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1. Cardiomyocyte Proliferative Capacity Is Restricted in Mice With Lmna Mutation

Author

Kenji Onoue, Hiroko Wakimoto, Jiangming Jiang, Michael Parfenov, Steven DePalma, David Conner, Joshua Gorham, David McKean, Jonathan G. Seidman, Christine E. Seidman, and Yoshihiko Saito

Subjects
dilated cardiomyopathy, lamin A/C, cell cycle, p21, repressed proliferating capacity, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

LMNA is one of the leading causative genes of genetically inherited dilated cardiomyopathy (DCM). Unlike most DCM-causative genes, which encode sarcomeric or sarcomere-related proteins, LMNA encodes nuclear envelope proteins, lamin A and C, and does not directly associate with contractile function. However, a mutation in this gene could lead to the development of DCM. The molecular mechanism of how LMNA mutation contributes to DCM development remains largely unclear and yet to be elucidated. The objective of this study was to clarify the mechanism of developing DCM caused by LMNA mutation.Methods and Results: We assessed cardiomyocyte phenotypes and characteristics focusing on cell cycle activity in mice with Lmna mutation. Both cell number and cell size were reduced, cardiomyocytes were immature, and cell cycle activity was retarded in Lmna mutant mice at both 5 weeks and 2 years of age. RNA-sequencing and pathway analysis revealed “proliferation of cells” had the most substantial impact on Lmna mutant mice. Cdkn1a, which encodes the cell cycle regulating protein p21, was strongly upregulated in Lmna mutants, and upregulation of p21 was confirmed by Western blot and immunostaining. DNA damage, which is known to upregulate Cdkn1a, was more abundantly detected in Lmna mutant mice. To assess the proliferative capacity of cardiomyocytes, the apex of the neonate mouse heart was resected, and recovery from the insult was observed. A restricted cardiomyocyte proliferating capacity after resecting the apex of the heart was observed in Lmna mutant mice.Conclusions: Our results strongly suggest that loss of lamin function contributes to impaired cell proliferation through cell cycle defects. The inadequate inborn or responsive cell proliferation capacity plays an essential role in developing DCM with LMNA mutation.

Published
2021
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2. ViroFind: A novel target-enrichment deep-sequencing platform reveals a complex JC virus population in the brain of PML patients.

Author

Spyros Chalkias, Joshua M Gorham, Erica Mazaika, Michael Parfenov, Xin Dang, Steve DePalma, David McKean, Christine E Seidman, Jonathan G Seidman, and Igor J Koralnik

Subjects
Medicine, Science
Abstract

Deep nucleotide sequencing enables the unbiased, broad-spectrum detection of viruses in clinical samples without requiring an a priori hypothesis for the source of infection. However, its use in clinical research applications is limited by low cost-effectiveness given that most of the sequencing information from clinical samples is related to the human genome, which renders the analysis of viral genomes challenging. To overcome this limitation we developed ViroFind, an in-solution target-enrichment platform for virus detection and discovery in clinical samples. ViroFind comprises 165,433 viral probes that cover the genomes of 535 selected DNA and RNA viruses that infect humans or could cause zoonosis. The ViroFind probes are used in a hybridization reaction to enrich viral sequences and therefore enhance the detection of viral genomes via deep sequencing. We used ViroFind to detect and analyze all viral populations in the brain of 5 patients with progressive multifocal leukoencephalopathy (PML) and of 18 control subjects with no known neurological disease. Compared to direct deep sequencing, by using ViroFind we enriched viral sequences present in the clinical samples up to 127-fold. We discovered highly complex polyoma virus JC populations in the PML brain samples with a remarkable degree of genetic divergence among the JC virus variants of each PML brain sample. Specifically for the viral capsid protein VP1 gene, we identified 24 single nucleotide substitutions, 12 of which were associated with amino acid changes. The most frequent (4 of 5 samples, 80%) amino acid change was D66H, which is associated with enhanced tissue tropism, and hence likely a viral fitness advantage, compared to other variants. Lastly, we also detected sparse JC virus sequences in 10 of 18 (55.5%) of control samples and sparse human herpes virus 6B (HHV6B) sequences in the brain of 11 of 18 (61.1%) control subjects. In sum, ViroFind enabled the in-depth analysis of all viral genomes in PML and control brain samples and allowed us to demonstrate a high degree of JC virus genetic divergence in vivo that has been previously underappreciated. ViroFind can be used to investigate the structure of the virome with unprecedented depth in health and disease state.

