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1. Tangent normalization for somatic copy-number inference in cancer genome analysis.

Author: Galen F. Gao, Coyin Oh, Gordon Saksena, Davy Deng, Lindsay C. Westlake, Barbara A. Hill, Michael Reich, Steven E. Schumacher, Ashton C. Berger, Scott L. Carter, Andrew D. Cherniack, Matthew Meyerson, Barbara Tabak, Rameen Beroukhim, and Gad Getz
Published: 2022
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2. The Tangent copy-number inference pipeline for cancer genome analyses

Author: Barbara Tabak, Gordon Saksena, Coyin Oh, Galen F. Gao, Barbara Hill Meyers, Michael Reich, Steven E. Schumacher, Lindsay C. Westlake, Ashton C. Berger, Scott L.b Carter, Andrew D. Cherniack, Matthew Meyerson, Rameen Beroukhim, and Gad Getz
Subjects: 0303 health sciences, genetic structures, Computer science, Somatic cell, Inference, Tangent, Computational biology, Genome, Quantitative Biology::Genomics, DNA sequencing, Novel gene, 03 medical and health sciences, 0302 clinical medicine, Cancer genome, Cancer development, 030217 neurology & neurosurgery, 030304 developmental biology, SNP array
Abstract: MotivationSomatic copy-number alterations (SCNAs) play an important role in cancer development. Systematic noise in sequencing and array data present a significant challenge to the inference of SCNAs for cancer genome analyses. As part of The Cancer Genome Atlas (TCGA), the Broad Institute Genome Characterization Center developed the Tangent copy-number inference pipeline to generate copy-number profiles using single-nucleotide polymorphism (SNP) array and whole-exome sequencing (WES) data from over 10,000 pairs of tumors and matched normal samples. Here, we describe the Tangent pipeline, which begins with DNA sequencing data in the form of .bam files or raw SNP array probe-level intensity data, and ends with segmented copy-number calls to facilitate the identification of novel genes potentially targeted by SCNAs. We also describe a modification of Tangent, Pseudo-Tangent, which enables denoising through comparisons between tumor profiles when few normal samples are available.ResultsTangent Normalization offers substantial signal-to-noise ratio (SNR) improvements compared to conventional normalization methods in both SNP array and WES analyses. The improvement in SNRs is achieved primarily through noise reduction with minimal effect on signal. Pseudo-Tangent also reduces noise when few normal samples are available. Tangent and Pseudo-Tangent are broadly applicable and enable more accurate inference of SCNAs from DNA sequencing and array data.Availability and ImplementationTangent is available at https://github.com/coyin/tangent and as a Docker image (https://hub.docker.com/r/coyin/tangent). Tangent is also the normalization method for the Copy Number pipeline in Genome Analysis Toolkit 4 (GATK4).Contactmatthew_meyerson@dfci.harvard.edu, rameen@broadinstitute.org, gadgetz@broadinstitute.org
Published: 2019
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3. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas

Author: Noreen Dhalla, Saianand Balu, Alexander Potapov, Yiling Lu, Antonio Iavarone, Roel G.W. Verhaak, Alessandro Perin, Bradley A. Murray, Lee Lichtenstein, Nils Gehlenborg, Zhenlin Ju, Simon G. Coetzee, Stephanie Weaver, Gaetano Finocchiaro, Susan M. Staugaitis, Scott Morris, Da Yang, Rosy Singh, Erik Zmuda, Wei Zhang, Aaron D. Black, Roger E. McLendon, J. Bradley Elder, J. Todd Auman, Arvind Rao, Harshad S. Mahadeshwar, Yunhu Wan, Liming Yang, Stacey Gabriel, Andreas Unterberg, Adam E. Flanders, Piotr A. Mieczkowski, Jianjiong Gao, Robert Penny, Andrew Wei Xu, Peter W. Laird, Gad Getz, Cynthia Taylor, Adrian Ally, Ilya Shmulevich, Tina Wong, Christopher M. McPherson, Heidi J. Sofia, Matthew G. Soloway, Jonna Grimsby, Caterina Giannini, Mark L. Cohen, Johanna Gardner, Semin Lee, Alan P. Hoyle, Jianhua Zhang, Thais S. Sabedot, Felicia Williams, Mia Grifford, Daniela Pretti da Cunha Tirapelli, David Van Den Berg, Margi Sheth, Ye Wu, Jenny Eschbacher, Marco A. Marra, Katherine A. Hoadley, Angeliki Pantazi, Chris Benz, Michael S. Noble, Christopher R. Pierson, Kristen M. Leraas, Roy Tarnuzzer, Suzanne Sifri, Huandong Sun, Greg Eley, Eyas M. Hattab, David I. Heiman, Rehan Akbani, Todd Pihl, Michael Parfenov, Erwin G. Van Meir, Jill S. Barnholtz-Sloan, Peggy Yena, Josh Stuart, Richard A. Moore, Toshinori Hinoue, Kelly Senecal, Andrew D. Cherniack, Donald W. Parsons, Rileen Sinha, Dennis T. Maglinte, Timothy A. Chan, Reanne Bowlby, Phuong L. Nguyen, Juok Cho, Andrew E. Sloan, Alexei Protopopov, Matthew Schniederjan, Yun Wang, Yuexin Liu, Rameen Beroukhim, Kristian Cibulskis, Ty Abel, Ronald E. Warnick, Sahil Seth, Richard A. Gibbs, Rebecca Duell, W. Kimryn Rathmell, Jay Bowen, Michael S. Lawrence, Darell D. Bigner, Mary McGraw, Wen-Bin Liu, Xiaojia Ren, Umadevi Veluvolu, Erin Curley, Lynda Chin, Andy Chu, Laila M. Poisson, Harindra Arachchi, Jean C. Zenklusen, Ardene Noss, Sue E. Bell, Karen Devine, Moiz S. Bootwalla, Rebecca Carlsen, David Mallery, Eric S. Lipp, Hailei Zhang, Bradley A. Ozenberger, Andrew J. Mungall, Amie Radenbaugh, Luciano Neder, Sol Katzman, Lisa Iype, Shaowu Meng, Wendi Barrett, S. Onur Sumer, Katie Dicostanzo, Mark Vitucci, Phillip H. Lai, Vsevolod Shurkhay, D. Neil Hayes, Jiabin Tang, Hui Shen, Christopher A. Bristow, Stefania Cuzzubbo, Quinn T. Ostrom, Yasin Senbabaoglu, Ruth Steele, Peter J. Park, Jacqueline E. Schein, Lior Pachter, Jia Liu, Payal Sipahimalani, Angela Hadjipanayis, Scott L. Carter, Donghui Tan, Travis I. Zack, Kristen Shimmel, Steven E. Schumacher, Leigh B. Thorne, Kenna R. Mills Shaw, Troy Shelton, Julien Baboud, Jianan Zhang, Olga Potapova, Stuart R. Jefferys, Andreas von Deimling, B. Arman Aksoy, Carrie Sougnez, Howard Colman, Tom Mikkelsen, Amanda Clarke, Houtan Noushmehr, Daniel Crain, Mark A. Jensen, D L Rotin, Stephen B. Baylin, Barry S. Taylor, Gordon Saksena, Benito Campos, Sudha Chudamani, Ouida Liu, Lisle E. Mose, Jonathan G. Seidman, Corbin D. Jones, Norman L. Lehman, Eric S. Lander, David Haussler, Franklin W. Huang, Nina Thiessen, Charles M. Perou, Gregory N. Fuller, Kosuke Yoshihara, C. Ryan Miller, Brenda Ayala, Dina Aziz, Sara Sadeghi, Cameron Brennan, Randy Mandt, Aditya Raghunathan, Jeffrey Roach, Robert A. Holt, Timothy J. Triche, Barbara Tabak, Kenneth Aldape, John N. Weinstein, Kevin Lau, Ady Kendler, Lee Cooper, Carlos Gilberto Carlotti, Siyuan Zheng, Isaac Joseph, Jason T. Huse, Steven J.M. Jones, Brady Bernard, Chip Stewart, Lixing Yang, Lisa Wise, A. Gordon Robertson, Ronglai Shen, Lisa Scarpace, Richard Kreisberg, Shiyun Ling, Michael Mayo, Jordonna Fulop, Cathy Brewer, Denise Brooks, Daniel E. Carlin, Nils Weinhold, Angela Tam, Beth Hermes, Kalle Leinonen, Giovanni Ciriello, Mahitha Vallurupalli, John A. Demchok, Bianca Pollo, Christel Herold-Mende, Rajan Jain, Liu Xi, Francesco DiMeco, Nilsa C. Ramirez, Tara M. Lichtenberg, Ashley Fehrenbach, Yingchun Liu, Miruna Balasundaram, Sofie R. Salama, Rivka R. Colen, Olena Morozova, Yussanne Ma, Zhining Wang, W. K. Alfred Yung, Scott R. VandenBerg, Esther Rheinbay, Junyuan Wu, Katayoon Kasaian, Tanja M. Davidsen, William A. Friedman, Kathy Smolenski, Yichao Sun, Anders Jacobsen, Chiara Calatozzolo, Matthew D. Wilkerson, Lucia Cuppini, Gordon B. Mills, Xingzhi Song, Joseph Paulauskis, Jaegil Kim, Pei Lin, Scott Frazer, William M. Lee, Evan O. Paull, Sheila A. Fisher, Carolyn M. Hutter, Janae V. Simons, Gene Barnett, Mara Rosenberg, Scot Waring, Timothy R. Fennell, Raju Kucherlapati, Christine Jungk, Martin L. Ferguson, Julie M. Gastier-Foster, Cathy Schilero, Yingli Wolinsky, Rohini Raman, Zack Sanborn, Ranabir Guin, Matthew Meyerson, Daniel J. Brat, Cheryl A. Palmer, Nikolaus Schultz, Erik P. Sulman, Eric Chuah, Mark E. Sherman, Theo A. Knijnenburg, Mitchel S. Berger, Lihua Zou, Hoon Kim, Daniel DiCara, Sam Ng, Joel S. Parker, Sheila Reynolds, Raffaele Nunziata, Daniel J. Weisenberger, Natalie Tasman, Chris Sander, Doug Voet, Yaron S.N. Butterfield, Brian P. O'Neill, Lori Boice, Brat D.J., Verhaak R.G.W., Aldape K.D., Yung W.K.A., Salama S.R., Cooper L.A.D., Rheinbay E., Miller C.R., Vitucci M., Morozova O., Robertson A.G., Noushmehr H., Laird P.W., Cherniack A.D., Akbani R., Huse J.T., Ciriello G., Poisson L.M., Barnholtz-Sloan J.S., Berger M.S., Brennan C., Colen R.R., Colman H., Flanders A.E., Giannini C., Grifford M., Iavarone A., Jain R., Joseph I., Kim J., Kasaian K., Mikkelsen T., Murray B.A., O'Neill B.P., Pachter L., Parsons D.W., Sougnez C., Sulman E.P., Vandenberg S.R., Van Meir E.G., Von Deimling A., Zhang H., Crain D., Lau K., Mallery D., Morris S., Paulauskis J., Penny R., Shelton T., Sherman M., Yena P., Black A., Bowen J., Dicostanzo K., Gastier-Foster J., Leraas K.M., Lichtenberg T.M., Pierson C.R., Ramirez N.C., Taylor C., Weaver S., Wise L., Zmuda E., Davidsen T., Demchok J.A., Eley G., Ferguson M.L., Hutter C.M., Shaw K.R.M., Ozenberger B.A., Sheth M., Sofia H.J., Tarnuzzer R., Wang Z., Yang L., Zenklusen J.C., Ayala B., Baboud J., Chudamani S., Jensen M.A., Liu J., Pihl T., Raman R., Wan Y., Wu Y., Ally A., Auman J.T., Balasundaram M., Balu S., Baylin S.B., Beroukhim R., Bootwalla M.S., Bowlby R., Bristow C.A., Brooks D., Butterfield Y., Carlsen R., Carter S., Chin L., Chu A., Chuah E., Cibulskis K., Clarke A., Coetzee S.G., Dhalla N., Fennell T., Fisher S., Gabriel S., Getz G., Gibbs R., Guin R., Hadjipanayis A., Hayes D.N., Hinoue T., Hoadley K., Holt R.A., Hoyle A.P., Jefferys S.R., Jones S., Jones C.D., Kucherlapati R., Lai P.H., Lander E., Lee S., Lichtenstein L., Ma Y., Maglinte D.T., Mahadeshwar H.S., Marra M.A., Mayo M., Meng S., Meyerson M.L., Mieczkowski P.A., Moore R.A., Mose L.E., Mungall A.J., Pantazi A., Parfenov M., Park P.J., Parker J.S., Perou C.M., Protopopov A., Ren X., Roach J., Sabedot T.S., Schein J., Schumacher S.E., Seidman J.G., Seth S., Shen H., Simons J.V., Sipahimalani P., Soloway M.G., Song X., Sun H., Tabak B., Tam A., Tan D., Tang J., Thiessen N., Triche T., Van Den Berg D.J., Veluvolu U., Waring S., Weisenberger D.J., Wilkerson M.D., Wong T., Wu J., Xi L., Xu A.W., Zack T.I., Zhang J., Aksoy B.A., Arachchi H., Benz C., Bernard B., Carlin D., Cho J., DiCara D., Frazer S., Fuller G.N., Gao J., Gehlenborg N., Haussler D., Heiman D.I., Iype L., Jacobsen A., Ju Z., Katzman S., Kim H., Knijnenburg T., Kreisberg R.B., Lawrence M.S., Lee W., Leinonen K., Lin P., Ling S., Liu W., Liu Y., Lu Y., Mills G., Ng S., Noble M.S., Paull E., Rao A., Reynolds S., Saksena G., Sanborn Z., Sander C., Schultz N., Senbabaoglu Y., Shen R., Shmulevich I., Sinha R., Stuart J., Sumer S.O., Sun Y., Tasman N., Taylor B.S., Voet D., Weinhold N., Weinstein J.N., Yang D., Yoshihara K., Zheng S., Zhang W., Zou L., Abel T., Sadeghi S., Cohen M.L., Eschbacher J., Hattab E.M., Raghunathan A., Schniederjan M.J., Aziz D., Barnett G., Barrett W., Bigner D.D., Boice L., Brewer C., Calatozzolo C., Campos B., Carlotti C.G., Chan T.A., Cuppini L., Curley E., Cuzzubbo S., Devine K., DiMeco F., Duell R., Elder J.B., Fehrenbach A., Finocchiaro G., Friedman W., Fulop J., Gardner J., Hermes B., Herold-Mende C., Jungk C., Kendler A., Lehman N.L., Lipp E., Liu O., Mandt R., McGraw M., Mclendon R., McPherson C., Neder L., Nguyen P., Noss A., Nunziata R., Ostrom Q.T., Palmer C., Perin A., Pollo B., Potapov A., Potapova O., Rathmell W.K., Rotin D., Scarpace L., Schilero C., Senecal K., Shimmel K., Shurkhay V., Sifri S., Singh R., Sloan A.E., Smolenski K., Staugaitis S.M., Steele R., Thorne L., Tirapelli D.P.C., Unterberg A., Vallurupalli M., Wang Y., Warnick R., Williams F., Wolinsky Y., Bell S., Rosenberg M., Stewart C., Huang F., Grimsby J.L., and Radenbaugh A.J.
Subjects: Adult, Male, Pathology, medicine.medical_specialty, IDH1, Adolescent, Kaplan-Meier Estimate, 1p/19q Codeletion, Biology, Article, Glioma, Molecular genetics, Grade II Glioma, medicine, Cluster Analysis, Humans, neoplasms, Exome, ATRX, Proportional Hazards Models, Aged, Cluster Analysi, DNA, Neoplasm, Sequence Analysis, DNA, General Medicine, Middle Aged, Genes, p53, medicine.disease, Chromosomes, Human, Pair 1, Mutation, Proportional Hazards Model, Cancer research, GLIOMA, Female, Oligodendroglioma, Neoplasm Grading, Glioblastoma, Chromosomes, Human, Pair 19, Human, Signal Transduction
Abstract: BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.)
Published: 2015
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4. Higher-order inter-chromosomal hubs shape 3-dimensional genome organization in the nucleus

