik J., Frick, Jessica, Lichtenberg, Tara M., Brookens, Robin, George, Myra M., Gerken, Mark A., Harper, Hollie A., Leraas, Kristen M., Wise, Lisa J., Tabler, Teresa R., McAllister, Cynthia, Barr, Thomas, Hart-Kothari, Melissa, Tarvin, Katie, Saller, Charles, Sandusky, George, Mitchell, Colleen, Iacocca, Mary V., Brown, Jennifer, Rabeno, Brenda, Czerwinski, Christine, Petrelli, Nicholas, Dolzhansky, Oleg, Abramov, Mikhail, Voronina, Olga, Potapova, Olga, Marks, Jeffrey R., Suchorska, Wiktoria M., Murawa, Dawid, Kycler, Witold, Ibbs, Matthew, Korski, Konstanty, Spychała, Arkadiusz, Murawa, Paweł, Brzeziński, Jacek J., Perz, Hanna, Łaźniak, Radosław, Teresiak, Marek, Tatka, Honorata, Leporowska, Ewa, Bogusz-Czerniewicz, Marta, Malicki, Julian, Mackiewicz, Andrzej, Wiznerowicz, Maciej, Van Le, Xuan, Kohl, Bernard, Viet Tien, Nguyen, Thorp, Richard, Van Bang, Nguyen, Sussman, Howard, Duc Phu, Bui, Hajek, Richard, Phi Hung, Nguyen, Viet The Phuong, Tran, Quyet Thang, Huynh, Zaki Khan, Khurram, Penny, Robert, Mallery, David, Curley, Erin, Shelton, Candace, Yena, Peggy, Ingle, James N., Couch, Fergus J., Lingle, Wilma L., King, Tari A., Maria Gonzalez-Angulo, Ana, Dyer, Mary D., Liu, Shuying, Meng, Xiaolong, Patangan, Modesto, Waldman, Frederic, Stöppler, Hubert, Kimryn Rathmell, W., Thorne, Leigh, Huang, Mei, Boice, Lori, Hill, Ashley, Morrison, Carl, Gaudioso, Carmelo, Bshara, Wiam, Daily, Kelly, Egea, Sophie C., Pegram, Mark D., Gomez-Fernandez, Carmen, Dhir, Rajiv, Bhargava, Rohit, Brufsky, Adam, Shriver, Craig D., Hooke, Jeffrey A., Leigh Campbell, Jamie, Mural, Richard J., Hu, Hai, Somiari, Stella, Larson, Caroline, Deyarmin, Brenda, Kvecher, Leonid, Kovatich, Albert J., Ellis, Matthew J., Stricker, Thomas, White, Kevin, Olopade, Olufunmilayo, Luo, Chunqing, Chen, Yaqin, Bose, Ron, Chang, Li-Wei, Beck, Andrew H., Pihl, Todd, Jensen, Mark, Sfeir, Robert, Kahn, Ari, Chu, Anna, Kothiyal, Prachi, Wang, Zhining, Snyder, Eric, Pontius, Joan, Ayala, Brenda, Backus, Mark, Walton, Jessica, Baboud, Julien, Berton, Dominique, Nicholls, Matthew, Srinivasan, Deepak, Raman, Rohini, Girshik, Stanley, Kigonya, Peter, Alonso, Shelley, Sanbhadti, Rashmi, Barletta, Sean, Pot, David, Sheth, Margi, Demchok, John A., Mills Shaw, Kenna R., Yang, Liming, Eley, Greg, Ferguson, Martin L., Tarnuzzer, Roy W., Zhang, Jiashan, Dillon, Laura A. L., Buetow, Kenneth, Fielding, Peter, Ozenberger, Bradley A., Guyer, Mark S., Sofia, Heidi J., and Palchik, Jacqueline D.

Published
2012
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16. Comprehensive molecular characterization of human colon and rectal cancer

Author

Muzny, Donna M., Bainbridge, Matthew N., Chang, Kyle, Dinh, Huyen H., Drummond, Jennifer A., Fowler, Gerald, Kovar, Christie L., Lewis, Lora R., Morgan, Margaret B., Newsham, Irene F., Reid, Jeffrey G., Santibanez, Jireh, Shinbrot, Eve, Trevino, Lisa R., Wu, Yuan-Qing, Wang, Min, Gunaratne, Preethi, Donehower, Lawrence A., Creighton, Chad J., Wheeler, David A., Gibbs, Richard A., Lawrence, Michael S., Voet, Douglas, Jing, Rui, Cibulskis, Kristian, Sivachenko, Andrey, Stojanov, Petar, McKenna, Aaron, Lander, Eric S., Gabriel, Stacey, Getz, Gad, Ding, Li, Fulton, Robert S., Koboldt, Daniel C., Wylie, Todd, Walker, Jason, Dooling, David J., Fulton, Lucinda, Delehaunty, Kim D., Fronick, Catrina C., Demeter, Ryan, Mardis, Elaine R., Wilson, Richard K., Chu, Andy, Chun, Hye-Jung E., Mungall, Andrew J., Pleasance, Erin, Robertson, Gordon A., Stoll, Dominik, Balasundaram, Miruna, Birol, Inanc, Butterfield, Yaron S. N., Chuah, Eric, Coope, Robin J. N., Dhalla, Noreen, Guin, Ranabir, Hirst, Carrie, Hirst, Martin, Holt, Robert A., Lee, Darlene, Li, Haiyan I., Mayo, Michael, Moore, Richard A., Schein, Jacqueline E., Slobodan, Jared R., Tam, Angela, Thiessen, Nina, Varhol, Richard, Zeng, Thomas, Zhao, Yongjun, Jones, Steven J. M., Marra, Marco A., Bass, Adam J., Ramos, Alex H., Saksena, Gordon, Cherniack, Andrew D., Schumacher, Stephen E., Tabak, Barbara, Carter, Scott L., Pho, Nam H., Nguyen, Huy, Onofrio, Robert C., Crenshaw, Andrew, Ardlie, Kristin, Beroukhim, Rameen, Winckler, Wendy, Meyerson, Matthew, Protopopov, Alexei, Zhang, Juinhua, Hadjipanayis, Angela, Lee, Eunjung, Xi, Ruibin, Yang, Lixing, Ren, Xiaojia, Zhang, Hailei, Sathiamoorthy, Narayanan, Shukla, Sachet, Chen, Peng-Chieh, Haseley, Psalm, Xiao, Yonghong, Lee, Semin, Seidman, Jonathan, Chin, Lynda, Park, Peter J., Kucherlapati, Raju, Auman, Todd J., Hoadley, Katherine A., Du, Ying, Wilkerson, Matthew D., Shi, Yan, Liquori, Christina, Meng, Shaowu, Li, Ling, Turman, Yidi J., Topal, Michael D., Tan, Donghui, Waring, Scot, Buda, Elizabeth, Walsh, Jesse, Jones, Corbin D., Mieczkowski, Piotr A., Singh, Darshan, Wu, Junyuan, Gulabani, Anisha, Dolina, Peter, Bodenheimer, Tom, Hoyle, Alan P., Simons, Janae V., Soloway, Matthew, Mose, Lisle E., Jefferys, Stuart R., Balu, Saianand, O’Connor, Brian D., Prins, Jan F., Chiang, Derek Y., Hayes, Neil D., Perou, Charles M., Hinoue, Toshinori, Weisenberger, Daniel J., Maglinte, Dennis T., Pan, Fei, Berman, Benjamin P., Van Den Berg, David J., Shen, Hui, Triche, Timothy, Jr, Baylin, Stephen B., Laird, Peter W., Noble, Michael, Voet, Doug, Gehlenborg, Nils, DiCara, Daniel, Wu, Chang-Jiun, Yingchun Liu, Spring, Zhou, Lihua, Lin, Pei, Park, Richard W., Nazaire, Marc-Danie, Robinson, Jim, Thorvaldsdottir, Helga, Mesirov, Jill, Thorsson, Vesteinn, Reynolds, Sheila M., Bernard, Brady, Kreisberg, Richard, Lin, Jake, Iype, Lisa, Bressler, Ryan, Erkkilä, Timo, Gundapuneni, Madhumati, Liu, Yuexin, Norberg, Adam, Robinson, Tom, Yang, Da, Zhang, Wei, Shmulevich, Ilya, de Ronde, Jorma J., Schultz, Nikolaus, Cerami, Ethan, Ciriello, Giovanni, Goldberg, Arthur P., Gross, Benjamin, Jacobsen, Anders, Gao, Jianjiong, Kaczkowski, Bogumil, Sinha, Rileen, Aksoy, Arman B., Antipin, Yevgeniy, Reva, Boris, Shen, Ronglai, Taylor, Barry S., Chan, Timothy A., Ladanyi, Marc, Sander, Chris, Akbani, Rehan, Zhang, Nianxiang, Broom, Bradley M., Casasent, Tod, Unruh, Anna, Wakefield, Chris, Hamilton, Stanley R., Cason, Craig R., Baggerly, Keith A., Weinstein, John N., Haussler, David, Benz, Christopher C., Stuart, Joshua M., Benz, Stephen C., Sanborn, Zachary J., Vaske, Charles J., Zhu, Jingchun, Szeto, Christopher, Scott, Gary K., Yau, Christina, Ng, Sam, Goldstein, Ted, Ellrott, Kyle, Collisson, Eric, Cozen, Aaron E., Zerbino, Daniel, Wilks, Christopher, Craft, Brian, Spellman, Paul, Penny, Robert, Shelton, Troy, Hatfield, Martha, Morris, Scott, Yena, Peggy, Shelton, Candace, Sherman, Mark, Paulauskis, Joseph, Gastier-Foster, Julie M., Bowen, Jay, Ramirez, Nilsa C., Black, Aaron, Pyatt, Robert, Wise, Lisa, White, Peter, Bertagnolli, Monica, Brown, Jen, Chu, Gerald C., Czerwinski, Christine, Denstman, Fred, Dhir, Rajiv, Dörner, Arnulf, Fuchs, Charles S., Guillem, Jose G., Iacocca, Mary, Juhl, Hartmut, Kaufman, Andrew, Kohl, Bernard, III, Van Le, Xuan, Mariano, Maria C., Medina, Elizabeth N., Meyers, Michael, Nash, Garrett M., Paty, Phillip B., Petrelli, Nicholas, Rabeno, Brenda, Richards, William G., Solit, David, Swanson, Pat, Temple, Larissa, Tepper, Joel E., Thorp, Richard, Vakiani, Efsevia, Weiser, Martin R., Willis, Joseph E., Witkin, Gary, Zeng, Zhaoshi, Zinner, Michael J., Zornig, Carsten, Jensen, Mark A., Sfeir, Robert, Kahn, Ari B., Chu, Anna L., Kothiyal, Prachi, Wang, Zhining, Snyder, Eric E., Pontius, Joan, Pihl, Todd D., Ayala, Brenda, Backus, Mark, Walton, Jessica, Whitmore, Jon, Baboud, Julien, Berton, Dominique L., Nicholls, Matthew C., Srinivasan, Deepak, Raman, Rohini, Girshik, Stanley, Kigonya, Peter A., Alonso, Shelley, Sanbhadti, Rashmi N., Barletta, Sean P., Greene, John M., Pot, David A., Mills Shaw, Kenna R., Dillon, Laura A. L., Buetow, Ken, Davidsen, Tanja, Demchok, John A., Eley, Greg, Ferguson, Martin, Fielding, Peter, Schaefer, Carl, Sheth, Margi, Yang, Liming, Guyer, Mark S., Ozenberger, Bradley A., Palchik, Jacqueline D., Peterson, Jane, Sofia, Heidi J., and Thomson, Elizabeth

Published
2012
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17. Identification and Analyses of Extra-Cranial and Cranial Rhabdoid Tumor Molecular Subgroups Reveal Tumors with Cytotoxic T Cell Infiltration

Author

Chun, Hye-Jung E., primary, Johann, Pascal D., additional, Milne, Katy, additional, Zapatka, Marc, additional, Buellesbach, Annette, additional, Ishaque, Naveed, additional, Iskar, Murat, additional, Erkek, Serap, additional, Wei, Lisa, additional, Tessier-Cloutier, Basile, additional, Lever, Jake, additional, Titmuss, Emma, additional, Topham, James T., additional, Bowlby, Reanne, additional, Chuah, Eric, additional, Mungall, Karen L., additional, Ma, Yussanne, additional, Mungall, Andrew J., additional, Moore, Richard A., additional, Taylor, Michael D., additional, Gerhard, Daniela S., additional, Jones, Steven J.M., additional, Korshunov, Andrey, additional, Gessler, Manfred, additional, Kerl, Kornelius, additional, Hasselblatt, Martin, additional, Frühwald, Michael C., additional, Perlman, Elizabeth J., additional, Nelson, Brad H., additional, Pfister, Stefan M., additional, Marra, Marco A., additional, and Kool, Marcel, additional

Published
2019
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19. Analysis of 4,664 high-quality sequence-finished poplar full-length cDNA clones and their utility for the discovery of genes responding to insect feeding

Author

Douglas Carl J, Tuskan Gerald A, Gunter Lee, Kolosova Natalia, Kirkpatrick Robert, Cooper Dawn, Chun Hye Jung E, Ralph Steven G, Holt Robert A, Jones Steven JM, Marra Marco A, and Bohlmann Jörg