Author: Mitchell Guttman, Vickie Trinh, Pamela Russell, Mason Lai, Sofia A. Quinodoz, Erik Aznauryan, Alexander A. Shishkin, Prashant Bhat, Amy Y. M. Chow, Jan Marten Schmidt, Manuel Garber, Marko Jovanovic, Noah Ollikainen, Christine S. Cheng, Patrick McDonel, Elizabeth Detmar, Barbara Tabak, and Ali Palla
Subjects: 0303 health sciences, biology, Nucleolus, Genomics, RNA polymerase II, Genome, 03 medical and health sciences, genomic DNA, 0302 clinical medicine, medicine.anatomical_structure, Order (biology), Evolutionary biology, biology.protein, medicine, Nucleus, 030217 neurology & neurosurgery, 030304 developmental biology, Genomic organization
Abstract: Eukaryotic genomes are packaged into a 3-dimensional structure in the nucleus of each cell. There are currently two distinct views of genome organization that are derived from different technologies. The first view, derived from genome-wide proximity ligation methods (e.g. Hi-C), suggests that genome organization is largely organized around chromosomes. The second view, derived fromin situimaging, suggests a central role for nuclear bodies. Yet, because microscopy and proximity-ligation methods measure different aspects of genome organization, these two views remain poorly reconciled and our overall understanding of how genomic DNA is organized within the nucleus remains incomplete. Here, we develop Split-Pool Recognition of Interactions by Tag Extension (SPRITE), which moves away from proximity-ligation and enables genome-wide detection of higher-order DNA interactions within the nucleus. Using SPRITE, we recapitulate known genome structures identified by Hi-C and show that the contact frequencies measured by SPRITE strongly correlate with the 3-dimensional distances measured by microscopy. In addition to known structures, SPRITE identifies two major hubs of inter-chromosomal interactions that are spatially arranged around the nucleolus and nuclear speckles, respectively. We find that the majority of genomic regions exhibit preferential spatial association relative to one of these nuclear bodies, with regions that are highly transcribed by RNA Polymerase II organizing around nuclear speckles and transcriptionally inactive and centromere-proximal regions organizing around the nucleolus. Together, our results reconcile the two distinct pictures of nuclear structure and demonstrate that nuclear bodies act as inter-chromosomal hubs that shape the overall 3-dimensional packaging of genomic DNA in the nucleus.
Published: 2017
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5. Epstein-Barr Virus Latent Membrane Protein 1 Genetic Variability in Peripheral Blood B Cells and Oropharyngeal Fluids

Author: Eric R. Weiss, Frank E. Brewster, James A. Coderre, Barbara Tabak, Timothy F. Kowalik, Mohan Somasundaran, Margaret M. McManus, Katherine Luzuriaga, Nicholas Renzette, Manuel Garber, and Thomas C. Greenough
Subjects: Epstein-Barr Virus Infections, Herpesvirus 4, Human, Time Factors, Mononucleosis, Sequence analysis, Molecular Sequence Data, Immunology, Oropharynx, Biology, Microbiology, Genome, Virus, Viral Matrix Proteins, Young Adult, Virology, Genetic variation, medicine, Cluster Analysis, Humans, Genetic variability, Gene, Phylogeny, B-Lymphocytes, Genetic Variation, Sequence Analysis, DNA, Epstein–Barr virus latent membrane protein 1, medicine.disease, Genome Replication and Regulation of Viral Gene Expression, Insect Science, DNA, Viral
Abstract: We report the diversity of latent membrane protein 1 (LMP1) gene founder sequences and the level of Epstein-Barr virus (EBV) genome variability over time and across anatomic compartments by using virus genomes amplified directly from oropharyngeal wash specimens and peripheral blood B cells during acute infection and convalescence. The intrahost nucleotide variability of the founder virus was 0.02% across the region sequences, and diversity increased significantly over time in the oropharyngeal compartment ( P = 0.004). The LMP1 region showing the greatest level of variability in both compartments, and over time, was concentrated within the functional carboxyl-terminal activating regions 2 and 3 (CTAR2 and CTAR3). Interestingly, a deletion in a proline-rich repeat region (amino acids 274 to 289) of EBV commonly reported in EBV sequenced from cancer specimens was not observed in acute infectious mononucleosis (AIM) patients. Taken together, these data highlight the diversity in circulating EBV genomes and its potential importance in disease pathogenesis and vaccine design. IMPORTANCE This study is among the first to leverage an improved high-throughput deep-sequencing methodology to investigate directly from patient samples the degree of diversity in Epstein-Barr virus (EBV) populations and the extent to which viral genome diversity develops over time in the infected host. Significant variability of circulating EBV latent membrane protein 1 (LMP1) gene sequences was observed between cellular and oral wash samples, and this variability increased over time in oral wash samples. The significance of EBV genetic diversity in transmission and disease pathogenesis are discussed.
Published: 2014
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6. SQSTM1 Is a Pathogenic Target of 5q Copy Number Gains in Kidney Cancer

Author: Chris Sander, Steven M. Bair, David E. Root, Giovanni Ciriello, Ella Liberzon, Su-Chun Cheng, Lianjie Li, Rameen Beroukhim, Pablo Tamayo, Chuan Shen, Glenn S. Cowley, Aviad Tsherniak, William G. Kaelin, Eijiro Nakamura, James J. Hsieh, Kiyohiro Ando, Sabina Signoretti, Patrick H. Lizotte, Anders Jacobsen, Barbara Tabak, Nikolaus Schultz, and A. Ari Hakimi
Subjects: Cancer Research, Tumor suppressor gene, NF-E2-Related Factor 2, Molecular Sequence Data, Gene Dosage, Biology, Gene dosage, Article, Mice, Downregulation and upregulation, Cell Line, Tumor, Sequestosome-1 Protein, medicine, Animals, Humans, Carcinoma, Renal Cell, Adaptor Proteins, Signal Transducing, Base Sequence, Oncogene, Chromosome, Cell Biology, medicine.disease, Molecular biology, Kidney Neoplasms, Clear cell renal cell carcinoma, HIF1A, Oncology, Chromosomes, Human, Pair 5, Kidney cancer
Abstract: SummaryClear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer and is often linked to loss of chromosome 3p, which harbors the VHL tumor suppressor gene, loss of chromosome 14q, which includes HIF1A, and gain of chromosome 5q. The relevant target(s) on chromosome 5q is not known. Here, we show that 5q amplification leads to overexpression of the SQSTM1 oncogene in ccRCC lines and tumors. Overexpression of SQSTM1 in ccRCC lines promoted resistance to redox stress and increased soft agar growth, while downregulation of SQSTM1 decreased resistance to redox stress, impaired cellular fitness, and decreased tumor formation. Therefore, the selection pressure to amplify 5q in ccRCC is driven, at least partly, by SQSTM1.
Published: 2013
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7. The Somatic Genomic Landscape of Glioblastoma

Author: Cameron W. Brennan, Roel G.W. Verhaak, Aaron McKenna, Benito Campos, Houtan Noushmehr, Sofie R. Salama, Siyuan Zheng, Debyani Chakravarty, J. Zachary Sanborn, Samuel H. Berman, Rameen Beroukhim, Brady Bernard, Chang-Jiun Wu, Giannicola Genovese, Ilya Shmulevich, Jill Barnholtz-Sloan, Lihua Zou, Rahulsimham Vegesna, Sachet A. Shukla, Giovanni Ciriello, W.K. Yung, Wei Zhang, Carrie Sougnez, Tom Mikkelsen, Kenneth Aldape, Darell D. Bigner, Erwin G. Van Meir, Michael Prados, Andrew Sloan, Keith L. Black, Jennifer Eschbacher, Gaetano Finocchiaro, William Friedman, David W. Andrews, Abhijit Guha, Mary Iacocca, Brian P. O’Neill, Greg Foltz, Jerome Myers, Daniel J. Weisenberger, Robert Penny, Raju Kucherlapati, Charles M. Perou, D. Neil Hayes, Richard Gibbs, Marco Marra, Gordon B. Mills, Eric Lander, Paul Spellman, Richard Wilson, Chris Sander, John Weinstein, Matthew Meyerson, Stacey Gabriel, Peter W. Laird, David Haussler, Gad Getz, Lynda Chin, Christopher Benz, Wendi Barrett, Quinn Ostrom, Yingli Wolinsky, Bikash Bose, Paul T. Boulos, Madgy Boulos, Jenn Brown, Christine Czerinski, Matthew Eppley, Thelma Kempista, Teresa Kitko, Yakov Koyfman, Brenda Rabeno, Pawan Rastogi, Michael Sugarman, Patricia Swanson, Kennedy Yalamanchii, Ilana P. Otey, Yingchun Spring Liu, Yonghong Xiao, J.Todd Auman, Peng-Chieh Chen, Angela Hadjipanayis, Eunjung Lee, Semin Lee, Peter J. Park, Jonathan Seidman, Lixing Yang, Steven Kalkanis, Laila M. Poisson, Aditya Raghunathan, Lisa Scarpace, Ryan Bressler, Andrea Eakin, Lisa Iype, Richard B. Kreisberg, Kalle Leinonen, Sheila Reynolds, Hector Rovira, Vesteinn Thorsson, Matti J. Annala, Joseph Paulauskis, Erin Curley, Martha Hatfield, David Mallery, Scott Morris, Troy Shelton, Candace Shelton, Mark Sherman, Peggy Yena, Lucia Cuppini, Francesco DiMeco, Marica Eoli, Emanuela Maderna, Bianca Pollo, Marco Saini, Saianand Balu, Katherine A. Hoadley, Ling Li, C. Ryan Miller, Yan Shi, Michael D. Topal, Junyuan Wu, Gavin Dunn, Caterina Giannini, Brian P. O'Neill, B. Arman Aksoy, Yevgeniy Antipin, Laetitia Borsu, Ethan Cerami, Jianjiong Gao, Benjamin Gross, Anders Jacobsen, Marc Ladanyi, Alex Lash, Yupu Liang, Boris Reva, Nikolaus Schultz, Ronglai Shen, Nicholas D. Socci, Agnes Viale, Martin L. Ferguson, Qing-Rong Chen, John A. Demchok, Laura A.L. Dillon, Kenna R. Mills Shaw, Margi Sheth, Roy Tarnuzzer, Zhining Wang, Liming Yang, Tanja Davidsen, Mark S. Guyer, Bradley A. Ozenberger, Heidi J. Sofia, Julie Bergsten, John Eckman, Jodi Harr, Christine Smith, Kelly Tucker, Cindy Winemiller, Leigh Anne Zach, Julia Y. Ljubimova, Greg Eley, Brenda Ayala, Mark A. Jensen, Ari Kahn, Todd D. Pihl, David A. Pot, Yunhu Wan, Nathan Hansen, Parvi Hothi, Biaoyang Lin, Nameeta Shah, Jae-geun Yoon, Ching Lau, Michael Berens, Kristin Ardlie, Scott L. Carter, Andrew D. Cherniack, Mike Noble, Juok Cho, Kristian Cibulskis, Daniel DiCara, Scott Frazer, Stacey B. Gabriel, Nils Gehlenborg, Jeff Gentry, David Heiman, Jaegil Kim, Rui Jing, Eric S. Lander, Michael Lawrence, Pei Lin, Will Mallard, Robert C. Onofrio, Gordon Saksena, Steve Schumacher, Petar Stojanov, Barbara Tabak, Doug Voet, Hailei Zhang, Nathan N. Dees, Li Ding, Lucinda L. Fulton, Robert S. Fulton, Krishna-Latha Kanchi, Elaine R. Mardis, Richard K. Wilson, Stephen B. Baylin, Larry Harshyne, Mark L. Cohen, Karen Devine, Andrew E. Sloan, Scott R. VandenBerg, Mitchel S. Berger, Daniel Carlin, Brian Craft, Kyle Ellrott, Mary Goldman, Theodore Goldstein, Mia Grifford, Singer Ma, Sam Ng, Joshua Stuart, Teresa Swatloski, Peter Waltman, Jing Zhu, Robin Foss, Barbara Frentzen, Raquel McTiernan, Anthony Yachnis, Yong Mao, Rehan Akbani, Oliver Bogler, Gregory N. Fuller, Wenbin Liu, Yuexin Liu, Yiling Lu, Gordon Mills, Alexei Protopopov, Xiaojia Ren, Youting Sun, W.K. Alfred Yung, Jianhua Zhang, Ken Chen, John N. Weinstein, Moiz S. Bootwalla, Phillip H. Lai, Timothy J. Triche, David J. Van Den Berg, David H. Gutmann, Norman L. Lehman, Erwin G. VanMeir, Daniel Brat, Jeffrey J. Olson, Gena M. Mastrogianakis, Narra S. Devi, Zhaobin Zhang, Darell Bigner, Eric Lipp, and Roger McLendon
Subjects: Male, Telomerase, Proteome, REGULAÇÃO GÊNICA, Somatic cell, Mesenchymal Glioblastoma, PDGFRA, Computational biology, Biology, medicine.disease_cause, Article, General Biochemistry, Genetics and Molecular Biology, medicine, Humans, Gene Regulatory Networks, Gene, Genetics, Glioblastoma cell, Mutation, Brain Neoplasms, Biochemistry, Genetics and Molecular Biology(all), Gene Expression Profiling, Phenotype, Gene expression profiling, DNA methylation, Cancer research, Female, Glioblastoma, Signal Transduction
Abstract: SummaryWe describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.
Published: 2013
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8. Pan-cancer patterns of somatic copy number alteration

Author: Gad Getz, Matthew Meyerson, Scott L. Carter, Gordon Saksena, Carrie Sougnez, Hui Shen, Craig H. Mermel, Steven E. Schumacher, Jeremiah Wala, Barbara Tabak, Cheng-Zhong Zhang, Andrew D. Cherniack, Rameen Beroukhim, Michael S. Lawrence, Stacey Gabriel, Bryan Hernandez, Travis I. Zack, and Peter W. Laird
Subjects: Genetics, 0303 health sciences, Oncogene, Tumor suppressor gene, Somatic cell, Gene regulatory network, Biology, SCNA, Article, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Epigenetics, Gene, 030304 developmental biology, Epigenesis
Abstract: Determining how somatic copy number alterations (SCNAs) promote cancer is an important goal. We characterized SCNA patterns in 4,934 cancers from The Cancer Genome Atlas Pan-Cancer data set. Whole-genome doubling, observed in 37% of cancers, was associated with higher rates of every other type of SCNA, TP53 mutations, CCNE1 amplifications and alterations of the PPP2R complex. SCNAs that were internal to chromosomes tended to be shorter than telomere-bounded SCNAs, suggesting different mechanisms underlying their generation. Significantly recurrent focal SCNAs were observed in 140 regions, including 102 without known oncogene or tumor suppressor gene targets and 50 with significantly mutated genes. Amplified regions without known oncogenes were enriched for genes involved in epigenetic regulation. When levels of genomic disruption were accounted for, 7% of region pairs were anticorrelated, and these regions tended to encompass genes whose proteins physically interact, suggesting related functions. These results provide insights into mechanisms of generation and functional consequences of cancer-related SCNAs.
Published: 2013
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9. COMPREHENSIVE MOLECULAR CHARACTERIZATION OF CLEAR CELL RENAL CELL CARCINOMA