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background The genus Populus includes poplars, aspens and cottonwoods, which will be collectively referred to as poplars hereafter unless otherwise specified. Poplars are the dominant tree species in many forest ecosystems in the Northern Hemisphere and are of substantial economic value in plantation forestry. Poplar has been established as a model system for genomics studies of growth, development, and adaptation of woody perennial plants including secondary xylem formation, dormancy, adaptation to local environments, and biotic interactions. Results As part of the poplar genome sequencing project and the development of genomic resources for poplar, we have generated a full-length (FL)-cDNA collection using the biotinylated CAP trapper method. We constructed four FLcDNA libraries using RNA from xylem, phloem and cambium, and green shoot tips and leaves from the P. trichocarpa Nisqually-1 genotype, as well as insect-attacked leaves of the P. trichocarpa × P. deltoides hybrid. Following careful selection of candidate cDNA clones, we used a combined strategy of paired end reads and primer walking to generate a set of 4,664 high-accuracy, sequence-verified FLcDNAs, which clustered into 3,990 putative unique genes. Mapping FLcDNAs to the poplar genome sequence combined with BLAST comparisons to previously predicted protein coding sequences in the poplar genome identified 39 FLcDNAs that likely localize to gaps in the current genome sequence assembly. Another 173 FLcDNAs mapped to the genome sequence but were not included among the previously predicted genes in the poplar genome. Comparative sequence analysis against Arabidopsis thaliana and other species in the non-redundant database of GenBank revealed that 11.5% of the poplar FLcDNAs display no significant sequence similarity to other plant proteins. By mapping the poplar FLcDNAs against transcriptome data previously obtained with a 15.5 K cDNA microarray, we identified 153 FLcDNA clones for genes that were differentially expressed in poplar leaves attacked by forest tent caterpillars. Conclusion This study has generated a high-quality FLcDNA resource for poplar and the third largest FLcDNA collection published to date for any plant species. We successfully used the FLcDNA sequences to reassess gene prediction in the poplar genome sequence, perform comparative sequence annotation, and identify differentially expressed transcripts associated with defense against insects. The FLcDNA sequences will be essential to the ongoing curation and annotation of the poplar genome, in particular for targeting gaps in the current genome assembly and further improvement of gene predictions. The physical FLcDNA clones will serve as useful reagents for functional genomics research in areas such as analysis of gene functions in defense against insects and perennial growth. Sequences from this study have been deposited in NCBI GenBank under the accession numbers EF144175 to EF148838.

Published
2008
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20. Additional file 5: Supplementary Figures. of Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability

Author

Zahir, Farah, Mwenifumbo, Jill, Chun, Hye-Jung, Lim, Emilia, Karnebeek, Clara Van, Couse, Madeline, Mungall, Karen, Lee, Leora, Makela, Nancy, Linlea Armstrong, Boerkoel, Cornelius, Langlois, Sylvie, McGillivray, Barbara, Jones, Steven, Friedman, Jan, and Marra, Marco

Abstract

Figure S1. IGV image and Sanger verification trace files for indel in ARID1B and missense variation in UPF1. Figure S2. UK10K mutation load â counts as per variant annotation type on one patient. Figure S3. Histogram of mutation burden per patient in the UK10K cohort. Figure S4. Pathway interactions showing convergence onto UPP pathway. Figure S5. Plots for CNV distribution for two chromosomes as called by CNAseq. (DOCX 1972 kb)

Published
2017
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21. Additional file 1: of Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability

Author

Zahir, Farah, Mwenifumbo, Jill, Chun, Hye-Jung, Lim, Emilia, Karnebeek, Clara Van, Couse, Madeline, Mungall, Karen, Lee, Leora, Makela, Nancy, Linlea Armstrong, Boerkoel, Cornelius, Langlois, Sylvie, McGillivray, Barbara, Jones, Steven, Friedman, Jan, and Marra, Marco

Abstract

Supplementary Methods - Additional details on methods presented succinctly in main text. (DOCX 53 kb)

Published
2017
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22. Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability

Author

Zahir, Farah R., primary, Mwenifumbo, Jill C., additional, Chun, Hye-Jung E., additional, Lim, Emilia L., additional, Van Karnebeek, Clara D. M., additional, Couse, Madeline, additional, Mungall, Karen L., additional, Lee, Leora, additional, Makela, Nancy, additional, Armstrong, Linlea, additional, Boerkoel, Cornelius F., additional, Langlois, Sylvie L., additional, McGillivray, Barbara M., additional, Jones, Steven J. M., additional, Friedman, Jan M., additional, and Marra, Marco A., additional

Published
2017
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23. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin

Author

Hoadley, Katherine A., Yau, Christina, Wolf, Denise M., Cherniack, Andrew D., Tamborero, David, Sam, Ng, Leiserson, Max D. M., Niu, Beifang, Mclellan, Michael D., Uzunangelov, Vladislav, Zhang, Jiashan, Kandoth, Cyriac, Akbani, Rehan, Shen, Hui, Omberg, Larsson, Chu, Andy, Margolin, Adam A., Van'T Veer, Laura J., Lopez Bigas, Nuria, Laird, Peter W., Raphael, Benjamin J., Ding, Li, Robertson, A. Gordon, Byers, Lauren A., Mills, Gordon B., Weinstein, John N., Van Waes, Carter, Chen, Zhong, Collisson, Eric A., Benz, Christopher C, Perou, Charles M., Stuart, Joshua M., Rachel, Abbott, Scott, Abbott, Arman Aksoy, B., Kenneth, Aldape, Adrian, Ally, Samirku mar Amin, Dimitris, Anastassiou, Todd Auman, J., Baggerly, Keith A., Miruna, Balasundaram, Saianand, Balu, Baylin, Stephen B., Benz, Stephen C., Berman, Benjamin P., Brady, Bernard, Bhatt, Ami S., Inanc, Birol, Black, Aaron D., Tom, Bodenheimer, Bootwalla, Moiz S., Jay, Bowen, Ryan, Bressler, Bristow, Christopher A., Brooks, Angela N., Bradley, Broom, Elizabeth, Buda, Robert, Burton, Butterfield, Yaron S. N., Daniel, Carlin, Carter, Scott L., Casasent, Tod D., Kyle, Chang, Stephen, Chanock, Lynda, Chin, Dong Yeon Cho, Juok, Cho, Eric, Chuah, Chun, Hye Jung E., Kristian, Cibulskis, Giovanni, Ciriello, James Cle land, Melisssa, Cline, Brian, Craft, Creighton, Chad J., Ludmila, Danilova, Tanja, Davidsen, Caleb, Davis, Dees, Nathan D., Kim, Delehaunty, Demchok, John A., Noreen, Dhalla, Daniel, Dicara, Huyen, Dinh, Dobson, Jason R., Deepti, Dodda, Harshavardhan, Doddapaneni, Lawrence, Donehower, Dooling, David J., Gideon, Dresdner, Jennifer, Drummond, Andrea, Eakin, Mary, Edgerton, Eldred, Jim M., Greg, Eley, Kyle, Ellrott, Cheng, Fan, Suzanne, Fei, Ina, Felau, Scott, Frazer, Freeman, Samuel S., Jessica, Frick, Fronick, Catrina C., Ful ton, Lucinda L., Robert, Fulton, Gabriel, Stacey B., Jianjiong, Gao, Gastier Foster, Julie M., Nils, Gehlenborg, Myra, George, Gad, Getz, Richard, Gibbs, Mary, Goldman, Abel Gonzalez Perez, Benjamin, Gross, Ranabir, Guin, Preethi, Gunaratne, Angela, Hadjipanayis, Hamilton, Mark P., Hamilton, Stanley R., Leng, Han, Han, Yi, Harper, Hollie A., Psalm, Haseley, David, Haussler, Neil Hayes, D., Heiman, David I., Elena, Helman, Carmen, Helsel, Herbrich, Shelley M., Her man, James G., Toshinori, Hinoue, Carrie, Hirst, Martin, Hirst, Holt, Robert A., Hoyle, Alan P., Lisa, Iype, Anders, Jacobsen, Jeffreys, Stuart R., Jensen, Mark A., Jones, Corbin D., Jones, Steven J. M., Zhenlin, Ju, Joonil, Jung, Andre, Kahles, Ari, Kahn, Joelle Kalicki Veizer, Divya, Kalra, Krishna Latha Kanchi, Kane, David W., Hoon, Kim, Jaegil, Kim, Theo, Knijnenburg, Koboldt, Daniel C., Christie, Kovar, Roger, Kramer, Richard, Kreisberg, Raju, Kucherlapati, Marc, Ladanyi, Lander, Eric S., Larson, David E., Lawrence, Michael S., Darlene, Lee, Eunjung, Lee, Semin, Lee, William, Lee, Kjong Van Lehmann, Kalle, Leinonen, Ler aas, Kristen M., Seth, Lerner, Levine, Douglas A., Lora, Lewis, Ley, Timothy J., Haiyan I., Li, Jun, Li, Wei, Li, Han, Liang, Lichtenberg, Tara M., Jake, Lin, Ling, Lin, Pei, Lin, Wen bin Liu, Yingchun, Liu, Yuexin, Liu, Lorenzi, Philip L., Charles, Lu, Yiling, Lu, Luquette, Love lace J., Singer, Ma, Magrini, Vincent J., Mahadeshwar, Harshad S., Mardis, Elaine R., Adam, Margolin, Marra, Marco A., Michael, Mayo, Cynthia, Mcallister, Mcguire, Sean E., Mcmichael, Joshua F., James, Melott, Shaowu, Meng, Matthew, Meyerson, Mieczkowski, Piotr A., Miller, Christopher A., Miller, Martin L., Michael, Miller, Moore, Richard A., Margaret, Morgan, Donna, Morton, Mose, Lisle E., Mungall, Andrew J., Donna, Muzny, Lam, Nguyen, Noble, Michael S., Houtan, Noushmehr, Michelle, O’Laughlin, Ojesina, Akinyemi I., Tai Hsien Ou Yang, Brad, Ozenberger, Angeliki, Pantazi, Michael, Parfenov, Park, Peter J., Parker, Joel S., Evan, Paull, Chandra Sekhar Pedamallu, Todd, Pihl, Craig, Pohl, David, Pot, Alexei, Protopopov, Teresa, Przytycka, Amie Raden baugh, Ramirez, Nilsa C., Ricardo, Ramirez, Gunnar Ra, ̈ tsch, Jeffrey, Reid, Xiao jia Ren, Boris, Reva, Reynolds, Sheila M., Rhie, Suhn K., Jeffrey, Roach, Hector, Rovira, Michael, Ryan, Gordon, Saksena, Sofie, Salama, Chris, Sander, Netty, Santoso, Schein, Jacqueline E., Heather, Schmidt, Nikolaus, Schultz, Schumacher, Steven E., Jonathan, Seidman, Yasin, Senbabaoglu, Sahil, Seth, Saman tha Sharpe, Ronglai, Shen, Margi, Sheth, Yan, Shi, Ilya, Shmulevich, Silva, Grace O., Simons, Janae V., Rileen, Sinha, Payal, Sipahimalani, Smith, Scott M., Sofia, Heidi J., Artem, Sokolov, Soloway, Mathew G., Xingzhi, Song, Carrie Soug nez, Paul, Spellman, Louis, Staudt, Chip, Stewart, Petar, Stojanov, Xiaoping, Su, Onur Sumer, S., Yichao, Sun, Teresa, Swatloski, Barbara, Tabak, Angela, Tam, Donghui, Tan, Jiabin, Tang, Roy, Tarnuzzer, Taylor, Barry S., Nina, Thiessen, Ves teinn Thorsson, Timothy Triche, J. r., Van Den Berg, David J., Vandin, Fabio, Varhol, Richard J., Vaske, Charles J., Umadevi, Veluvolu, Roeland, Verhaak, Doug, Voet, Jason, Walker, Wallis, John W., Peter, Waltman, Yunhu, Wan, Min, Wang, Wenyi, Wang, Zhining, Wang, Scot, Waring, Nils, Weinhold, Weisenberger, Daniel J., Wendl, Michael C., David, Wheeler, Wilkerson, Matthew D., Wilson, Richard K., Lisa, Wise, Andrew, Wong, Chang Jiun Wu, Chia Chin Wu, Hsin Ta Wu, Junyuan, Wu, Todd, Wylie, Liu, Xi, Ruibin, Xi, Zheng, Xia, Andrew W., Xu, Yang, Da, Liming, Yang, Lixing, Yang, Yang, Yang, Jun, Yao, Rong, Yao, Kai, Ye, Ko suke Yoshihara, Yuan, Yuan, Yung, Alfred K., Travis, Zack, Dong, Zeng, Jean Claude Zenklusen, Hailei, Zhang, Jianhua, Zhang, Nianxiang, Zhang, Qunyuan, Zhang, Wei, Zhang, Wei, Zhao, Siyuan, Zheng, Jing, Zhu, Erik, Zmuda, and Lihua, Zou

Subjects
Genetics and Molecular Biology (all), Cluster Analysis, Humans, Neoplasms, Transcriptome, Biochemistry, Genetics and Molecular Biology (all), Extramural, Biochemistry, Genetics and Molecular Biology(all), Cancer, Computational biology, Disease, Biology, medicine.disease, Bioinformatics, Biochemistry, General Biochemistry, Genetics and Molecular Biology, Article, 3. Good health, Molecular classification, TP63, CLUSTERS (ANÁLISE), medicine, Head and neck, Gene
Abstract

Summary Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.