Author: Kelinda Tucker, Raju Kucherlapati, Ng Sam, John N. Weinstein, Lori Boice, Satish K. Tickoo, Saianand Balu, John C. Cheville, B. Arman Aksoy, Chip Stewart, Preethi H. Gunaratne, Martin L. Ferguson, Bogdan Czerniak, Christie Kovar, Theodore C. Goldstein, Mark E. Sherman, Juan M. Mosquera, Chris Sander, Yaron S.N. Butterfield, Leigh Anne Zach, Yiling Lu, Chandra Lebovitz, Gary Witkin, David Pot, Gordon Robertson, Richard A. Gibbs, James J. Hsieh, Benjamin P. Berman, Doug Voet, Kyle Chang, W. Marston Linehan, Margaret Morgan, Joan Pontius, Jodi Harr, Lihua Zhou, Joel S. Parker, David Van Den Berg, Michael B. Atkins, Sheila Reynolds, Petar Stojanov, Joel B. Nelson, Gordon B. Mills, Toni K. Choueiri, Weimin Xiao, Hye Jung E. Chun, Ronglai Shen, Rebecca Carlsen, Jennifer Brown, Tod D. Casasent, Sabina Signoretti, Jo Ellen Weaver, Phillip H. Lai, Dominique L. Berton, Patrick Plettner, Irina Ostrovnaya, Lisle E. Mose, Leslie Cope, Nils Gehlenborg, Heidi J. Sofia, Peter J. Park, Scott Morris, Hsin-Ta Wu, Fabio Vandin, Ranabir Guin, Daniel E. Carlin, Jacqueline E. Schein, Xi Liu, Nils Weinhold, Wandaliz Torres-Garcia, Cureline Olga Potapova, Daniel DiCara, Juok Cho, Steve Schumacher, Chris Wakefield, A. Rose Brannon, Susan M. Benton, Tom Bodenheimer, J. Todd Auman, Brenda Rabeno, Sharon M. Gorski, Eric E. Snyder, Divya Kalra, Brenda Ayala, Jiashan Zhang, Zhang Wei, Kyle Ellrott, Zhining Wang, Stacey Gabriel, Dominik Stoll, Daniel L. Rubin, W. Kimryn Rathmell, Eric Chuah, David Mallery, Tanja Davidsen, David Cogdell, Anders Jacobsen, John A. Demchok, Robert C. Onofrio, Anna Chu, Piotr A. Mieczkowski, Zhiyong Ding, Erin Curley, Johanna Gardner, Robert Worrell, Hailei Zhang, Jennifer C. Fisher, Donna M. Muzny, Rajiv Dhir, Walker Hale, Ari B. Kahn, Sheila Fisher, Giovanni Ciriello, Ken Burnett, Marco A. Marra, Wiam Bshara, Anil V. Parwani, Joshua M. Stuart, Richard Varhol, Kristin G. Ardlie, Han Yi, Lisa R. Trevino, Roy Tarnuzzer, Michael S. Noble, Erin Pleasance, Jesse Walsh, Leigh B. Thorne, Andy Chu, Peter W. Laird, Andrew J. Mungall, Rashmi N. Sanbhadti, Mark Backus, David A. Wheeler, Bradley A. Ozenberger, Jodi K. Maranchie, William Mallard, Jared R. Slobodan, Christine Czerwinski, Jireh Santibanez, Andrew J. Stout, Donghui Tan, Laura S. Schmidt, Junyuan Wu, Jianjiong Gao, Daniel J. Weisenberger, D. Neil Hayes, Scott Frazer, Alan P. Hoyle, Konstantin V. Fedosenko, Rehan Akbani, Todd Pihl, Rahul Vegesna, Lynda Chin, Shelley Alonso, Jeffrey G. Reid, Donna Morton, Cathy D. Vocke, R. Houston Thompson, Christopher C. Benz, Kenna R. Mills Shaw, Liming Yang, Carmelo Gaudioso, Nianxiang Zhang, Caleb F. Davis, Carrie Hirst, Shi Yan, Michael L. Blute, Barry S. Taylor, Mathew G. Soloway, Nina Thiessen, Paul T. Spellman, Deepak Srinivasan, Yongjun Zhao, Boris Reva, Wang Min, Stuart R. Jefferys, Benjamin J. Raphael, Nicholas J. Petrelli, Arash Shafiei, Lora Lewis, Eric Jonasch, David I. Heiman, Scot Waring, Richard A. Moore, Eric S. Lander, Evan O. Paull, Hoon Kim, Janae V. Simons, Stephen B. Baylin, Gad Getz, Stanley Girshik, Victor E. Reuter, Benjamin Gross, Ethan Cerami, Andrew D. Cherniack, Christine I. Smith, Christina Yau, Michael D. Topal, Peter Waltman, Jeff Boyd, Rameen Beroukhim, Angela Tam, Yingchun Liu, Peter A. Kigonya, Miruna Balasundaram, Maria J. Merino, David Haussler, Dinh Huyen, Elizabeth Buda, Michael S. Lawrence, Lin Pei, Charles M. Perou, Timothy J. Triche, Jessica Walton, Greg Eley, Tiffany Ting Liu, Joseph Paulauskis, Matthew Meyerson, Marc Ladanyi, Jaegil Kim, Katherine A. Hoadley, Huang Mei, Ilya Shmulevich, Robin J.N. Coope, Mary Iacocca, Natasja Wye, Adrian Ally, Mark A. Rubin, A. Ari Hakimi, Lori Huelsenbeck-Dill, Steven J.M. Jones, James Peterson, Mark A. Jensen, Barbara Tabak, Andrey Sivachenko, Julie Bergsten, John Eckman, Inanc Birol, Rohini Raman, Nipun Kakkar, Christina Liquori, Rileen Sinha, Dennis T. Maglinte, Lichtenstein Lee, Haiyan I. Li, William G. Kaelin, Anna K. Unruh, Noreen Dhalla, Candace Shelton, Roel G.W. Verhaak, Christopher J. Ricketts, Carrie Sougnez, Harsha Doddapaneni, Mark S. Guyer, Robert Penny, Michael F. Berger, Margi Sheth, Darlene Lee, Dimitra Tsavachidou, Chad J. Creighton, Prachi Kothiyal, Scott L. Carter, Michael Mayo, Zhu Jing, Kenneth Aldape, Corbin D. Jones, Moiz S. Bootwalla, Payal Sipahimalani, Martin Hirst, Sean P. Barletta, Kristian Cibulskis, Jerome Myers, Matthew C. Nicholls, Yidi J. Turman, Julien Baboud, Jeff Gentry, Carl Morrison, Gordon Saksena, Troy Shelton, Swapna Mahurkar, Robert A. Holt, Robert Sfeir, Shen Hui, Suzanne S. Fei, Christopher G. Wood, Candace Carter, S. Onur Sumer, Pheroze Tamboli, Yiming Zhu, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Biology, Getz, Gad Asher, Voet, Douglas, Lin, Pei, Chin, Lynda, and Lander, Eric Steven
Subjects: DNA Mutational Analysis, GRB10 Adaptor Protein, AMP-Activated Protein Kinases, Epigenesis, Genetic, PBRM1, Pentose Phosphate Pathway, Phosphatidylinositol 3-Kinases, RNA, Neoplasm, BAP1, Genome, Multidisciplinary, Genomics, Chromatin, Gene Expression Regulation, Neoplastic, DNA methylation, Signal transduction, Acetyl-CoA Carboxylase, Carcinoma, Renal Cell, Chromatin Assembly and Disassembly, Citric Acid Cycle, DNA Methylation, Gene Expression Profiling, Genome, Human, Histone-Lysine N-Methyltransferase, Humans, Metabolic Networks and Pathways, MicroRNAs, Mutation, PTEN Phosphohydrolase, Proto-Oncogene Proteins c-akt, Signal Transduction, Survival Analysis, Human, Biology, Article, Genetic, SETD2, microRNA, medicine, Neoplastic, Carcinoma, Renal Cell, medicine.disease, Clear cell renal cell carcinoma, Gene Expression Regulation, Cancer research, RNA, Neoplasm, Epigenesis
Abstract: Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.
Published: 2013

10. Integrated genomic characterization of endometrial carcinoma

Author: Ding Li, Esther Elishaev, Linda Dao, Juok Cho, Alexei Protopopov, Heather Schmidt, Tod D. Casasent, Bobbie S. Gostout, P.J. DiSaia, Jacqueline E. Schein, J. Todd Auman, Jay Bowen, S. Onur Sumer, Beth Y. Karlan, Gordon Saksena, Prachi Kothiyal, Robert E. Pyatt, Theodore C. Goldstein, Lisle E. Mose, Paul J. Goodfellow, Brenda Ayala, Nilsa C. Ramirez, Thomas Barr, Payal Sipahimalani, Gordon B. Mills, Rebecca Carlsen, Linda Van Le, Andy Chu, Peter W. Laird, Russell Broaddus, Helga B. Salvesen, Sam Ng, Cyriac Kandoth, Christopher Adams, Yiling Lu, Donghui Tan, Peter White, Lori Boice, Saianand Balu, Daniel DiCara, Robert A. Holt, Christopher C. Benz, Shi Yan, Joel S. Parker, Jessica Frick, Adrian Ally, Boris Winterhoff, Pamela M. Pollock, Patrick Plettner, Ethan Cerami, Angela Tam, Katherine A. Hoadley, Melissa Hart-Kothari, Robert C. Onofrio, John N. Weinstein, Sheila Reynolds, David Haussler, Kristian Cibulskis, Charles M. Perou, Timothy J. Triche, Rehan Akbani, Jeff Roach, Michael Mayo, Ranabir Guin, W. Kimryn Rathmell, Carmen Helsel, Junyuan Wu, Will Mallard, Nandita Barnabas, Todd Pihl, Ruibin Xi, Nianxiang Zhang, David Mallery, Douglas A. Levine, Aaron D. Black, David I. Heiman, Sugy Kodeeswaran, Lynda Chin, Guoyan Liu, Mark E. Borowsky, Daniel J. Weisenberger, Yuexin Liu, Hailei Zhang, Kenna R. Mills Shaw, Anna K. Unruh, Andrew Berchuck, Michael Button, Noreen Dhalla, Bryan Hernandez, Rayna K. Matsuno, David G. Mutch, Chen Wang, Teresa R. Tabler, Yaron S.N. Butterfield, Jeff Gentry, Stuart R. Jefferys, Thomas Grossman, Kelley Kneile, Fanny Dao, Scot Waring, Barbara Tabak, Eric E. Snyder, Eric S. Lander, Richard A. Moore, David J. Dooling, David Van Den Berg, Jiabin Tang, Piotr A. Mieczkowski, Victoria Blanc, Wei Zhang, Inanc Birol, Harkness Kuck, Mathew G. Soloway, Johanna Gardner, Gary Witkin, Sahil Seth, Heidi J. Sofia, B. Arman Aksoy, Nikolaus Schultz, Marco A. Marra, Andrew D. Cherniack, D L Rotin, Anders Jacobsen, Erik Zmuda, Candace Carter, Christina Yau, Stephen C. Benz, Alexander A. Green, Michael D. Topal, Jean MacKenzie, Elena Nemirovich-Danchenko, Nicholas J. Petrelli, Dana Nicholson, Eve Shinbrot, Han Liang, Rameen Beroukhim, Charlenia Berry-Green, Kristin G. Ardlie, Joan Pontius, David Pot, Ari B. Kahn, Marc T. Goodman, Yevgeniy Antipin, Christopher Szeto, Jianhua Zhang, Ilya Shmulevich, Lori Huelsenbeck-Dill, Steven J.M. Jones, Carrie Sougnez, Kristen M. Leraas, Pei Lin, Robert A. Soslow, Erin Curley, Leigh B. Thorne, Hye Jung E. Chun, Michael S. Lawrence, Michelle O'Laughlin, Moiz S. Bootwalla, Lixing Yang, Mark A. Jensen, Rajiv Dhir, David A. Wheeler, C. Blake Gilks, Jianjiong Gao, Lisa Wise, Giovanni Ciriello, Joelle Kalicki-Veizer, Shaowu Meng, Mei Huang, Elaine R. Mardis, Faina Bogomolniy, Kai Ye, Jenny Lester, Lihua Zou, Hollie A. Harper, Robert Edwards, Ronglai Shen, Xiaojia Ren, Nils Weinhold, Harshad S. Mahadeshwar, Sandra Orsulic, Tom Bodenheimer, Zhenlin Ju, Chris Wakefield, Scott Frazer, John M. S. Bartlett, Gideon Dresdner, Hui Shen, Deepak Srinivasan, Aaron Hobensack, Cynthia McAllister, Marc Ladanyi, Tanja Davidsen, Lucinda Fulton, Michael D. McLellan, Richard K. Wilson, Zeng Dong, Olga Potapova, Sean C. Dowdy, Rui Jing, Kristin K. Zorn, Robert S. Fulton, Matti Annala, Chris Sander, Michael S. Noble, Benjamin Gross, Janae V. Simons, Phillip H. Lai, Laura Monovich, Andrew J. Mungall, Peter J. Park, Fedor Moiseenko, Liming Yang, Gad Getz, John Deardurff, Matthew Meyerson, Jeremy Parfitt, A. Gordon Robertson, Bradley M. Broom, Blaise A. Clarke, Greg Eley, Jennifer O. Fisher, Andrey Sivachenko, Narciso Olvera, Carrie Hirst, Adam M. Farkas, Karuna Garg, Wendy Winckler, Eric Chuah, Stacey Gabriel, Michael E. Carney, Stephen B. Baylin, Doug Voet, Miruna Balasundaram, Christine Czerwinski, Daphne W. Bell, Richard Varhol, Alexandra Meuter, Alan P. Hoyle, Darlene Lee, Elizabeth Buda, Li Ding, Xingzhi Song, Steven E. Schumacher, Anna L. Chu, Attila Teoman, Mary Iacocca, Semin Lee, Rileen Sinha, Itai Pashtan, Haiyan I. Li, Mikhail Abramov, Mark S. Guyer, Robert Penny, Margi Sheth, Scott L. Carter, Corbin D. Jones, Michael J. Birrer, Julie M. Gastier-Foster, D. Neil Hayes, Nathan Vanhoose, Brenda Rabeno, Raju Kucherlapati, Martin L. Ferguson, Joshua M. Stuart, Steve E. Kalloger, Mark G. Cadungog, Petar Stojanov, Tara M. Lichtenberg, Bradley A. Ozenberger, Angela Hadjipanayis, Barry S. Taylor, Boris Reva, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Park, Peter J.
Subjects: DNA Copy Number Variations, endocrine system diseases, ARID1A, DNA Mutational Analysis, Breast Neoplasms, Biology, medicine.disease_cause, Article, Uterine serous carcinoma, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, PTEN, Exome, Poly-ADP-Ribose Binding Proteins, neoplasms, 030304 developmental biology, Chromosome Aberrations, Ovarian Neoplasms, 0303 health sciences, Endometrial intraepithelial neoplasia, Multidisciplinary, Genome, Human, Microsatellite instability, DNA Polymerase II, Genomics, medicine.disease, Molecular biology, female genital diseases and pregnancy complications, Endometrial Neoplasms, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Serous fluid, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, biology.protein, Female, KRAS, Signal Transduction, Transcription Factors
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., National Institutes of Health (U.S.) (Grant 5U24CA143799-04), National Institutes of Health (U.S.) (Grant 5U24CA143835-04), National Institutes of Health (U.S.) (Grant 5U24CA143840-04), National Institutes of Health (U.S.) (Grant 5U24CA143843-04), National Institutes of Health (U.S.) (Grant 5U24CA143845-04), National Institutes of Health (U.S.) (Grant 5U24CA143848-04), National Institutes of Health (U.S.) (Grant 5U24CA143858-04), National Institutes of Health (U.S.) (Grant 5U24CA143866-04), National Institutes of Health (U.S.) (Grant 5U24CA143867-04), National Institutes of Health (U.S.) (Grant 5U24CA143882-04), National Institutes of Health (U.S.) (Grant 5U24CA143883-04), National Institutes of Health (U.S.) (Grant 5U24CA144025-04), National Institutes of Health (U.S.) (Grant U54HG003067-11), National Institutes of Health (U.S.) (Grant U54HG003079-10), National Institutes of Health (U.S.) (Grant U54HG003273-10)
Published: 2013
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11. Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1