Published
2014

24. Genome-Wide Profiles of Extra-cranial Malignant Rhabdoid Tumors Reveal Heterogeneity and Dysregulated Developmental Pathways

Author

Chun, Hye-Jung E., primary, Lim, Emilia L., additional, Heravi-Moussavi, Alireza, additional, Saberi, Saeed, additional, Mungall, Karen L., additional, Bilenky, Mikhail, additional, Carles, Annaick, additional, Tse, Kane, additional, Shlafman, Inna, additional, Zhu, Kelsey, additional, Qian, Jenny Q., additional, Palmquist, Diana L., additional, He, An, additional, Long, William, additional, Goya, Rodrigo, additional, Ng, Michelle, additional, LeBlanc, Veronique G., additional, Pleasance, Erin, additional, Thiessen, Nina, additional, Wong, Tina, additional, Chuah, Eric, additional, Zhao, Yong-Jun, additional, Schein, Jacquie E., additional, Gerhard, Daniela S., additional, Taylor, Michael D., additional, Mungall, Andrew J., additional, Moore, Richard A., additional, Ma, Yussanne, additional, Jones, Steven J.M., additional, Perlman, Elizabeth J., additional, Hirst, Martin, additional, and Marra, Marco A., additional

Published
2016
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25. Reversion to an Embryonic Alternative Splicing Program Enhances Leukemia Stem Cell Self-Renewal

Author

Holm, Frida Linnea, primary, Hellqvist, Eva, additional, Mason, Cayla N, additional, Ali, Shawn, additional, Delos Santos, Nathaniel, additional, Barrett, Christian, additional, Chun, Hye-Jung, additional, Minden, Mark D., additional, Richard, Moore, additional, Marra, Marco A, additional, Frazer, Kelly A., additional, Sadarangani, Anil, additional, and Jamieson, Catriona, additional

Published
2015
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26. Comprehensive molecular portraits of human breast tumours

Author

Moore, Richard A., Fulton, Lucinda L., Hirst, Martin, Chun, Hye-Jung E., Fulton, Robert S., Mardis, Elaine R., Dhalla, Noreen, Ally, Adrian, Koboldt, Daniel C., Dooling, David J., Chuah, Eric, Holt, Robert A., Ding, Li, Kalicki-Veizer, Joelle, Chu, Andy, Mungall, Andrew J., Butterfield, Yaron S. N., Li, Haiyan I., Pleasance, Erin, Schmidt, Heather, Carlsen, Rebecca, Carter, Candace, McLellan, Michael D., Balasundaram, Miruna, Hirst, Carrie, Guin, Ranabir, Lee, Darlene, Coope, Robin J. N., Wilson, Richard K., McMichael, Joshua F., Mayo, Michael, and Gordon Robertson, A.

Subjects
skin and connective tissue diseases
Abstract

This Article from the Cancer Genome Atlas consortium describes a multifaceted analysis of primary breast cancers in 825 people. Exome sequencing, copy number variation, DNA methylation, messenger RNA arrays, microRNA sequencing and proteomic analyses were performed and integrated to shed light on breast-cancer heterogeneity. Just three genes — TP53, PIK3CA and GATA3 — are mutated at greater than 10% frequency across all breast cancers. Many subtype-associated and novel mutations were identified, as well as two breast-cancer subgroups with specific signalling-pathway signatures. The analyses also suggest that much of the clinically observable plasticity and heterogeneity occurs within, and not across, the major subtypes of breast cancer.

Published
2012
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27. Bioinformatics approach to investigate genetic differences underlying breast tumours with specific outcomes of adoptive T-cell therapy using a mouse model

Author

Chun, Hye-Jung

Abstract

The immune system plays a critical role in cancer prevention and development. The stimulation of natural immune reaction in a cancer patient by adoptive T-cell therapy has shown success in treating metastatic melanomas and renal cell carcinomas. However, the use of adoptive T-cell therapy remains limited due to unpredictable outcomes and low response rates. In particular, adoptive T-cell therapy for breast cancer has not been realized, despite of the presence of immunogenic antigens such as over-expressed HER2, present in 20-40% of breast tumours. Using a unique transgenic mouse model, the global profiles of gene expression, miRNA abundance and single nucleotide variants (SNVs) were investigated to identify the molecular difference of murine mammary tumours with isogenic background, which exhibited complete regression (CR), partial regression (PR) or progressive disease (PD) outcome of adoptive T-cell therapy. The bioinformatics analyses were further carried out to identify uniquely activated pathways, prognostic gene expression signatures, the effect of post-transcriptional gene regulation and mutated genes unique to tumours with specific outcome. The largest differences in gene expression, miRNA and SNV profiles were repeatedly observed between the regressing (CR, PR) and non-regressing (PD) tumours, supporting the attribution of molecular differences to the immunotherapy outcome. In particular, the gene expression signatures derived from genes in immune-related pathways were experimentally validated to be strong prognostic markers for predicting the CR outcome. Comparison with the human breast cancer subtypes further revealed similarities of the non-regressing tumours with the basal subtype, and the regressing tumours with the HER2 subtype. The difference in miRNA profiles between CR and PR tumours suggested potential translational activities unique to PR, which was nearly identical to CR at the transcriptome level. The findings from this study show that tumour-derivied factors that either promote or suppress the immune system are responsible for the varying outcome of immunotherapy, and that the molecular characteristics can be further applied for the development of clinical prognostic tools, cancer vaccines and drug targets to enhance the efficacy of adoptive T-cell therapy.

Published
2010
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28. Loss of the Notch effector RBPJ promotes tumorigenesis

Author

Kulic, Iva, primary, Robertson, Gordon, additional, Chang, Linda, additional, Baker, Jennifer H.E., additional, Lockwood, William W., additional, Mok, Winnie, additional, Fuller, Megan, additional, Fournier, Michèle, additional, Wong, Nelson, additional, Chou, Vennie, additional, Robinson, Mark D., additional, Chun, Hye-Jung Elizabeth, additional, Gilks, Blake, additional, Kempkes, Bettina, additional, Thomson, Thomas A., additional, Hirst, Martin, additional, Minchinton, Andrew I., additional, Lam, Wan L., additional, Jones, Steven, additional, Marra, Marco, additional, and Karsan, Aly, additional

Published
2014
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29. Malignant Reprogramming of Progenitors into Leukemia Stem Cells Is Enhanced By Upregulation of CD44 Transcript Variant 3 in Malignant Microenvironments

Author

Holm, Frida L, primary, Hellqvist, Eva, additional, Mason, Cayla N, additional, Barrett, Christian L, additional, Ali, Shawn, additional, Chun, Hye-Jung, additional, Marra, Marco A., additional, Runza, Valeria, additional, Frazer, Kelly A, additional, Sadarangani, Anil, additional, and Jamieson, Catriona, additional

Published
2014
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30. Abstract 3087: Whole genome sequencing of rhabdoid tumors of the kidney

Author

Chun, Hye-Jung E., primary, Zhu, Kelsey, additional, Qian, Jenny Q., additional, Mungall, Karen L., additional, Ma, Yussanne, additional, Zhao, Yong-Jun, additional, Mungall, Andrew J., additional, Moore, Richard A., additional, Schein, Jacquie E., additional, Gerhard, Daniela S., additional, Perlman, Elizabeth J., additional, and Marra, Marco A., additional

Published
2014
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31. Abstract 247: ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia.