Author: Guillaume Bergthold, Rameen Beroukhim, Michael S. Lawrence, Steven E. Schumacher, Cynthia Hawkins, Gad Getz, Ian F. Dunn, Keith L. Ligon, Azra H. Ligon, Sandro Santagata, Scott L. Pomeroy, Justin M. Craig, D. Ashley Hill, Liliana Goumnerova, Paul Van Hummelen, Peleg M. Horowitz, Priscilla K. Brastianos, Mark W. Kieran, Laura E. MacConaill, Tina Pouissant-Young, Linda R. Margraf, Lori A. Ramkissoon, Jennifer A. Chan, Daniel C. Bowers, Hala Taha, Uri Tabori, Shakti Ramkissoon, Charles G. Eberhart, Benjamin E. Rich, Barbara Tabak, Aaron McKenna, Charles D. Stiles, Madeha Mahmoud, Roger J. Packer, William C. Hahn, Yoon Jae Cho, and Matthew D. Ducar
Subjects: Male, Mice, Nude, Biology, 3T3 cells, Cohort Studies, Mice, Diffuse Astrocytoma, Cell Line, Tumor, Proto-Oncogene Proteins, medicine, Animals, Humans, MYB, Child, Transcription factor, Alleles, Comparative Genomic Hybridization, Multidisciplinary, Brain Neoplasms, Kinase, Breakpoint, Cancer, 3T3 Cells, Glioma, Sequence Analysis, DNA, Biological Sciences, medicine.disease, Protein Structure, Tertiary, medicine.anatomical_structure, Child, Preschool, Multigene Family, Mutation, Trans-Activators, Cancer research, Tandem exon duplication
Abstract: Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but, apart from BRAF kinase mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. We performed high-resolution copy-number analysis on 44 formalin-fixed, paraffin-embedded diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gain, was observed in 28% of diffuse astrocytoma grade IIs and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene v-myb avian myeloblastosis viral oncogene homolog ( MYB ) on 6q23.3. Whole-genome sequencing of a MYBL1 -rearranged diffuse astrocytoma grade II demonstrated MYBL1 tandem duplication and few other events. Truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas.
Published: 2013
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12. High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

Author: Mohan Somasundaran, Yasin Bakis, Javier Gordon Ogembo, Eric R. Weiss, Galit Alter, Jennifer L. Henderson, Manuel Garber, Katherine Luzuriaga, Barbara Tabak, Liisa K. Selin, BAİBÜ, Fen Edebiyat Fakültesi, Biyoloji Bölümü, and Bakış, Yasin
Subjects: 0301 basic medicine, Herpesvirus 4, Human, Antibodies, Viral, medicine.disease_cause, Monocytes, Neutralizing antibody, B-Lymphocytes, Membrane Glycoproteins, ADCP, Viral Load, Interaction with host, Acute Disease, Host-Pathogen Interactions, Antibody, Epstein-Barr Virus, Viral load, Adult, Primary Cell Culture, 030106 microbiology, Immunology, Biology, Microbiology, Antibodies, Viral Matrix Proteins, 03 medical and health sciences, Neutralization, Phagocytosis, Viral envelope, EBV, Viral entry, Cell Line, Tumor, Virology, medicine, Humans, Amino Acid Sequence, Infectious Mononucleosis, Base Sequence, Genetic Variation, Convalescence, Sequence Analysis, DNA, Antibodies, Neutralizing, Epstein–Barr virus, 030104 developmental biology, Viral replication, Case-Control Studies, Immunoglobulin G, Insect Science, Gp350, Chronic Disease, DNA, Viral, biology.protein, Pathogenesis and Immunity, Sequence Alignment
Abstract: The Epstein-Barr virus (EBV) gp350 glycoprotein interacts with the cellular receptor to mediate viral entry and is thought to be the major target for neutralizing antibodies. To better understand the role of EBV-specific antibodies in the control of viral replication and the evolution of sequence diversity, we measured EBV gp350-specific antibody responses and sequenced the gp350 gene in samples obtained from individuals experiencing primary EBV infection (acute infectious mononucleosis [AIM]) and again 6 months later (during convalescence [CONV]). EBV gp350-specific IgG was detected in the sera of 17 (71%) of 24 individuals at the time of AIM and all 24 (100%) individuals during CONV; binding antibody titers increased from AIM through CONV, reaching levels equivalent to those in age-matched, chronically infected individuals. Antibody-dependent cell-mediated phagocytosis (ADCP) was rarely detected during AIM (4 of 24 individuals; 17%) but was commonly detected during CONV (19 of 24 individuals; 79%). The majority (83%) of samples taken during AIM neutralized infection of primary B cells; all samples obtained at 6 months postdiagnosis neutralized EBV infection of cultured and primary target cells. Deep sequencing revealed interpatient gp350 sequence variation but conservation of the CR2-binding site. The levels of gp350-specific neutralizing activity directly correlated with higher peripheral blood EBV DNA levels during AIM and a greater evolution of diversity in gp350 nucleotide sequences from AIM to CONV. In summary, we conclude that the viral load and EBV gp350 diversity during early infection are associated with the development of neutralizing antibody responses following AIM. IMPORTANCE Antibodies against viral surface proteins can blunt the spread of viral infection by coating viral particles, mediating uptake by immune cells, or blocking interaction with host cell receptors, making them a desirable component of a sterilizing vaccine. The EBV surface protein gp350 is a major target for antibodies. We report the detection of EBV gp350-specific antibodies capable of neutralizing EBV infection in vitro . The majority of gp350-directed vaccines focus on glycoproteins from lab-adapted strains, which may poorly reflect primary viral envelope diversity. We report some of the first primary gp350 sequences, noting that the gp350 host receptor binding site is remarkably stable across patients and time. However, changes in overall gene diversity were detectable during infection. Patients with higher peripheral blood viral loads in primary infection and greater changes in viral diversity generated more efficient antibodies. Our findings provide insight into the generation of functional antibodies, necessary for vaccine development.
Published: 2017
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13. Genomic Classification of Cutaneous Melanoma

Author: W. Kimryn Rathmell, Lauren E. Haydu, Nils Gehlenborg, David Mallery, Lynn M. Herbert, Hailei Zhang, Darlene Lee, Payal Sipahimalani, Richard A. Scolyer, Jonathan R. Stretch, Amanda Clarke, Sudha Chudamani, Dirk Schadendorf, Jeffrey Roach, Troy Shelton, Kerwin F. Shannon, Kadir C. Akdemir, Alexander J. Lazar, Lixing Yang, D. Murawa, Jingchun Zhu, Michael Mayo, Steven E. Schumacher, Marc Ladanyi, Yiling Lu, Levi A. Garraway, Andrew J. Spillane, Giandomenico Russo, Ian R. Watson, Matthew D. Wilkerson, Mei Huang, Chang Jiun Wu, Pedamallu Chandra Sekhar, Laura Brockway-Lunardi, Wiktoria Maria Suchorska, Michael A. Davies, John M. S. Bartlett, Benjamin Gross, Mark Gerken, Georgy Manikhas, William R. Jeck, Michael Dinikin, Sam Ng, Antje Sucker, Sharon K. Huang, Donghui Tan, Semin Lee, Da Yang, Yardena Samuels, Boris C. Bastian, Katherine A. Hoadley, Kenna R. Mills Shaw, Shaowu Meng, Kunal Rai, Sheila Fisher, Tom Bodenheimer, Robyn P. M. Saw, Joel S. Parker, Victoria Fulidou, Scot Waring, Vesteinn Thorsson, Jacqueline E. Schein, Heidi J. Sofia, Jia Liu, Eric S. Lander, Martin L. Miller, Scott E. Woodman, Yunhu Wan, Olga Voronina, Brenda Ayala, Moiz S. Bootwalla, Rileen Sinha, Yonathan Lissanu Deribe, Yussanne Ma, Gabriel Sica, Matthew Ibbs, Pam Bartlett, Arkadiusz Spychała, Sheila Reynolds, Nikolaus Schultz, Jianhua Zhang, Stephen B. Baylin, Saianand Balu, Jay Bowen, Eran Hodis, Olga Potapova, Lori Boice, Julie M. Gastier-Foster, Singer Ma, Victor G. Prieto, Steven J.M. Jones, Konstantin V. Fedosenko, Rehan Akbani, Todd Pihl, Ruibin Xi, Stergios J. Moschos, Lisa Iype, Robert Penny, Vonn Walter, Peter Hersey, Umadevi Veluvolu, Jiabin Tang, Mark A. Jensen, Aaron Chevalier, Nils Weinhold, Yaron S.N. Butterfield, S. Onur Sumer, Lisle E. Mose, Leslie Cope, Angela Tam, Carmelo Gaudioso, Giovanni Ciriello, Jaegil Kim, Noreen Dhalla, Candace Shelton, Andrzej Mackiewicz, Travis I. Zack, James G. Herman, Lisa Zimmer, Chia Chin Wu, Elena Pagani, Franklin W. Huang, Tanja Davidsen, Stuart R. Jefferys, Andy Chu, Harmanjatinder S. Sekhon, Richard A. Moore, Scott L. Carter, Ludmila Danilova, Peter W. Laird, Nicholas K. Hayward, Julien Baboud, A. Gordon Robertson, Scott Morris, Honorata Tatka, Gordon Saksena, Robert A. Holt, Angela Hadjipanayis, Jakub Brzezinski, Lihua Zou, Nilsa C. Ramirez, Witold Kycler, Yasin Senbabaoglu, Xingzhi Song, Barbara Tabak, Christopher C. Benz, Michael Dubina, Wei Zhang, Sophie Egea, Fedor Moiseenko, Marcus Bosenberg, Piotr A. Mieczkowski, Michael J. Quinn, Harindra Arachchi, Andrew J. Mungall, Lynn Cherney, Suresh Ramalingam, Christopher A. Bristow, Hojabr Kakavand, Chris Sander, Peiling Tsou, Anil Korkut, Alan P. Hoyle, Arshi Arora, Kenneth K. Lee, Netty Santoso, Raymond J. Cho, Ricardo Ramirez, Melissa Saul, Haiyan I. Li, Jeremy Parfitt, Valerie Jakrot, Tiffany L. Calderone, Jessica Frick, John N. Weinstein, Brady Bernard, John M. Kirkwood, Dave S.B. Hoon, Carolyn J. Shiau, Carmen Gomez-Fernandez, Michael Krauthammer, Carrie Sougnez, George E. Sandusky, Xiaojia Ren, Charles Schwallier, Carolyn M. Hutter, Radoslaw Łaźniak, Dmitry Belyaev, Richard F. Kefford, Jeffrey M. Trent, Ouida Liu, J. Stephen Ebrom, Yoon La Choi, Maciej Wiznerowicz, Ranabir Guin, Yan Shi, Ewa Leporowska, Zhenlin Ju, Charles Saller, Hyojin Kang, Jean C. Zenklusen, Tony Gutschner, Peter White, Luigi Nezi, Oxana Paklina, Harshad S. Mahadeshwar, Wiam Bshara, Roeland Verhaak, Kenneth Y. Tsai, Ilya Shmulevich, Kristian Cibulskis, Jonathan G. Seidman, Corbin D. Jones, Ayush T. Raman, D. Neil Hayes, Nandita Barnabas, Uma Rao, Jennifer Eschbacher, Timothy R. Fennell, Jeffrey E. Lee, Matthew Meyerson, Jeffrey E. Gershenwald, Elizabeth Buda, Xiaobei Zhao, Jason Roszik, M. Teresiak, Daniel DiCara, Pei Lin, Eliezer M. Van Allen, Scott Frazer, Genevieve M. Boland, Zhining Wang, Susan Hoppough, Konstanty Korski, Michael S. Noble, B. Arman Aksoy, Reanne Bowlby, Adeboye Osunkoya, Taofeek K. Owonikoko, Madhusmita Behera, Shiyun Ling, Erin Curley, Rajiv Dhir, Andrew Wei Xu, David I. Heiman, Samirkumar B. Amin, Andrew D. Cherniack, Brenna Matejka, Rameen Beroukhim, Michael S. Lawrence, Kelsey Zhu, Wen-Bin Liu, Stacey Gabriel, Martin L. Ferguson, Samantha Sharpe, Giannicola Genovese, Jay Engel, Johanna Gardner, Junyuan Wu, Marco A. Marra, Roy Tarnuzzer, John F. Thompson, Denise Brooks, Lawrence N. Kwong, Woong-Yang Park, Daniel J. Weisenberger, J. Todd Auman, Kristen M. Leraas, Margi Sheth, Riccardo Bono, John A. Demchok, Stefania D'Atri, Candace D. Carter, Miruna Balasundaram, Natalie Bir, Matthew G. Soloway, Angeliki Pantazi, Sahil Seth, Qixia A. Deng, Junehawk Lee, Dana Nicholson, Ye Wu, Keith T. Flaherty, Peter J. Park, Amie Radenbaugh, Benjamin Hanf, Katherine Tarvin, James S. Wilmott, Giancarlo Antonini Cappellini, Pawel Murawa, Maria Synott, Jonna Grimsby, Stephen Coons, Joachim Klode, Michael Button, Alyssa Janning, Alexei Protopopov, Florian L. Muller, Donald L. Morton, Joshua M. Stuart, Ina Felau, Cindy Sander, Ruth Halaban, John P. Miller, David Haussler, Monique Albert, Charles M. Perou, Timothy J. Triche, Yichao Sun, Aaron D. Black, Adrian Ally, Sousan Mehrabi, David Van Den Berg, Graham J. Mann, Erik Zmuda, Carl Morrison, Daniel Crain, Douglas Voet, Janae V. Simons, Norman E. Sharpless, Fadlo R. Khuri, Phillip H. Lai, Liming Yang, Anders Jacobsen, Keith A. Delman, Teresa R. Tabler, Gad Getz, Tara M. Lichtenberg, William Lee, Georgina V. Long, Nina Thiessen, Ronglai Shen, Francesca Passarelli, Bradley A. Ozenberger, Gordon B. Mills, Jessica Walton, Greg Eley, Leigh B. Thorne, Merrick I. Ross, Jared Malke, Barry S. Taylor, Juok Cho, William R. Burns, Michael Parfenov, Thomas Gribbin, Yuling Wang, Raju Kucherlapati, Lynda Chin, Bradley A. Murray, Lee Lichtenstein, Jianjiong Gao, and Lisa Wise
Subjects: Skin Neoplasms, Mutant, Medizin, Biology, General Biochemistry, Genetics and Molecular Biology, Subclass, Article, Transcriptome, chemistry.chemical_compound, Databases, Genetic, medicine, Humans, Gene, Melanoma, Genetics, Biochemistry, Genetics and Molecular Biology(all), Cancer, Binimetinib, medicine.disease, National Cancer Institute (U.S.), United States, 3. Good health, chemistry, Cutaneous melanoma, Mutation, Cancer research
Abstract: Summary We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF , mutant RAS , mutant NF1 , and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.
Published: 2015

14. Comparative Analysis of Immune Cells Reveals a Conserved Regulatory Lexicon

Author: William E. Diehl, Sean M. McCauley, Patrick McDonel, Jeremy Luban, Manuel Garber, Anetta Nowosielska, Alper Kucukural, Nir Yosef, Pranitha Vangala, Xiaopeng Zhu, Shaked Afik, Barbara Tabak, and Elisa Donnard
Subjects: Male, 0301 basic medicine, Histology, Computational biology, Biology, Article, Epigenesis, Genetic, Pathology and Forensic Medicine, Evolution, Molecular, Mice, 03 medical and health sciences, Gene expression, Animals, Humans, Epigenetics, Enhancer, Gene, Conserved Sequence, Regulation of gene expression, Comparative genomics, Innate immune system, Toll-Like Receptors, Genomics, Cell Biology, Immunity, Innate, Mice, Inbred C57BL, Enhancer Elements, Genetic, 030104 developmental biology, Gene Expression Regulation, Female, Sequence motif
Abstract: Summary Most well-characterized enhancers are deeply conserved. In contrast, genome-wide comparative studies of steady-state systems showed that only a small fraction of active enhancers are conserved. To better understand conservation of enhancer activity, we used a comparative genomics approach that integrates temporal expression and epigenetic profiles in an innate immune system. We found that gene expression programs diverge among mildly induced genes, while being highly conserved for strongly induced genes. The fraction of conserved enhancers varies greatly across gene expression programs, with induced genes and early-response genes, in particular, being regulated by a higher fraction of conserved enhancers. Clustering of conserved accessible DNA sequences within enhancers resulted in over 60 sequence motifs including motifs for known factors, as well as many with unknown function. We further show that the number of instances of these motifs is a strong predictor of the responsiveness of a gene to pathogen detection.
Published: 2018
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15. Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype

Author: Yujin Hoshida, Ruben Ferrer-Luna, Benjamin E. Rich, Pratiti Bandopadhayay, Todd R. Golub, Shakti H. Ramkissoon, Lori A. Ramkissoon, Rosalind A. Segal, Mark W. Kieran, Guillaume Bergthold, Jennifer A. Chan, Steven E. Schumacher, Cecile L. Maire, Patrick Y. Wen, Charles D. Stiles, Aydin Sav, M. Memet Özek, Azra H. Ligon, Jacques Grill, Liliana Goumnerova, Barbara Tabak, Brenton R. Paolella, Rameen Beroukhim, Keith L. Ligon, Sandro Santagata, and Acibadem University Dspace
Subjects: Male, Cancer Research, Pathology, medicine.medical_specialty, Adolescent, Biology, pediatric low-grade glioma, Transcriptome, Glioma, expression, medicine, Cluster Analysis, Humans, Child, In Situ Hybridization, Fluorescence, Oligonucleotide Array Sequence Analysis, BRAF duplication, Neoplasm Grading, Pilocytic astrocytoma, Brain Neoplasms, Gene Expression Profiling, Not Otherwise Specified, Infant, Newborn, Infant, Histology, medicine.disease, Immunohistochemistry, Gene expression profiling, BRAF mutation, Oncology, Child, Preschool, Basic and Translational Investigations, Female, Neurology (clinical), heterogeneity
Abstract: Pediatric low-grade gliomas (PLGGs), the most frequent pediatric brain tumor, comprise a heterogeneous group of diseases. Recent genomic analyses suggest that these tumors are mostly driven by mitogene-activated protein kinase (MAPK) pathway alterations. However, little is known about the molecular characteristics inherent to their clinical and histological heterogeneity. We performed gene expression profiling on 151 paraffin-embedded PLGGs from different locations, ages, and histologies. Using unsupervised and supervised analyses, we compared molecular features with age, location, histology, and BRAF genomic status. We compared molecular differences with normal pediatric brain expression profiles to observe whether those patterns were mirrored in normal brain. Unsupervised clustering distinguished 3 molecular groups that correlated with location in the brain and histological subtype. ``Not otherwise specified{''} (NOS) tumors did not constitute a unified class. Supratentorial pilocytic astrocytomas (PAs) were significantly enriched with genes involved in pathways related to inflammatory activity compared with infratentorial tumors. Differences based on tumor location were not mirrored in location-dependent differences in expression within normal brain tissue. We identified significant differences between supratentorial PAs and diffuse astrocytomas as well as between supratentorial PAs and dysembryoplastic neuroepithelial tumors but not between supratentorial PAs and gangliogliomas. Similar expression patterns were observed between childhood and adolescent PAs. We identified differences between BRAF-duplicated and V600E-mutated tumors but not between primary and recurrent PLGGs. Expression profiling of PLGGs reveals significant differences associated with tumor location, histology, and BRAF genomic status. Supratentorial PAs, in particular, are enriched in inflammatory pathways that appear to be tumor-related.
Published: 2015
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16. Functional annotation of native enhancers with a Cas9-histone demethylase fusion

Author: Noah J. Silverstein, Nicola A. Kearns, Barbara Tabak, Manuel Garber, René Maehr, Hannah Pham, and Ryan M.J. Genga
Subjects: Enhancer RNAs, Computational biology, Biology, Neisseria meningitidis, Biochemistry, Article, Gene Expression Regulation, Enzymologic, Histones, Mice, Bacterial Proteins, Genes, Reporter, Epigenome editing, Animals, Epigenetics, Enhancer, Molecular Biology, Cells, Cultured, Embryonic Stem Cells, Genetics, Histone Demethylases, Cas9, Gene targeting, Cell Biology, Caspase 9, Recombinant Proteins, Histone, Enhancer Elements, Genetic, biology.protein, Demethylase, Biotechnology
Abstract: Understanding of mammalian enhancer function is limited by the lack of a technology to rapidly and thoroughly test their cell type-specific function. Here, we use a nuclease-deficient (d)Cas9 histone demethylase fusion to functionally characterize previously described and novel enhancer elements for their roles in the embryonic stem cell state. Further, we distinguish the mechanism of action of dCas9-LSD1 at enhancers from previous dCas9-effectors.
Published: 2014

17. The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

Author: Caleb F. Davis, Christopher J. Ricketts, Min Wang, Lixing Yang, Andrew D. Cherniack, Hui Shen, Christian Buhay, Hyojin Kang, Sang Cheol Kim, Catherine C. Fahey, Kathryn E. Hacker, Gyan Bhanot, Dmitry A. Gordenin, Andy Chu, Preethi H. Gunaratne, Michael Biehl, Sahil Seth, Benny A. Kaipparettu, Christopher A. Bristow, Lawrence A. Donehower, Eric M. Wallen, Angela B. Smith, Satish K. Tickoo, Pheroze Tamboli, Victor Reuter, Laura S. Schmidt, James J. Hsieh, Toni K. Choueiri, A. Ari Hakimi, Lynda Chin, Matthew Meyerson, Raju Kucherlapati, Woong-Yang Park, A. Gordon Robertson, Peter W. Laird, Elizabeth P. Henske, David J. Kwiatkowski, Peter J. Park, Margaret Morgan, Brian Shuch, Donna Muzny, David A. Wheeler, W. Marston Linehan, Richard A. Gibbs, W. Kimryn Rathmell, Chad J. Creighton, Sabina Signoretti, Christopher Ricketts, Michael Seiler, Hsu Chao, Mike Dahdouli, Liu Xi, Nipun Kakkar, Jeffrey G. Reid, Brittany Downs, Jennifer Drummond, Donna Morton, Harsha Doddapaneni, Lora Lewis, Adam English, Qingchang Meng, Christie Kovar, Qiaoyan Wang, Walker Hale, Alicia Hawes, Divya Kalra, Kimberly Walker, Bradley A. Murray, Carrie Sougnez, Gordon Saksena, Scott L. Carter, Steven E. Schumacher, Barbara Tabak, Travis I. Zack, Gad Getz, Rameen Beroukhim, Stacey B. Gabriel, Adrian Ally, Miruna Balasundaram, Inanc Birol, Denise Brooks, Yaron S.N. Butterfield, Eric Chuah, Amanda Clarke, Noreen Dhalla, Ranabir Guin, Robert A. Holt, Katayoon Kasaian, Darlene Lee, Haiyan I. Li, Emilia Lim, Yussanne Ma, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Tina Wong, Steven J.M. Jones, Marco A. Marra, J. Todd Auman, Donghui Tan, Shaowu Meng, Corbin D. Jones, Katherine A. Hoadley, Piotr A. Mieczkowski, Lisle E. Mose, Stuart R. Jefferys, Jeffrey Roach, Umadevi Veluvolu, Matthew D. Wilkerson, Scot Waring, Elizabeth Buda, Junyuan Wu, Tom Bodenheimer, Alan P. Hoyle, Janae V. Simons, Mathew G. Soloway, Saianand Balu, Joel S. Parker, D. Neil Hayes, Charles M. Perou, Daniel J. Weisenberger, Moiz S. Bootwalla, Timothy Triche, Phillip H. Lai, David J. Van Den Berg, Stephen B. Baylin, Fengju Chen, Cristian Coarfa, Michael S. Noble, Daniel DiCara, Hailei Zhang, Juok Cho, David I. Heiman, Nils Gehlenborg, Doug Voet, Pei Lin, Scott Frazer, Petar Stojanov, Yingchun Liu, Lihua Zou, Jaegil Kim, Michael S. Lawrence, Alexei Protopopov, Xingzhi Song, Jianhua Zhang, Angeliki Pantazi, Angela Hadjipanayis, Eunjung Lee, Lovelace J. Luquette, Semin Lee, Michael Parfenov, Netty Santoso, Jonathan Seidman, Andrew W. Xu, Junehawk Lee, Steven A. Roberts, Leszek J. Klimczak, David Fargo, Martin Lang, Yoon-La Choi, June-Koo Lee, Wenyi Wang, Yu Fan, Jaeil Ahn, Rehan Akbani, John N. Weinstein, David Haussler, Singer Ma, Amie Radenbaugh, Jingchun Zhul, Tara M. Lichtenberg, Erik Zmuda, Aaron D. Black, Benjamin Hanf, Nilsa C. Ramirez, Lisa Wise, Jay Bowen, Kristen M. Leraas, Tracy M. Hall, Julie M. Gastier-Foster, William G. Kaelin, Leigh Thorne, Lori Boice, Mei Huang, Cathy Vocke, James Peterson, Robert Worrell, Maria Merino, Bogdan A. Czerniak, Kenneth D. Aldape, Christopher G. Wood, Paul T. Spellman, Michael B. Atkins, John Cheville, R. Houston Thompson, Mark A. Jensen, Todd Pihl, Yunhu Wan, Brenda Ayala, Julien Baboud, Sudhakar Velaga, Jessica Walton, Jia Liu, Sudha Chudamani, Ye Wu, Margi Sheth, Kenna R. Mills Shaw, John A. Demchok, Tanja Davidsen, Liming Yang, Zhining Wang, Roy W. Tarnuzzer, Jiashan Zhang, Greg Eley, Ina Felau, Jean Claude Zenklusen, Carolyn M. Hutter, Mark S. Guyer, Bradley A. Ozenberger, Heidi J. Sofia, and Intelligent Systems
Subjects: Mitochondrial DNA, Cancer Research, DNA Copy Number Variations, Somatic cell, Chromophobe Renal Cell Carcinoma, DNA Mutational Analysis, Molecular Sequence Data, Chromophobe cell, Biology, DNA, Mitochondrial, Article, Chromosome Breakpoints, Chromosomes, Human, Humans, Exome, Promoter Regions, Genetic, Carcinoma, Renal Cell, Telomerase, Genetics, Base Sequence, Genome, Human, Point mutation, Cell Biology, DNA Methylation, Kidney Neoplasms, Oncology, Kataegis, DNA methylation, Chromosome Deletion, Transcriptome
Abstract: We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) based on multidimensional and comprehensive characterization, including mitochondrial DNA (mtDNA) and whole genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared to other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT up-regulation in cancer distinct from previously-observed amplifications and point mutations.
Published: 2014

18. 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
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19. HIV type 1 (HIV-1) proviral reservoirs decay continuously under sustained virologic control in HIV-1-infected children who received early treatment

Author: Carrie Ziemniak, Margaret M. McManus, Manuel Garber, Danielle Murray, Katherine Luzuriaga, Matthew C. Strain, Deborah Persaud, Coleen K. Cunningham, Tae Wook Chun, Barbara Tabak, Douglas D. Richman, and Ya Hui Chen
Subjects: Male, Pediatric AIDS, HIV Infections, Medical and Health Sciences, Cohort Studies, Proviruses, Antiretroviral Therapy, Highly Active, Leukocytes, Secondary Prevention, Immunology and Allergy, Medicine, Child, proviral reservoirs, Pediatric, Transmission (medicine), virus diseases, Biological Sciences, Viral Load, Infectious Diseases, Treatment Outcome, Anti-Retroviral Agents, Child, Preschool, Cohort, HIV/AIDS, Female, Infection, Viral load, Cohort study, Cart, Adolescent, Mononuclear, Antiretroviral Therapy, Viral quasispecies, Early Therapy, reduced HIV reservoirs, Microbiology, Vaccine Related, Major Articles and Brief Reports, Clinical Research, Humans, Highly Active, Preschool, business.industry, Infant, Newborn, Infant, Newborn, Virology, Viral replication, continuous HIV-1 decay, HIV-1, Leukocytes, Mononuclear, prolonged viral suppression, early antiretroviral therapy, business
Abstract: (See the editorial commentary by Li and Gandhi on pages 1519–22.) Mother-to-child transmission (MTCT) remains the primary mode of pediatric human immunodeficiency virus type 1 (HIV-1) infection. Antiretroviral prophylaxis and maternal antiretroviral therapy (ART) have decreased MTCT, but >260 000 new pediatric infections occur globally each year [1]. Perinatally infected children experience more-rapid disease progression than adults [2, 3]. In limited-resource settings, one half of perinatally infected children die by their second birthday, while 75% die by their third birthday [4]. The initiation of combination antiretroviral therapy (cART) within the first several months of life effectively controls HIV-1 replication, preserves immune function [5–8], and markedly reduces HIV-1–related mortality [9]. Early diagnosis of HIV-1 infection with prompt initiation of cART in HIV-1–infected infants is thus recommended globally [10, 11]. Available data suggest that early therapy limits replication-competent HIV-1 reservoirs [12] and HIV-1 quasispecies diversity [13]. However, latently infected, resting CD4+ T cells carrying replication-competent HIV-1 remain detectable in most children (80%) studied up to 5 years following early initiation of therapy [13]. As a result, lifelong therapy, which is expensive and potentially toxic, is currently recommended. Because larger numbers of children access early cART and highly sensitive techniques to characterize and measure HIV-1 reservoirs have evolved, we have begun to use these techniques to characterize HIV-1 reservoirs in children undergoing durable suppression of virus replication following early cART. Here, we report long-term follow-up of a small cohort of perinatally infected youth aged 14–18 years who initiated cART between 2 and 11 weeks of age and who have maintained suppression of plasma HIV-1 RNA to below the limits of detection of clinical assays for up to 18 years following cART initiation.
Published: 2014
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20. The Cancer Genome Atlas Pan-Cancer analysis project