Author

Jiang, Qingfei, primary, Crews, Leslie A., additional, Barrett, Christian L., additional, Court-Recart, Angela, additional, Goff, Daniel, additional, Sadarangani, Anil, additional, Rusert, Jessica, additional, Morris, Sheldon, additional, Goldstein, Lawrence, additional, Chun, Hye-Jung, additional, Marra, Marco, additional, Fraser, Kelly, additional, Dao, Kim-Hien, additional, Minden, Mark, additional, and Jamieson, Catriona, additional

Published
2013
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32. A Pan-BCL2 Inhibitor Renders Bone-Marrow-Resident Human Leukemia Stem Cells Sensitive to Tyrosine Kinase Inhibition

Author

Goff, Daniel J., primary, Recart, Angela Court, additional, Sadarangani, Anil, additional, Chun, Hye-Jung, additional, Barrett, Christian L., additional, Krajewska, Maryla, additional, Leu, Heather, additional, Low-Marchelli, Janine, additional, Ma, Wenxue, additional, Shih, Alice Y., additional, Wei, Jun, additional, Zhai, Dayong, additional, Geron, Ifat, additional, Pu, Minya, additional, Bao, Lei, additional, Chuang, Ryan, additional, Balaian, Larisa, additional, Gotlib, Jason, additional, Minden, Mark, additional, Martinelli, Giovanni, additional, Rusert, Jessica, additional, Dao, Kim-Hien, additional, Shazand, Kamran, additional, Wentworth, Peggy, additional, Smith, Kristen M., additional, Jamieson, Christina A.M., additional, Morris, Sheldon R., additional, Messer, Karen, additional, Goldstein, Lawrence S.B., additional, Hudson, Thomas J., additional, Marra, Marco, additional, Frazer, Kelly A., additional, Pellecchia, Maurizio, additional, Reed, John C., additional, and Jamieson, Catriona H.M., additional

Published
2013
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33. Effect of stellate ganglion block on laryngopharyngeal reflux disease

Author

Chung, Ji Won, primary, Chun, Hye Jung, additional, Lee, Mi Soon, additional, Ahn, Ki Ryang, additional, Kim, Chun Sook, additional, Kang, Kyu Sik, additional, Yoo, Sie Hyeon, additional, Chung, Jin Hun, additional, Kim, Nan-Seol, additional, Seo, Yong Han, additional, Gong, Hyung Youn, additional, and Lee, Yong Man, additional

Published
2013
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34. ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia

Author

Jiang, Qingfei, primary, Crews, Leslie A., additional, Barrett, Christian L., additional, Chun, Hye-Jung, additional, Court, Angela C., additional, Isquith, Jane M., additional, Zipeto, Maria A., additional, Goff, Daniel J., additional, Minden, Mark, additional, Sadarangani, Anil, additional, Rusert, Jessica M., additional, Dao, Kim-Hien T., additional, Morris, Sheldon R., additional, Goldstein, Lawrence S. B., additional, Marra, Marco A., additional, Frazer, Kelly A., additional, and Jamieson, Catriona H. M., additional

Published
2012
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35. Combined JAK/STAT5A and BCR-ABL Inhibition Impairs Blast Crisis Chronic Myeloid Leukemia Stem Cell Self-Renewal

Author

Recart, Angela C Court, primary, Goff, Daniel J, additional, Sadarangani, Anil, additional, Mason, Cayla N, additional, Shih, Alice Y., additional, Wall, Russell, additional, Leu, Heather S., additional, Ma, Wenxue, additional, Chun, Hye-Jung, additional, Marra, Marco A., additional, Barrett, Christian L, additional, Frazer, Kelly A, additional, and Jamieson, Catriona, additional

Published
2012
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39. A conifer genomics resource of 200,000 spruce (Picea spp.) ESTs and 6,464 high-quality, sequence-finished full-length cDNAs for Sitka spruce (Picea sitchensis)

Author

Ralph, Steven G, primary, Chun, Hye Jung E, additional, Kolosova, Natalia, additional, Cooper, Dawn, additional, Oddy, Claire, additional, Ritland, Carol E, additional, Kirkpatrick, Robert, additional, Moore, Richard, additional, Barber, Sarah, additional, Holt, Robert A, additional, Jones, Steven JM, additional, Marra, Marco A, additional, Douglas, Carl J, additional, Ritland, Kermit, additional, and Bohlmann, Jörg, additional

Published
2008
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40. Analysis of 4,664 high-quality sequence-finished poplar full-length cDNA clones and their utility for the discovery of genes responding to insect feeding

Author

Ralph, Steven G, primary, Chun, Hye Jung E, additional, Cooper, Dawn, additional, Kirkpatrick, Robert, additional, Kolosova, Natalia, additional, Gunter, Lee, additional, Tuskan, Gerald A, additional, Douglas, Carl J, additional, Holt, Robert A, additional, Jones, Steven JM, additional, Marra, Marco A, additional, and Bohlmann, Jörg, additional

Published
2008
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43. Loss of the Notch effector RBPJ promotes tumorigenesis

Author

Kulic, Iva, Robertson, Gordon, Chang, Linda, Baker, Jennifer H.E., Lockwood, William W., Mok, Winnie, Fuller, Megan, Fournier, Michèle, Wong, Nelson, Chou, Vennie, Robinson, Mark D., Chun, Hye-Jung, Gilks, Blake, Kempkes, Bettina, Thomson, Thomas A., Hirst, Martin, Minchinton, Andrew I., Lam, Wan L., Jones, Steven, Marra, Marco, and Karsan, Aly

Abstract

Aberrant Notch activity is oncogenic in several malignancies, but it is unclear how expression or function of downstream elements in the Notch pathway affects tumor growth. Transcriptional regulation by Notch is dependent on interaction with the DNA-binding transcriptional repressor, RBPJ, and consequent derepression or activation of associated gene promoters. We show here that RBPJ is frequently depleted in human tumors. Depletion of RBPJ in human cancer cell lines xenografted into immunodeficient mice resulted in activation of canonical Notch target genes, and accelerated tumor growth secondary to reduced cell death. Global analysis of activated regions of the genome, as defined by differential acetylation of histone H4 (H4ac), revealed that the cell death pathway was significantly dysregulated in RBPJ-depleted tumors. Analysis of transcription factor binding data identified several transcriptional activators that bind promoters with differential H4ac in RBPJ-depleted cells. Functional studies demonstrated that NF-κB and MYC were essential for survival of RBPJ-depleted cells. Thus, loss of RBPJ derepresses target gene promoters, allowing Notch-independent activation by alternate transcription factors that promote tumorigenesis.

Published
2015
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44. Comprehensive molecular characterization of gastric adenocarcinoma

Author

Bass, Adam J., Thorsson, Vesteinn, Shmulevich, Ilya, Reynolds, Sheila M., Miller, Michael, Bernard, Brady, Hinoue, Toshinori, Laird, Peter W., Curtis, Christina, Shen, Hui, Weisenberger, Daniel J., Schultz, Nikolaus, Shen, Ronglai, Weinhold, Nils, Kelsen, David P., Bowlby, Reanne, Chu, Andy, Kasaian, Katayoon, Mungall, Andrew J., Robertson, A. Gordon, Sipahimalani, Payal, Cherniack, Andrew, Getz, Gad, Liu, Yingchun, Noble, Michael S., Pedamallu, Chandra, Sougnez, Carrie, Taylor-Weiner, Amaro, Akbani, Rehan, Lee, Ju-Seog, Liu, Wenbin, Mills, Gordon B., Yang, Da, Zhang, Wei, Pantazi, Angeliki, Parfenov, Michael, Gulley, Margaret, Piazuelo, M. Blanca, Schneider, Barbara G., Kim, Jihun, Boussioutas, Alex, Sheth, Margi, Demchok, John A., Rabkin, Charles S., Willis, Joseph E., Ng, Sam, Garman, Katherine, Beer, David G., Pennathur, Arjun, Raphael, Benjamin J., Wu, Hsin-Ta, Odze, Robert, Kim, Hark K., Bowen, Jay, Leraas, Kristen M., Lichtenberg, Tara M., Weaver, Stephanie, McLellan, Michael, Wiznerowicz, Maciej, Sakai, Ryo, Lawrence, Michael S., Cibulskis, Kristian, Lichtenstein, Lee, Fisher, Sheila, Gabriel, Stacey B., Lander, Eric S., Ding, Li, Niu, Beifang, Ally, Adrian, Balasundaram, Miruna, Birol, Inanc, Brooks, Denise, Butterfield, Yaron S. N., Carlsen, Rebecca, Chu, Justin, Chuah, Eric, Chun, Hye-Jung E., Clarke, Amanda, Dhalla, Noreen, Guin, Ranabir, Holt, Robert A., Jones, Steven J.M., Lee, Darlene, Li, Haiyan A., Lim, Emilia, Ma, Yussanne, Marra, Marco A., Mayo, Michael, Moore, Richard A., Mungall, Karen L., Nip, Ka Ming, Schein, Jacqueline E., Tam, Angela, Thiessen, Nina, Beroukhim, Rameen, Carter, Scott L., Cherniack, Andrew D., Cho, Juok, DiCara, Daniel, Frazer, Scott, Gehlenborg, Nils, Heiman, David I., Jung, Joonil, Kim, Jaegil, Lin, Pei, Meyerson, Matthew, Ojesina, Akinyemi I., Pedamallu, Chandra Sekhar, Saksena, Gordon, Schumacher, Steven E., Stojanov, Petar, Tabak, Barbara, Voet, Doug, Rosenberg, Mara, Zack, Travis I., Zhang, Hailei, Zou, Lihua, Protopopov, Alexei, Santoso, Netty, Lee, Semin, Zhang, Jianhua, Mahadeshwar, Harshad S., Tang, Jiabin, Ren, Xiaojia, Seth, Sahil, Yang, Lixing, Xu, Andrew W., Song, Xingzhi, Xi, Ruibin, Bristow, Christopher A., Hadjipanayis, Angela, Seidman, Jonathan, Chin, Lynda, Park, Peter J., Kucherlapati, Raju, Ling, Shiyun, Rao, Arvind, Weinstein, John N., Kim, Sang-Bae, Lu, Yiling, Mills, Gordon, Bootwalla, Moiz S., Lai, Phillip H., Triche, Timothy, Van Den Berg, David J., Baylin, Stephen B., Herman, James G., Murray, Bradley A., Askoy, B. Arman, Ciriello, Giovanni, Dresdner, Gideon, Gao, Jianjiong, Gross, Benjamin, Jacobsen, Anders, Lee, William, Ramirez, Ricardo, Sander, Chris, Senbabaoglu, Yasin, Sinha, Rileen, Sumer, S. Onur, Sun, Yichao, Thorsson, Vésteinn, Iype, Lisa, Kramer, Roger W., Kreisberg, Richard, Rovira, Hector, Tasman, Natalie, Ng, Santa Cruz Sam, Haussler, David, Stuart, Josh M., Verhaak, Roeland G.W., Leiserson, Mark D. M., Taylor, Barry S., Black, Aaron D., Carney, Julie Ann, Gastier-Foster, Julie M., Helsel, Carmen, McAllister, Cynthia, Ramirez, Nilsa C., Tabler, Teresa R., Wise, Lisa, Zmuda, Erik, Penny, Robert, Crain, Daniel, Gardner, Johanna, Lau, Kevin, Curely, Erin, Mallery, David, Morris, Scott, Paulauskis, Joseph, Shelton, Troy, Shelton, Candace, Sherman, Mark, Benz, Christopher, Lee, Jae-Hyuk, Fedosenko, Konstantin, Manikhas, Georgy, Potapova, Olga, Voronina, Olga, Belyaev, Smitry, Dolzhansky, Oleg, Rathmell, W. Kimryn, Brzezinski, Jakub, Ibbs, Matthew, Korski, Konstanty, Kycler, Witold, ŁaŸniak, Radoslaw, Leporowska, Ewa, Mackiewicz, Andrzej, Murawa, Dawid, Murawa, Pawel, Spychała, Arkadiusz, Suchorska, Wiktoria M., Tatka, Honorata, Teresiak, Marek, Abdel-Misih, Raafat, Bennett, Joseph, Brown, Jennifer, Iacocca, Mary, Rabeno, Brenda, Kwon, Sun-Young, Kemkes, Ariane, Curley, Erin, Alexopoulou, Iakovina, Engel, Jay, Bartlett, John, Albert, Monique, Park, Do-Youn, Dhir, Rajiv, Luketich, James, Landreneau, Rodney, Janjigian, Yelena Y., Cho, Eunjung, Ladanyi, Marc, Tang, Laura, McCall, Shannon J., Park, Young S., Cheong, Jae-Ho, Ajani, Jaffer, Camargo, M. Constanza, Alonso, Shelley, Ayala, Brenda, Jensen, Mark A., Pihl, Todd, Raman, Rohini, Walton, Jessica, Wan, Yunhu, Eley, Greg, Mills Shaw, Kenna R., Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean Claude, Davidsen, Tanja, Hutter, Carolyn M., Sofia, Heidi J., Burton, Robert, Chudamani, Sudha, and Liu, Jia

Abstract

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.