Author: Qunyuan Zhang, B. Arman Aksoy, Fabio Vandin, Eric A. Collisson, Larsson Omberg, S. Onur Sumer, John A. Demchok, Sven Nelander, Vladislav Uzunangelov, Michael C. Wendl, Roger Kramer, John W. Wallis, Brian Craft, Angeliki Pantazi, Leng Han, W. K. Alfred Yung, Brad Ozenberger, Philip L. Lorenzi, James G. Herman, Andy Chu, Sahil Seth, Richard A. Gibbs, Angela Hadjipanayis, Hector Rovira, Peter W. Laird, Inanc Birol, Richard K. Wilson, James Cleland, Peter J. Park, Jiashan Zhang, Payal Sipahimalani, Stanley R. Hamilton, Liming Yang, Seth Lerner, Amie Radenbaugh, Barry S. Taylor, Carrie Hirst, David Tamborero, Stephen B. Baylin, Gad Getz, Tanja Davidsen, Miruna Balasundaram, Cheng Fan, Yuan Yuan, Kristian Cibulskis, Yan Shi, Angela Tam, Divya Kalra, Chris Sander, Scott Abbott, Catrina Fronick, Margi Sheth, Chip Stewart, Angela N. Brooks, Noreen Dhalla, Lam Nguyen, Hui Shen, Travis I. Zack, Andrew J. Mungall, Artem Sokolov, Douglas A. Levine, Carrie Sougnez, Paul T. Spellman, Greg Eley, Deepti Dodda, Wenbin Liu, Michael B. Ryan, Liu Xi, Aaron D. Black, Rong Yao, Saianand Balu, Benjamin P. Berman, Raju Kucherlapati, James M. Melott, Xingzhi Song, Boris Reva, Huyen Dinh, David A. Pot, Michael D. McLellan, Kjong-Van Lehmann, Wenyi Wang, Petar Stojanov, Bradley McIntosh Broom, Timothy J. Ley, Da Yang, Mary Elizabeth Edgerton, Houtan Noushmehr, Mathew G. Soloway, Nina Thiessen, Zhenlin Ju, Mark D.M. Leiserson, Michael Parfenov, Laura van 't Veer, Scott L. Carter, Ludmila Danilova, Adrian Ally, Hailei Zhang, Ina Felau, Carmen Helsel, Kenneth Aldape, Teresia Kling, Charles Lu, Psalm Haseley, A. Gordon Robertson, Andrew Wei Xu, Jessica Frick, Benjamin Gross, Louis M. Staudt, Craig Pohl, Dimitris Anastassiou, Netty Santoso, Donna Muzny, Chad J. Creighton, Donghui Tan, Ryan Bressler, Andrew J. Wong, Barbara Tabak, Yasin Senbabaoglu, Daniel C. Koboldt, Darlene Lee, Doug Voet, Joonil Jung, Hollie A. Harper, Jianhua Zhang, Kyle Chang, Wei Zhao, Marc Ladanyi, Lisa Iype, Ricardo Ramirez, Ami S. Bhatt, Lisle E. Mose, Singer Ma, Abel Gonzalez-Perez, Jonathan G. Seidman, Kosuke Yoshihara, Denise M. Wolf, Corbin D. Jones, Patrik Johansson, Siyuan Zheng, André Kahles, Stacey Gabriel, John N. Weinstein, Han Liang, Samantha Sharpe, Steven E. Schumacher, Matthew Meyerson, D. Neil Hayes, David Haussler, Krishna L. Kanchi, Julie M. Gastier-Foster, Umadevi Veluvolu, Ari B. Kahn, Brady Bernard, Tod D. Casasent, Christopher A. Bristow, Akinyemi I. Ojesina, Sam Ng, Charles M. Perou, Moiz S. Bootwalla, Cyriac Kandoth, Lixing Yang, Joel S. Parker, Alan P. Hoyle, Timothy J. Triche, Dong Zeng, Sean E. McGuire, Christie Kovar, Kim D. Delehaunty, Juok Cho, Alexei Protopopov, Shaowu Meng, Ling Lin, Heather Schmidt, Nils Gehlenborg, Yuexin Liu, Elaine R. Mardis, Martin L. Miller, Jake Lin, Jason Walker, Lisa Wise, Suzanne S. Fei, Jacqueline E. Schein, Semin Lee, Christina Yau, Melisssa Cline, Tara M. Lichtenberg, David I. Heiman, Scot Waring, Richard A. Moore, Margaret B. Morgan, Robert S. Fulton, David E. Larson, Xiaoping Su, Kalle Leinonen, Samirkumar B. Amin, Joshua M. Stuart, J. Todd Auman, Rebecka Jörnsten, Rileen Sinha, Andrew D. Cherniack, Caleb F. Davis, Stephen J. Chanock, Nathan D. Dees, Adam Margolin, Haiyan I. Li, Yaron S.N. Butterfield, Daniel E. Carlin, Tai Hsien Ou Yang, Rameen Beroukhim, Vincent Magrini, Mark P. Hamilton, Grace O. Silva, Nils Weinhold, Harshad S. Mahadeshwar, Michael S. Lawrence, Eric Chuah, Jun Li, Wei Li, Robert A. Burton, Teresa M. Przytycka, Katherine A. Hoadley, Keith A. Baggerly, Sheila M. Reynolds, Daniel DiCara, Tom Bodenheimer, Charles J. Vaske, James M. Eldred, Richard Varhol, Mark A. Jensen, David W. Kane, Xiaojia Ren, Christopher A. Miller, Elizabeth Buda, Li Ding, Michael Mayo, Hsin-Ta Wu, Joelle Kalicki-Veizer, Shelley M. Herbrich, Eunjung Lee, Yingchun Liu, Joshua F. McMichael, Jennifer Drummond, Teresa Swatloski, Harshavardhan Doddapaneni, William Lee, Daniel J. Weisenberger, David A. Wheeler, Chia Chin Wu, Richard Kreisberg, Roeland Verhaak, Elena Helman, Piotr A. Mieczkowski, Mary Goldman, Ilya Shmulevich, Nikolaus Schultz, Min Wang, Lovelace J. Luquette, Marco A. Marra, Todd Pihl, Roy Tarnuzzer, Ronglai Shen, Donna Morton, Yichao Sun, Lawrence A. Donehower, Jun Yao, Theo A. Knijnenburg, Benjamin J. Raphael, Lora Lewis, Peter Waltman, Andrea Eakin, Martin Hirst, Jaegil Kim, Lihua Zou, Ranabir Guin, Yi Han, Scott M. Smith, Hoon Kim, Kristen M. Leraas, Heidi J. Sofia, Erik Zmuda, Matthew D. Wilkerson, Michelle O'Laughlin, Jianjiong Gao, Jeffrey G. Reid, Jing Zhu, Toshinori Hinoue, Gunnar Rätsch, Hye Jung E. Chun, Anders Jacobsen, Stephen C. Benz, Kenna R. Mills Shaw, Gordon B. Mills, Zhining Wang, Cynthia McAllister, Michael S. Noble, Christopher C. Benz, Rehan Akbani, Ruibin Xi, Nianxiang Zhang, Jay Bowen, Wei Zhang, Chandra Sekhar Pedamallu, Eric S. Lander, Yunhu Wan, David J. Dooling, Dong Yeon Cho, Preethi Gunaratne, Todd Wylie, Pei Lin, Chang-Jiun Wu, Jeffrey Roach, Scott Frazer, Samuel S. Freeman, Rachel Abbott, Zheng Xia, Lucinda Fulton, Kyle Ellrott, Nuria Lopez-Bigas, Yang Yang, Michael Miller, Nilsa C. Ramirez, Evan O. Paull, Janae V. Simons, Junyuan Wu, Lynda Chin, Gordon Saksena, Jiabin Tang, Vesteinn Thorsson, Robert A. Holt, Suhn K. Rhie, Steven J.M. Jones, Stuart R. Jeffreys, Giovanni Ciriello, Sofie R. Salama, Gideon Dresdner, Yiling Lu, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Park, Peter J.
Subjects: Genetics, medicine.medical_specialty, Genome, Gene Expression Profiling, Genomics, Computational biology, Biology, Humans, Neoplasms, Article, Analysis Project, Gene expression profiling, GENÉTICA MOLECULAR, Cancer genome, Genomic Profile, medicine, Medical genetics, Epigenetics
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., National Cancer Institute (U.S.), National Human Genome Research Institute (U.S.)
Published: 2013

21. Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities

Author: Silvia Buonamici, Yu Sun, Shakti Ramkissoon, Jarom Chung, Maria F. Pazyra-Murphy, Yanping Sun, Ekaterina Pak, Matthew A. Theisen, David S. Shulman, Keith L. Ligon, Joseph Kelleher, Mariella G. Filbin, Rameen Beroukhim, Jean J. Zhao, Marion Dorsch, Rosalind A. Segal, Barbara Tabak, Qi Wang, Andrew L. Kung, Sukriti K. Dabral, Yoko Franchetti, and Navid Redjal
Subjects: Pyridines, Morpholines, Aminopyridines, Mice, Nude, CNS cancer, PI3K signaling, General Biochemistry, Genetics and Molecular Biology, Article, Mice, Phosphatidylinositol 3-Kinases, In vivo, Cell Line, Tumor, medicine, PTEN, Animals, Humans, Hedgehog Proteins, Enzyme Inhibitors, Phosphoinositide-3 Kinase Inhibitors, biology, Brain Neoplasms, Ribosomal Protein S6 Kinases, Biphenyl Compounds, PTEN Phosphohydrolase, General Medicine, Human brain, medicine.disease, Xenograft Model Antitumor Assays, medicine.anatomical_structure, Immunology, biology.protein, Cancer research, Glioblastoma, Signal Transduction
Abstract: In glioblastoma, phosphatidylinositol 3-kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN). However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. We interrogated large databases and found that sonic hedgehog (SHH) signaling is activated in PTEN-deficient glioblastoma. We demonstrate that the SHH and PI3K pathways synergize to promote tumor growth and viability in human PTEN-deficient glioblastomas. A combination of PI3K and SHH signaling inhibitors not only suppressed the activation of both pathways but also abrogated S6 kinase (S6K) signaling. Accordingly, targeting both pathways simultaneously resulted in mitotic catastrophe and tumor apoptosis and markedly reduced the growth of PTEN-deficient glioblastomas in vitro and in vivo. The drugs tested here appear to be safe in humans; therefore, this combination may provide a new targeted treatment for glioblastoma.
Published: 2013

22. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes

Author: Augusto Villanueva, Manel Solé, Josep M. Llovet, Sasan Roayaie, Brandy Klotzle, Myron Schwartz, Clara Alsinet, Barbara Tabak, Daniela Sia, Victoria Tovar, Yujin Hoshida, Jian-Bing Fan, Joana Ferrer, Swan N. Thung, Samuel Waxman, Helena Cornella, Jordi Bruix, Juan Carlos García-Valdecasas, Vincenzo Mazzaferro, Rameen Beroukhim, Christian Cotsoglou, Josep Fuster, and Judit Peix
Subjects: Male, DNA Copy Number Variations, Databases, Factual, DNA Mutational Analysis, Human leukocyte antigen, Kaplan-Meier Estimate, Biology, medicine.disease_cause, Article, Cholangiocarcinoma, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Gene, Intrahepatic Cholangiocarcinoma, In Situ Hybridization, 030304 developmental biology, Aged, Retrospective Studies, Genetics, Regulation of gene expression, 0303 health sciences, Hepatology, Gene Expression Profiling, Biopsy, Needle, Liver Neoplasms, Gastroenterology, Middle Aged, medicine.disease, Prognosis, Immunohistochemistry, Survival Analysis, 3. Good health, Gene expression profiling, Gene Expression Regulation, Neoplastic, Bile Ducts, Intrahepatic, Bile Duct Neoplasms, 030220 oncology & carcinogenesis, Cancer research, Disease Progression, Female, KRAS, Liver cancer
Abstract: Background & Aims Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma. We performed an integrative genomic analysis of ICC samples from a large series of patients. Methods We performed a gene expression profile, high-density single-nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinicopathologic traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations were identified by Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC). Results We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. Copy number variation–based clustering was able to refine these molecular groups further. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class ( P Conclusions We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, activation of oncogenic pathways, and is associated with worse outcome. Different classes of ICC, based on molecular features, therefore might require different treatment approaches.
Published: 2012

23. Comprehensive genomic characterization of squamous cell lung cancers

Author: Charles J. Vaske, Ying Du, Theodore C. Goldstein, Ping Yang, Yufeng Liu, Bryan Hernandez, Daniel R. Zerbino, Kenneth H. Buetow, Khurram Z. Khan, Semin Lee, Martin Peifer, Kristin G. Ardlie, James G. Herman, Sanja Dacic, Ashley Hill, Christopher Szeto, Jianjiong Gao, Singer Ma, Peng Chieh Chen, Carl F. Schaefer, David G. Beer, Kerstin David, Brent W. Zanke, Karen Mungall, Beverly Lee, Daniel DiCara, Kristen Rogers, Rui Jing, Christina Liquori, Carrie Sougnez, Ron Bose, Brian O'Connor, Piotr A. Mieczkowski, Scott L. Carter, Andy Chu, Peter W. Laird, David J. Kwiatkowski, R. Craig Cason, Marie Christine Aubry, Rileen Sinha, Dennis T. Maglinte, Chad J. Creighton, Howard H. Sussman, Jill M. Siegfried, Laura A.L. Dillon, Agnes Viale, Marco A. Marra, Stephen E. Schumacher, Dennis A. Wigle, Yongjun Zhao, Robert C. Onofrio, Heidi J. Sofia, Ranabir Guin, Lori Boice, Ling Li, Mark Backus, Pei Lin, Prachi Kothiyal, Jan F. Prins, Lauren Averett Byers, Haiyan I. Li, An He, Ka Ming Nip, Chang-Jiun Wu, Peter Dolina, James A. Robinson, Saianand Balu, Collisson E, Jinze Liu, Nicholas D. Socci, Erin Pleasance, Joan Pontius, Christina Yau, Eric E. Snyder, Shaowu Meng, Mei Huang, Aaron McKenna, Corbin D. Jones, Carl Morrison, Malcolm V. Brock, Chris Wakefield, Jared R. Slobodan, Ethan Cerami, Angela Tam, Jane Peterson, Michael D. Topal, Jacob M. Kaufman, Elena Helman, Richard T. Cheney, Dominik Stoll, Cristiane M. Ida, Dante Trusty, Peter S. Hammerman, Yevgeniy Antipin, D. Neil Hayes, Anders Jacobsen, Anna K. Unruh, Noreen Dhalla, Candace Shelton, Peter Waltman, Chris Sander, Zhining Wang, Derek Y. Chiang, Elizabeth J. Thomson, Vonn Walter, JoEllen Weaver, Elena Nemirovich-Danchenko, Jacqueline E. Schein, Bradley M. Broom, Sandra C. Tomaszek, Peter A. Kigonya, Tod D. Casasent, Ari B. Kahn, Joanne Yi, Kyle Ellrott, John M. S. Bartlett, Payal Sipahimalani, William D. Travis, Douglas Voet, Sean P. Barletta, Elizabeth Chun, J. Todd Auman, Ludmila Danilova, Katherine A. Hoadley, Marcin Imielinski, Ramaswamy Govindan, David P. Carbone, Leigh B. Thorne, David A. Wheeler, Carrie Hirst, Barbara Tabak, Sugy Kodeeswaran, Ijeoma A. Azodo, James Stephen Marron, Michael S. Noble, Jianjua John Zhang, Paul K. Paik, Deepak Srinivasan, Boris Reva, B. Arman Aksoy, Kristian Cibulskis, Douglas B. Flieder, Fei Pan, Daniel J. Weisenberger, Ronglai Shen, Jinhua Zhang, Nils Weinhold, Harman Sekhon, David Van Den Berg, Mark S. Guyer, Robert Penny, Hartmut Juhl, Marc Danie Nazaire, Yiqun Zhang, Eric A. Collisson, Robin J.N. Coope, Tom Bodenheimer, Richard Thorp, Junyuan Wu, Matthew Meyerson, Nguyen Phi Hung, Jerome Myers, Artem Sokolov, Yidi J. Turman, Thomas Muley, Stephen B. Baylin, Anisha Gulabani, A. Gordon Robertson, Lynda Chin, Eric Chuah, Richard Varhol, Margi Sheth, Janae V. Simons, Nils Gehlenborg, Tanja Davidsen, Psalm Haseley, Miruna Balasundaram, Olga Potapova, Spring Yingchun Liu, W. Kimryn Rathmell, Bizhan Bandarchi-Chamkhaleh, Wendy Winckler, David Mallery, Nicholas J. Petrelli, Nicole Todaro, Alex E. Lash, James Shin, Travis Brown, Igor Jurisica, Benjamin Gross, Hailei Zhang, Nikolaus Schultz, Kenna R. Mills Shaw, Nam Pho, William Pao, Darlene Lee, Zhen Fan, Troy Shelton, Yan Shi, Shelley Alonso, Carmelo Gaudioso, Peter B. Illei, Stuart R. Jefferys, Maureen F. Zakowski, Marian Rutledge, Bruce E. Johnson, Andrew J. Mungall, Eric S. Lander, Matthew G. Soloway, Michael Mayo, Christopher G. Maher, John V. Heymach, Lihua Zou, Dominique L. Berton, Nina Thiessen, Gary K. Scott, Anna L. Chu, Richard A. Hajek, Ming-Sound Tsao, Liming Yang, Qianxing Mo, Nguyen Van Bang, Martin Hirst, John Eckman, Erin Curley, Rajiv Dhir, Gad Getz, Stanley Girshik, Xuan Van Le, Jeff Boyd, Roman K. Thomas, Konstantin V. Fedosenko, Juok Cho, Alexei Protopopov, Nguyen Viet Tien, Lixing Yang, Laetitia Borsu, Steven J.M. Jones, Matthew D. Wilkerson, Mark Sherman, Andrew Crenshaw, Doug Voet, Elizabeth Buda, Jennifer Brown, Yaron S.N. Butterfield, Rehan Akbani, Todd Pihl, Ruibin Xi, Nianxiang Zhang, Jessica Walton, Ricardo Ramirez, Lisle E. Mose, Leslie Cope, Greg Eley, Mark A. Jensen, John N. Weinstein, Li Ding, Li-Wei Chang, Matthew C. Nicholls, Peter J. Park, Bui Duc Phu, Christopher R. Cabanski, Bernard Kohl, Julien Baboud, Joseph Paulauskis, David Pot, Gordon Robertson, Jingchun Zhu, John A. Demchok, Eunjung Lee, Giovanni Ciriello, Mary Iacocca, Gordon Saksena, Jesse Walsh, Yupu Liang, William K. Funkhouser, Rashmi N. Sanbhadti, Sam Ng, Venkatraman E. Seshan, Valerie W. Rusch, Robert A. Holt, Robert Sfeir, Jung E. Hye-Chun, Kai Wang, Helga Thorvaldsdottir, Huy V. Nguyen, Christopher Wilks, Brian Craft, Donghui Tan, David Haussler, Charles M. Perou, Timothy J. Triche, Christopher C. Benz, Scot Waring, Peggy Yena, Richard A. Moore, Darshan Singh, Andrew D. Cherniack, Rameen Beroukhim, Michael S. Lawrence, Xiaojia Ren, Stacey Gabriel, Martha Hatfield, Christine Czerwinski, Alan P. Hoyle, Marc Ladanyi, Joshua M. Stuart, Andrey Sivachenko, Jacqueline D. Palchik, Thomas Zeng, Inanc Birol, Rohini Raman, Ijeoma Azodo, Jianhua Zhang, Adam B. Olshen, Bradley A. Ozenberger, Angela Hadjipanayis, Sachet A. Shukla, Barry S. Taylor, John M. Greene, Jill P. Mesirov, Petar Stojanov, Raju Kucherlapati, Richard Corbett, Farhad Kosari, Martin L. Ferguson, Natasha Rekhtman, Keith A. Baggerly, Scott Morris, Brenda Rabeno, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Park, Peter J.
Subjects: Lung Neoplasms, Squamous Differentiation, DNA Mutational Analysis, Adenocarcinoma of Lung, Biology, Adenocarcinoma, Article, Phosphatidylinositol 3-Kinases, Gefitinib, Mutation Rate, CDKN2A, Carcinoma, medicine, Humans, Molecular Targeted Therapy, Lung cancer, Multidisciplinary, Genome, Human, Gene Expression Profiling, Genes, p16, Genomics, medicine.disease, Genes, p53, Gene expression profiling, Gene Expression Regulation, Neoplastic, Mutation, Cancer research, Carcinoma, Squamous Cell, Gene Deletion, medicine.drug, Necitumumab, Signal Transduction
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., National Institutes of Health (U.S.) (Grant U24 CA126561), National Institutes of Health (U.S.) (Grant U24 CA126551), National Institutes of Health (U.S.) (Grant U24 CA126554), National Institutes of Health (U.S.) (Grant U24 CA126543), National Institutes of Health (U.S.) (Grant U24 CA126546), National Institutes of Health (U.S.) (Grant U24 CA126563), National Institutes of Health (U.S.) (Grant U24 CA126544), National Institutes of Health (U.S.) (Grant U24 CA143845), National Institutes of Health (U.S.) (Grant U24 CA143858), National Institutes of Health (U.S.) (Grant U24 CA144025), National Institutes of Health (U.S.) (Grant U24 CA143882), National Institutes of Health (U.S.) (Grant U24 CA143866), National Institutes of Health (U.S.) (Grant U24 CA143867), National Institutes of Health (U.S.) (Grant U24 CA143848), National Institutes of Health (U.S.) (Grant U24 CA143840), National Institutes of Health (U.S.) (Grant U24 CA143835), National Institutes of Health (U.S.) (Grant U24 CA143799), National Institutes of Health (U.S.) (Grant U24 CA143883), National Institutes of Health (U.S.) (Grant U24 CA143843), National Institutes of Health (U.S.) (Grant U54 HG003067), National Institutes of Health (U.S.) (Grant U54 HG003079), National Institutes of Health (U.S.) (Grant U54 HG003273)
Published: 2012

24. Comprehensive molecular characterization of human colon and rectal cancer

Author: Donghui Tan, Nils Gehlenborg, Robert S. Fulton, Pat Swanson, Pei Lin, Chang-Jiun Wu, Piotr A. Mieczkowski, David Haussler, Marco A. Marra, Stephen E. Schumacher, Bernard Kohl, Jingchun Zhu, Lucinda Fulton, Charles M. Perou, Timothy J. Triche, Madhumati Gundapuneni, Mark Backus, Eve Shinbrot, Yonghong Xiao, Xuan Van Le, Liming Yang, Gad Getz, Stanley Girshik, Jessica Walton, Barbara Tabak, Greg Eley, Brian O'Connor, Larissa K. Temple, Saianand Balu, Eric A. Collisson, Tanja Davidsen, Elizabeth Buda, Janae V. Simons, Anisha Gulabani, Joseph Willis, Tod D. Casasent, Scott Morris, Doug Voat, Jireh Santibanez, Jennifer Drummond, Li Ding, Nicholas J. Petrelli, Andrew J. Mungall, Michael Mayo, Aaron D. Black, Gerald C. Chu, Elizabeth N. Medina, Huy V. Nguyen, Aaron E. Cozen, Yongjun Zhao, Hui Shen, Christopher Szeto, Brenda Rabeno, Martin Hirst, Bogumil Kaczkowski, Lisle E. Mose, Lora Lewis, Brian Craft, Joseph Paulauskis, Ari B. Kahn, Andy Chu, Peter W. Laird, Benjamin Gross, Matthew D. Wilkerson, Raju Kucherlapati, Matthew C. Nicholls, David Van Den Berg, Vesteinn Thorsson, Richard W. Park, Ethan Cerami, David A. Wheeler, Laura A.L. Dillon, Angela Tam, Julien Baboud, Kim D. Delehaunty, Katherine A. Hoadley, Ranabir Guin, Donna M. Muzny, Gordon Saksena, Shaowu Meng, Richard Kreisberg, Kenneth H. Buetow, Rajiv Dhir, Inanc Birol, Timo Erkkilä, Martin L. Ferguson, Robert A. Holt, Elaine R. Mardis, Aaron McKenna, Rohini Raman, Robert Sfeir, Mark Sherman, Andrew Crenshaw, J. Zachary Sanborn, Spring Yingchun Liu, Yuan Qing Wu, Jane Peterson, Eric E. Snyder, Lisa Iype, John N. Weinstein, Helga Thorvaldsdottir, Adam J. Bass, Dominik Stoll, Brady Bernard, Steven J.M. Jones, Peter Dolina, Julie M. Gastier-Foster, Jared R. Slobodan, Mark A. Jensen, Jacqueline E. Schein, Christie Kovar, Anders Jacobsen, Stephen C. Benz, J. Todd Auman, Juinhua Zhang, Peter Fielding, Paul T. Spellman, Jacqueline D. Palchik, Jay Bowen, Thomas Zeng, Douglas Voet, Arnulf Dörner, Joshua M. Stuart, Ryan Demeter, Theodore C. Goldstein, Keith A. Baggerly, Jorma J. de Ronde, Deepak Srinivasan, Boris Reva, Robert E. Pyatt, Andrew Kaufman, Timothy A. Chan, Alexei Protopopov, William G. Richards, Daniel R. Zerbino, Brenda Ayala, Martin R. Weiser, Psalm Haseley, Margaret Morgan, Mary Iacocca, Thomas Robinson, Chad J. Creighton, Dominique L. Berton, Da Yang, Peng Chieh Chen, Carl F. Schaefer, Peter White, Fred Denstman, Giovanni Ciriello, Matthew N. Bainbridge, Heidi J. Sofia, Irene Newsham, Jill P. Mesirov, Ling Li, Benjamin P. Berman, Daniel J. Weisenberger, Garrett M. Nash, Jason Walker, Nina Thiessen, Narayanan Sathiamoorthy, James A. Robinson, Petar Stojanov, Todd Wylie, Derek Y. Chiang, Kristin G. Ardlie, Jianjiong Gao, Lisa Wise, Bradley A. Ozenberger, Jeffrey G. Reid, Angela Hadjipanayis, Sachet A. Shukla, Barry S. Taylor, John M. Greene, Eric Chuah, Richard Varhol, Lisa R. Trevino, Charles J. Vaske, Ying Du, Arthur P. Goldberg, Rui Jing, Jon Whitmore, Joan Pontius, Yevgeniy Antipin, Kyle Ellrott, Nilsa C. Ramirez, Tom Bodenheimer, Junyuan Wu, Lynda Chin, Scott L. Carter, Hailei Zhang, Ryan Bressler, Adam Norberg, Stacey Gabriel, Martha Hatfield, Jonathan G. Seidman, Corbin D. Jones, Huyen Dinh, D. Neil Hayes, Christine Czerwinski, Gerald R. Fowler, Mark S. Guyer, Robert Penny, Alan P. Hoyle, Hartmut Juhl, Catrina Fronick, Margi Sheth, Christopher C. Benz, Scot Waring, Peggy Yena, Richard A. Moore, Darshan Singh, Toshinori Hinoue, Yaron S.N. Butterfield, Andrew D. Cherniack, Maria C. Mariano, Rameen Beroukhim, Michael S. Lawrence, Xiaojia Ren, Marc Ladanyi, Anna K. Unruh, Noreen Dhalla, Candace Shelton, Gary Witkin, Andrey Sivachenko, David Pot, Michael J. Zinner, Richard Thorp, Jan F. Prins, Eunjung Lee, A. Gordon Robertson, Wendy Winckler, Efsevia Vakiani, Chris Wakefield, Alex H. Ramos, Semin Lee, Zhining Wang, Sam Ng, Lihua Zhou, Christina Liquori, Rileen Sinha, Dennis T. Maglinte, Michael S. Noble, Haiyan I. Li, B. Arman Aksoy, Preethi H. Gunaratne, Michael Meyers, Daniel C. Koboldt, Lawrence A. Donehower, Darlene Lee, Jake Lin, Gary K. Scott, Hye Jung E. Chun, Sheila Reynolds, Anna L. Chu, Rehan Akbani, Todd Pihl, Ruibin Xi, Charles S. Fuchs, Nianxiang Zhang, Stanley R. Hamilton, Bradley M. Broom, Wei Zhang, Chris Sander, Marc Danie Nazaire, Carrie Hirst, Stephen B. Baylin, Joel E. Tepper, Kyle Chang, Miruna Balasundaram, Jen Brown, Yan Shi, Matthew G. Soloway, Richard A. Gibbs, Richard K. Wilson, Peter J. Park, Zhaoshi Zeng, John A. Demchok, Jesse Walsh, Rashmi N. Sanbhadti, Troy Shelton, Lixing Yang, Prachi Kothiyal, Monica M. Bertagnolli, Sean P. Barletta, Kristian Cibulskis, Yidi J. Turman, Nikolaus Schultz, Min Wang, Shelley Alonso, Carsten Zornig, P. Paty, Elizabeth J. Thomson, Peter A. Kigonya, Fei Pan, Yuexin Liu, Matthew Meyerson, Kenna R. Mills Shaw, Nam Pho, Stuart R. Jefferys, Daniel DiCara, Robert C. Onofrio, Erin Pleasance, Eric S. Lander, David J. Dooling, Christina Yau, Michael D. Topal, David B. Solit, Christopher Wilks, Ilya Shmulevich, Robin J.N. Coope, Ronglai Shen, Jose G. Guillem, R. Craig Cason, Massachusetts Institute of Technology. Department of Biology, and Lander, Eric S.
Subjects: DNA Copy Number Variations, Colorectal cancer, Biology, medicine.disease_cause, MLH1, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Mutation Rate, microRNA, medicine, Humans, Exome, 030304 developmental biology, 0303 health sciences, Multidisciplinary, POLD1, Rectal Neoplasms, Gene Expression Profiling, Microsatellite instability, Sequence Analysis, DNA, DNA Methylation, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, DNA methylation, Colonic Neoplasms, Mutation, Cancer research, KRAS
Abstract: To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression., National Institutes of Health (U.S.) (Grant U24CA143799), National Institutes of Health (U.S.) (Grant U24CA143835), National Institutes of Health (U.S.) (Grant U24CA143840), National Institutes of Health (U.S.) (Grant U24CA143843), National Institutes of Health (U.S.) (Grant U24CA143845), National Institutes of Health (U.S.) (Grant U24CA143848), National Institutes of Health (U.S.) (Grant U24CA143858), National Institutes of Health (U.S.) (Grant U24CA143866), National Institutes of Health (U.S.) (Grant U24CA143867), National Institutes of Health (U.S.) (Grant U24CA143882), National Institutes of Health (U.S.) (Grant U24CA143883), National Institutes of Health (U.S.) (Grant U24CA144025), National Institutes of Health (U.S.) (Grant U54HG003067), National Institutes of Health (U.S.) (Grant U54HG003079), National Institutes of Health (U.S.) (Grant U54HG003273)
Published: 2011

25. A geometric characterization of harmonic diffeomorphisms between surfaces

Author: Barbara Tabak
Subjects: General Mathematics, Mathematical analysis, Harmonic (mathematics), Characterization (materials science), Mathematics
Published: 1985
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26. Integrated Genomic Characterization of Papillary Thyroid Carcinoma