Published
2014
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45. Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability

Author

Zahir, Farah R, Mwenifumbo, Jill C, Chun, Hye-Jung E, Lim, Emilia L, Van Karnebeek, Clara D M, Couse, Madeline, Mungall, Karen L, Lee, Leora, Makela, Nancy, Armstrong, Linlea, Boerkoel, Cornelius F, Langlois, Sylvie L, McGillivray, Barbara M, Jones, Steven J M, Friedman, Jan M, and Marra, Marco A

Subjects
3. Good health
Abstract

Background: Intellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment. Whole genome sequencing (WGS) is able to interrogate the entire genome, providing potential to diagnose idiopathic patients. Methods: We conducted WGS on eight children with idiopathic ID and brain structural defects, and their normal parents; carrying out an extensive data analyses, using standard and discovery approaches. Results: We verified de novo pathogenic single nucleotide variants (SNV) in ARID1B c.1595delG and PHF6 c.820C > T, potentially causative de novo two base indels in SQSTM1 c.115_116delinsTA and UPF1 c.1576_1577delinsA, and de novo SNVs in CACNB3 c.1289G > A, and SPRY4 c.508 T > A, of uncertain significance. We report results from a large secondary control study of 2081 exomes probing the pathogenicity of the above genes. We analyzed structural variation by four different algorithms including de novo genome assembly. We confirmed a likely contributory 165 kb de novo heterozygous 1q43 microdeletion missed by clinical microarray. The de novo assembly resulted in unmasking hidden genome instability that was missed by standard re-alignment based algorithms. We also interrogated regulatory sequence variation for known and hypothesized ID genes and present useful strategies for WGS data analyses for non-coding variation. Conclusion: This study provides an extensive analysis of WGS in the context of ID, providing genetic and structural insights into ID and yielding diagnoses.

46. Integrated genomic characterization of endometrial carcinoma

Author

Fulton, Lucinda, Gabriel, Stacey B., Mardis, Elaine R., Kalicki-Veizer, Joelle, Dooling, David, Carlsen, Rebecca, Schmidt, Heather, Ally, Adrian, Chu, Andy, Chuah, Eric, Chun, Hye-Jung E., Balasundaram, Miruna, Dhalla, Noreen, Sougnez, Carrie, McLellan, Michael D., Kandoth, Cyriac, O’Laughlin, Michelle, Sivachenko, Andrey, Hirst, Carrie, Fulton, Robert, Birol, Inanc, Lander, Eric, Cibulskis, Kristian, Butterfield, Yaron S. N., Holt, Robert A., Ding, Li, Lawrence, Mike, Carter, Candace, Ye, Kai, Wilson, Richard K., Guin, Ranabir, and Getz, Gad

Subjects
endocrine system diseases, neoplasms, female genital diseases and pregnancy complications, 3. Good health
Abstract

SummaryWe performed an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumors and ~25% of high-grade endometrioid tumors have extensive copy number alterations, few DNA methylation changes, low ER/PR levels, and frequent TP53 mutations. Most endometrioid tumors have few copy number alterations or TP53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, KRAS and novel mutations in the SWI/SNF gene ARID5B. A subset of endometrioid tumors we identified had a dramatically increased transversion mutation frequency, and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy number low, and copy number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may impact post-surgical adjuvant treatment for women with aggressive tumors.

47. Clinical and molecular risk factors in extracranial malignant rhabdoid tumors - Towards an integrated model of high-risk tumors.

Author

Fincke VE, Steinbügl M, Chun HE, Nemes K, Mucha M, Loßner M, Dorn F, Gastberger K, Bühner S, Sill M, Kröncke T, Siebert R, Melchior P, Furtwängler R, Schlesner M, Vokuhl C, Rocken C, Johann PD, and Frühwald MC

Abstract

Purpose: Extracranial malignant rhabdoid tumors (eMRT) are a challenging entity. Despite the use of multimodal treatment approaches, therapy failure occurs in 55-67%. Molecular markers for identification of patients at increased risk for relapse or refractory (R/R) disease are not available. Clinical characteristics may only insufficiently predict the individual course of disease., Experimental Design: Using the EU-RHAB database, we analyzed a cohort of 121 patients with eMRT clinically. For 81 patients, molecular and clinical data was available, which was complemented with publicly available DNA molecular data from 92 further eMRT. We aimed to delineate molecular risk factors by dissecting the DNA methylome of these tumors. Moreover, we establish clinical characteristics and treatment details of R/R disease in a subcohort of 80 patients., Results: Using consensus hierarchical clustering, we identified three distinct subgroups, one of which (eMRT standard risk) was associated with significantly improved survival, irrespective of germline status and/or localization. At the transcriptome level, this subgroup is characterized by an overexpression of genes involved in muscle development. A relevant proportion of patients develop distant relapses or progressions; median time to the event was four months, underlining the need for early identification and risk-stratification of R/R disease. Overall survival was significantly decreased in patients with progressive disease when compared to relapse cases and reaching complete remission during salvage therapy provided a survival benefit., Conclusions: Our analysis of eMRT in this comprehensive cohort provides novel insights into the patterns of relapse and integrates molecular and clinical risk factors to guide clinical decision making.

Published
2024
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48. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.

Author

Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, Hoadley K, Triche TJ Jr, Laird PW, Baty JD, Fulton LL, Fulton R, Heath SE, Kalicki-Veizer J, Kandoth C, Klco JM, Koboldt DC, Kanchi KL, Kulkarni S, Lamprecht TL, Larson DE, Lin L, Lu C, McLellan MD, McMichael JF, Payton J, Schmidt H, Spencer DH, Tomasson MH, Wallis JW, Wartman LD, Watson MA, Welch J, Wendl MC, Ally A, Balasundaram M, Birol I, Butterfield Y, Chiu R, Chu A, Chuah E, Chun HJ, Corbett R, Dhalla N, Guin R, He A, Hirst C, Hirst M, Holt RA, Jones S, Karsan A, Lee D, Li HI, Marra MA, Mayo M, Moore RA, Mungall K, Parker J, Pleasance E, Plettner P, Schein J, Stoll D, Swanson L, Tam A, Thiessen N, Varhol R, Wye N, Zhao Y, Gabriel S, Getz G, Sougnez C, Zou L, Leiserson MD, Vandin F, Wu HT, Applebaum F, Baylin SB, Akbani R, Broom BM, Chen K, Motter TC, Nguyen K, Weinstein JN, Zhang N, Ferguson ML, Adams C, Black A, Bowen J, Gastier-Foster J, Grossman T, Lichtenberg T, Wise L, Davidsen T, Demchok JA, Shaw KR, Sheth M, Sofia HJ, Yang L, Downing JR, and Eley G

Subjects
Adult, CpG Islands, DNA Methylation, Epigenomics, Female, Gene Expression, Gene Fusion, Genome, Human, Humans, Leukemia, Myeloid, Acute classification, Male, MicroRNAs genetics, Middle Aged, Nucleophosmin, Sequence Analysis, DNA methods, Leukemia, Myeloid, Acute genetics, Mutation
Abstract

Background: Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear., Methods: We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis., Results: AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories., Conclusions: We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.).

Published
2013
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