Author: Piotr A. Mieczkowski, Nishant Agrawal, Yiling Lu, Junyuan Wu, Marco A. Marra, Fabio Vandin, Margi Sheth, Roy Tarnuzzer, Jacqueline E. Schein, Heidi J. Sofia, Lori Boice, Phillip H. Lai, Rajiv Dhir, Matthew D. Wilkerson, Benjamin Gross, Liming Yang, Pei Lin, Yaron S.N. Butterfield, Julie M. Gastier-Foster, Jiashan Zhang, Tanja Davidsen, Andy Chu, J. Todd Auman, Sheila Fisher, Harindra Arachchi, Andrew J. Mungall, Suresh Ramalingam, Rehan Akbani, Gad Getz, Ranabir Guin, Jianhua Zhang, Saianand Balu, A. Gordon Robertson, Michael Parfenov, Stuart R. Jefferys, Gordon Saksena, John Paul Shen, Richard A. Moore, Martha A. Zeiger, Adel K El-Naggar, Umadevi Veluvolu, Scott L. Carter, Ludmila Danilova, Scott Frazer, Tom Bodenheimer, Rebecca Carlsen, Tobias Carling, Robert A. Holt, Katayoon Kasaian, Matthew Rosenthal, Trey Ideker, Gabriel Sica, Jiabin Tang, Richard Kreisberg, Angela Hadjipanayis, Thomas J. Giordano, Esther Rheinbay, Greg Eley, Bradley A. Ozenberger, Karen Gomez-Hernandez, Jonathan G. Seidman, Corbin D. Jones, Michael L. Miller, Paul M. Weinberger, Matthew D. Ringel, James A. Fagin, Jean C. Zenklusen, Wei Zhang, Chandra Sekhar Pedamallu, Michael Mayo, Eunjung Lee, Donghui Tan, Evan O. Paull, Franklin W. Huang, Semin Lee, Shaowu Meng, Justin A. Bishop, Lixing Yang, Payal Sipahimalani, Kristen M. Leraas, Marc Ladanyi, Aaron D. Black, Carolyn M. Hutter, D. Neil Hayes, Charles M. Perou, Lisa Iype, Robert C. Smallridge, Amanda Clarke, Jonathan V. Eldridge, Raja R. Seethala, Jessica Frick, John N. Weinstein, B. Arman Aksoy, Sara Sadeghi, Moiz S. Bootwalla, Sheliann S. Dookran, Dong Zeng, Rileen Sinha, Yichao Sun, Adrian Ally, Hollie A. Harper, Barry S. Taylor, Sylvia L. Asa, Joel S. Parker, Jay Bowen, John A. Copland, Reanne Bowlby, Stephanie Eng, Jeffrey Roach, Kyle R. Covington, William Lee, David A. Wheeler, Nina Thiessen, Ronglai Shen, Yingchun Liu, Christopher B. Umbricht, David Van Den Berg, Katherine A. Hoadley, S. Onur Sumer, James G. Herman, Peter W. Laird, Harshad S. Mahadeshwar, Alexei Protopopov, Roeland Verhaak, Chip Stewart, Brady Bernard, Timothy R. Fennell, Timothy A. Chan, Steven I. Sherman, Ni Zhao, Sheila Reynolds, Ilya Shmulevich, Kristian Cibulskis, Ian Ganly, Erik Zmuda, Janae V. Simons, Taofeek K. Owonikoko, Nils Gehlenborg, Madhusmita Behera, Fadlo R. Khuri, Elizabeth Buda, Jinze Liu, Scot Waring, Darlene Lee, Yussanne Ma, Chris Sander, Shiyun Ling, Tara M. Lichtenberg, Yuri E. Nikiforov, Michelle D. Williams, Giovanni Ciriello, Robert L. Ferris, David G. McFadden, Petar Stojanov, Steven E. Schumacher, Raju Kucherlapati, Electron Kebebew, Daniel J. Weisenberger, Lynda Chin, Bradley A. Murray, Roger Kramer, Dorothy Cheung, Lee Lichtenstein, Akinyemi I. Ojesina, Anders Jacobsen, Mei Huang, Juok Cho, Robin Brookens, Michelle Vinco, Noreen Dhalla, Netty Santoso, Nils Weinhold, Angela Tam, Joshua M. Stuart, Jonna Grimsby, Kenna R. Mills Shaw, Doug Voet, Ricardo Ramirez, W. Kimryn Rathmell, Jianjiong Gao, Lisa Wise, Hailei Zhang, Eric S. Lander, Vesteinn Thorsson, Steven J.M. Jones, Liu Xi, Xingzhi Song, Matan Hofree, Gordon B. Mills, Matthew Meyerson, Nikolaus Schultz, Travis I. Zack, Lihua Zou, Leigh B. Thorne, Robert Bryant, Vonn Walter, Daniel DiCara, David J. Kwiatkowski, Benjamin J. Raphael, Stephen B. Baylin, Yan Shi, Matthew G. Soloway, Daniel A. Winer, Angeliki Pantazi, Gary L. Clayman, Sahil Seth, R. Michael Tuttle, Peter J. Park, Denise Brooks, John A. Demchok, Amy Chen, Jan F. Prins, Zhining Wang, Miruna Balasundaram, Michael S. Noble, Gideon Dresdner, Levi A. Garraway, Eric Chuah, Michael Rivera, Jaegil Kim, Mara Rosenberg, Barbara Tabak, David I. Heiman, Andrew D. Cherniack, Rameen Beroukhim, Michael S. Lawrence, Wen-Bin Liu, Carrie Sougnez, Xiaojia Ren, Ronald Ghossein, Richard A. Gibbs, Jocelyn Wilson, Stacey Gabriel, Samantha Sharpe, Virginia A. LiVolsi, Lisle E. Mose, Leslie Cope, Sally E. Carty, Nilsa C. Ramirez, Yasin Senbabaoglu, Christopher A. Bristow, Alan P. Hoyle, and Andrew Wei Xu
Subjects: Genetics and Molecular Biology (all), DNA Copy Number Variations, endocrine system diseases, Carcinoma, Gene Fusion, Humans, Thyroid Gland, Thyroid Neoplasms, Mutation, Biochemistry, Genetics and Molecular Biology (all), Medicine (all), Noninvasive follicular thyroid neoplasm with papillary-like nuclear features, EIF1AX, Biology, Bioinformatics, Biochemistry, Article, General Biochemistry, Genetics and Molecular Biology, Thyroid carcinoma, Poorly Differentiated Thyroid Carcinoma, medicine, CHEK2, Thyroid cancer, Biochemistry, Genetics and Molecular Biology(all), Thyroid, medicine.disease, Carcinoma, Papillary, Carcinoma/genetics, 3. Good health, medicine.anatomical_structure, Thyroid Cancer, Papillary, Thyroid Neoplasms/genetics, Thyroid Gland/cytology
Abstract: Summary Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX , PPM1D , and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF -mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.
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27. Comprehensive molecular portraits of human breast tumours

Author: Julie M. Gastier-Foster, Nguyen Van Bang, Christopher Szeto, Daoud Meerzaman, Nguyen Viet Tien, Richard K. Wilson, Jennifer Brown, Singer Ma, Andrew H. Beck, Sam Ng, Phillip H. Lai, Peter J. Park, Khurram Z. Khan, Gordon B. Mills, Joel S. Parker, Li Ding, Ying Hu, Jill P. Mesirov, Rebecca Carlsen, Kevin P. White, Benjamin P. Berman, Michael C. Adams, Laura A.L. Dillon, Jake Lin, Giovanni Ciriello, Simeen Malik, Moiz S. Bootwalla, Sheila Reynolds, Petar Stojanov, B. Arman Aksoy, Jerry Usary, Mei Huang, Andrzej Mackiewicz, Prachi Kothiyal, Keith A. Baggerly, Hann Hsiang Chao, Timo Erkkilä, Elaine R. Mardis, Nils Gehlenborg, Bradley M. Broom, Tara M. Lichtenberg, Jeff Gentry, Payal Sipahimalani, Chris Wakefield, Zhining Wang, Anna Chu, Konstanty Korski, Michael S. Noble, Lawrence A. Donehower, Pavana Anur, Janita Thusberg, Rohit Bhargava, Chris Sander, Lori Boice, Juok Cho, Charles Saller, Sophie C. Egea, Marc Danie Nazaire, Heather Schmidt, Bui Duc Phu, Hye Jung E. Chun, Bradley A. Ozenberger, Robert S. Fulton, Carrie Hirst, Stephen B. Baylin, Miruna Balasundaram, Peter White, Fergus J. Couch, Saianand Balu, Christina Yau, Yevgeniy Antipin, Jacek J. Brzeziński, Rehan Akbani, Todd Pihl, Ari B. Kahn, Nianxiang Zhang, Sean P. Barletta, Mary Iacocca, Kelly Daily, Wiam Bshara, Marc Ladanyi, Michael D. Topal, Huy Nguyen, Theodore C. Goldstein, Tari A. King, Bernard Kohl, Jingchun Zhu, Wiktoria Maria Suchorska, Xuan Van Le, Wei Zhang, Yan Shi, Marta Bogusz-Czerniewicz, Barry S. Taylor, Li-Wei Chang, Matthew C. Nicholls, Julien Baboud, Honorata Tatka, Doug Voet, Vesteinn Thorsson, Richard W. Park, Aaron D. Black, Pawel Murawa, Leonid Kvecher, Raju Kucherlapati, Colleen Mitchell, Wei Zhao, Leigh B. Thorne, Artem Sokolov, Modesto Patangan, Yidi J. Turman, Teresa R. Tabler, Kyle Ellrott, Yaron S.N. Butterfield, Gordon Saksena, Ronglai Shen, Yaqin Chen, Olga Voronina, Candace Carter, Yiling Lu, Cynthia McAllister, Thomas Stricker, Chunqing Luo, Dominique L. Berton, Thomas Barr, Robert A. Holt, Christopher Wilks, David Van Den Berg, Robert Sfeir, Ilya Shmulevich, Ranabir Guin, Nilsa C. Ramirez, Hollie A. Harper, John A. Demchok, Matthew J. Ellis, David Haussler, Katherine A. Hoadley, Eric Chuah, Richard J. Mural, Charles M. Perou, Timothy J. Triche, Steven J.M. Jones, Mark A. Jensen, Jeffrey R. Marks, Hanna Perz, Rashmi N. Sanbhadti, Robin J.N. Coope, Brian Craft, Andy Chu, Peter W. Laird, Eric E. Snyder, Chunhua Yan, Martin L. Ferguson, Junyuan Wu, Richard Varhol, Daniel J. Weisenberger, Yongjun Zhao, Ewa Leporowska, Ashley Hill, Katie Tarvin, M. Teresiak, David Pot, Nguyen Phi Hung, Helga Thorvaldsdottir, Erik Zmuda, Spring Yingchun Liu, Melissa Hart-Kothari, Joshua M. Stuart, Caroline Larson, Erin Pleasance, Nikolaus Schultz, Matthew Ibbs, Hubert Stoppler, Joelle Kalicki-Veizer, Andrey Sivachenko, Christopher C. Benz, Dawid Murawa, Swapna Mahurkar, Nicholas J. Petrelli, Lynda Chin, Juinhua Zhang, Pei Lin, Michael Mayo, Wilma L. Lingle, Julian Malicki, Robin Brookens, Ethan Cerami, Angela Tam, Shelley Alonso, Carmelo Gaudioso, Dominik Stoll, Anders Jacobsen, Stephen C. Benz, Mark S. Guyer, Wendy Winckler, Roel R.G. Verhaak, Chang-Jiun Wu, Raktim Sinha, Xiaping He, Nina Thiessen, Craig D. Shriver, Kenna R. Mills Shaw, Heidi J. Sofia, Martin Hirst, Stuart R. Jefferys, Robert Penny, Adam Brufsky, Kristen M. Leraas, Joshua F. McMichael, Brenda Rabeno, Inanc Birol, David J. Dooling, Peggy Yena, Richard A. Moore, Andrew D. Cherniack, Lucinda Fulton, Jessica K. Booker, Lihua Zou, Rileen Sinha, Michael D. Iglesia, Dennis T. Maglinte, Rohini Raman, Evan O. Paull, Rameen Beroukhim, Oleg Dolzhansky, Grace O. Silva, Jiashan Zhang, Witold Kycler, Janae V. Simons, Anisha Gulabani, Michael S. Lawrence, Peter Fielding, Huynh Quyet Thang, Peter A. Kigonya, Myra M. George, Jay Bowen, Haiyan I. Li, Robert E. Pyatt, Margi Sheth, Stacey Gabriel, Ana M. Gonzalez-Angulo, Hui Shen, Andrew J. Mungall, Carmen Gomez-Fernandez, Liming Yang, Hai Hu, Radoslaw Łaźniak, Olufunmilayo I. Olopade, Christine Czerwinski, Richard A. Hajek, Michael D. McLellan, Arash Shafiei, Matthew Meyerson, Gad Getz, Stanley Girshik, Cheng Fan, Shuying Liu, Olga Potapova, Alan P. Hoyle, Mia Grifford, Daniel C. Koboldt, Jacqueline D. Palchik, Jessica Walton, Greg Eley, Jamie Leigh Campbell, Thomas Zeng, Mikhail Abramov, Benjamin Gross, Brenda Deyarmin, Maciej Wiznerowicz, Natasja Wye, Ron Bose, Darlene Lee, Carl Morrison, Albert J. Kovatich, Andrew Crenshaw, Jessica Frick, John N. Weinstein, Adrian Ally, Nam H. Pho, Brady Bernard, Scott L. Carter, Gary K. Scott, Steven E. Schumacher, Barbara Tabak, D. Neil Hayes, Robert C. Onofrio, Sean D. Mooney, Mary D. Dyer, Mark Gerken, Erin Curley, Rajiv Dhir, Anna K. Unruh, Noreen Dhalla, Candace Shelton, Kevin R. Coombes, Richard Thorp, George E. Sandusky, A. Gordon Robertson, Marco A. Marra, Roy Tarnuzzer, Mark Backus, Aleix Prat, Kristin G. Ardlie, Daniel Di Cara, Richard Kreisberg, Kenneth H. Buetow, Jacqueline E. Schein, J. Todd Auman, Jianjiong Gao, Lisa Wise, Ling Li, James A. Robinson, Jonathan S. Berg, Tod D. Casasent, James N. Ingle, Brenda Ayala, Xiaolong Meng, Boris Reva, Rui Jing, Mark D. Pegram, Arkadiusz Spychała, Joan Pontius, Jeffrey A. Hooke, Daniel E. Carlin, Nils Weinhold, Jared R. Slobodan, Tom Bodenheimer, Wenbin Liu, Christopher K. Wong, W. Kimryn Rathmell, David Mallery, Paul T. Spellman, Hailei Zhang, Ryan Bressler, Deepak Srinivasan, Lisle E. Mose, Bryan Hernandez, Stella Somiari, Chad J. Creighton, Howard H. Sussman, Frederic Waldman, Matthew G. Soloway, and Universitat de Barcelona
Subjects: Proteomics, Oncologia, DNA Mutational Analysis, Genes, BRCA1, Retinoblastoma Protein, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Breast cancer, Exome, RNA, Neoplasm, Exome sequencing, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Genetics, 0303 health sciences, Multidisciplinary, Triple Negative Breast Neoplasms, Genomics, 3. Good health, Gene Expression Regulation, Neoplastic, Receptors, Estrogen, Oncology, 030220 oncology & carcinogenesis, Female, DNA Copy Number Variations, Class I Phosphatidylinositol 3-Kinases, Protein Array Analysis, MAP Kinase Kinase Kinase 1, Breast Neoplasms, GATA3 Transcription Factor, Biology, Article, Càncer de mama, Genetic Heterogeneity, 03 medical and health sciences, medicine, Humans, RNA, Messenger, 030304 developmental biology, MicroRNA sequencing, Genome, Human, Genetic heterogeneity, Gene Expression Profiling, Cancer, DNA Methylation, Genes, erbB-2, Genes, p53, medicine.disease, Claudin-Low, Expressió gènica, MicroRNAs, Genòmica, Mutation, Gene expression, Genes, Neoplasm
Abstract: We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.

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27 results on '"Barbara Tabak"'

1. Tangent normalization for somatic copy-number inference in cancer genome analysis.

2. The Tangent copy-number inference pipeline for cancer genome analyses

3. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas

4. Higher-order inter-chromosomal hubs shape 3-dimensional genome organization in the nucleus

5. Epstein-Barr Virus Latent Membrane Protein 1 Genetic Variability in Peripheral Blood B Cells and Oropharyngeal Fluids

6. SQSTM1 Is a Pathogenic Target of 5q Copy Number Gains in Kidney Cancer

7. The Somatic Genomic Landscape of Glioblastoma

8. Pan-cancer patterns of somatic copy number alteration

9. COMPREHENSIVE MOLECULAR CHARACTERIZATION OF CLEAR CELL RENAL CELL CARCINOMA

10. Integrated genomic characterization of endometrial carcinoma

11. Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1

12. High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

13. Genomic Classification of Cutaneous Melanoma

14. Comparative Analysis of Immune Cells Reveals a Conserved Regulatory Lexicon

15. Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype

16. Functional annotation of native enhancers with a Cas9-histone demethylase fusion

17. The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

18. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin

19. HIV type 1 (HIV-1) proviral reservoirs decay continuously under sustained virologic control in HIV-1-infected children who received early treatment

20. The Cancer Genome Atlas Pan-Cancer analysis project

21. Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities

22. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes

23. Comprehensive genomic characterization of squamous cell lung cancers

24. Comprehensive molecular characterization of human colon and rectal cancer

25. A geometric characterization of harmonic diffeomorphisms between surfaces

26. Integrated Genomic Characterization of Papillary Thyroid Carcinoma

27. Comprehensive molecular portraits of human breast tumours

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27 results on '"Barbara Tabak"'

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