Published
2018
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3. A functional genomic approach to actionable gene fusions for precision oncology

Author

Jun Li, Hengyu Lu, Patrick Kwok-Shing Ng, Angeliki Pantazi, Carman Ka Man Ip, Kang Jin Jeong, Bianca Amador, Richard Tran, Yiu Huen Tsang, Lixing Yang, Xingzhi Song, Turgut Dogruluk, Xiaojia Ren, Angela Hadjipanayis, Christopher A. Bristow, Semin Lee, Melanie Kucherlapati, Michael Parfenov, Jiabin Tang, Sahil Seth, Harshad S. Mahadeshwar, Kamalika Mojumdar, Dong Zeng, Jianhua Zhang, Alexei Protopopov, Jonathan G. Seidman, Chad J. Creighton, Yiling Lu, Nidhi Sahni, Kenna R. Shaw, Funda Meric-Bernstam, Andrew Futreal, Lynda Chin, Kenneth L. Scott, Raju Kucherlapati, Gordon B. Mills, and Han Liang

Subjects
Genome, Multidisciplinary, Neoplasms, Humans, Genomics, Gene Fusion, Precision Medicine
Abstract

Fusion genes represent a class of attractive therapeutic targets. Thousands of fusion genes have been identified in patients with cancer, but the functional consequences and therapeutic implications of most of these remain largely unknown. Here, we develop a functional genomic approach that consists of efficient fusion reconstruction and sensitive cell viability and drug response assays. Applying this approach, we characterize ~100 fusion genes detected in patient samples of The Cancer Genome Atlas, revealing a notable fraction of low-frequency fusions with activating effects on tumor growth. Focusing on those in the RTK-RAS pathway, we identify a number of activating fusions that can markedly affect sensitivity to relevant drugs. Last, we propose an integrated, level-of-evidence classification system to prioritize gene fusions systematically. Our study reiterates the urgent clinical need to incorporate similar functional genomic approaches to characterize gene fusions, thereby maximizing the utility of gene fusions for precision oncology.

Published
2022

4. Genomic analyses implicate noncoding de novo variants in congenital heart disease

Author

Daniel Bernstein, Martin Tristani-Firouzi, Jane W. Newburger, Sarah U. Morton, Diane E. Dickel, Lauren K. Wasson, Seong Won Kim, Jonathan G. Seidman, Martina Brueckner, Hongjian Qi, Elizabeth Goldmuntz, George A. Porter, Eric E. Schadt, Olga G. Troyanskaya, Kathryn B. Manheimer, Jian Zhou, Jason Homsy, Michael Parfenov, Steven R. DePalma, Bruce D. Gelb, Andrew Farrell, Alexander Kitaygorodsky, Matt Velinder, Gabor T. Marth, Richard B. Kim, Nihir Patel, Jonathan R. Kaltman, Felix Richter, Deepak Srivastava, Kathleen M. Chen, Yufeng Shen, Joshua M. Gorham, Christine E. Seidman, Alessandro Giardini, and Wendy K. Chung

Subjects
Proband, Genetics, 0303 health sciences, Heart disease, Genomics, Odds ratio, Biology, medicine.disease, Genome, 03 medical and health sciences, 0302 clinical medicine, medicine, Young adult, Enhancer, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in individuals with CHD (n = 2,238 DNVs) compared to controls (n = 4,177; P = 8.7 × 10-4). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10-5). We observed significant overlap between these transcription-based approaches (odds ratio (OR) = 2.5, 95% confidence interval (CI) 1.1-5.0, P = 5.4 × 10-3). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. Finally, we observed a DNV burden in RNA-binding-protein regulatory sites (OR = 1.13, 95% CI 1.1-1.2, P = 8.8 × 10-5). Our findings demonstrate an enrichment of potentially disruptive regulatory noncoding DNVs in a fraction of CHD at least as high as that observed for damaging coding DNVs.

Published
2020

5. On Properties of Holomorphic Functions in Quaternionic Analysis

Author

Michael Parfenov

Subjects
Pure mathematics, Mathematics::Complex Variables, Generalization, Mathematical analysis, Holomorphic function, Landau's constants, General Medicine, Identity theorem, Quaternionic analysis, Quaternionic representation, Analyticity of holomorphic functions, Symmetry (geometry), Mathematics::Symplectic Geometry, Mathematics
Abstract

We draw the conclusions from the earlier presented quaternionic generalization of Cauchy-Riemann’s equations. The general expressions for constituents of -holomorphic functions as well as the relations between them are deduced. The symmetry properties of constituents of -holomorphic functions and their derivatives of all orders are proved. For full derivatives it is a consequence of uniting the left and right derivatives within the framework of the developed theory. Some -holomorphic generalizations of - holomorphic functions are discussed in detail to demonstrate particularities of constructing H-holomorphic functions. The power functions are considered in detail.

Published
2017

6. Droplet Digital PCR with EvaGreen Assay: Confirmational Analysis of Structural Variants

Author

Michael Parfenov, Joshua M. Gorham, and Angela C. Tai

Subjects
0301 basic medicine, Oligonucleotide, Chemistry, Microfluidics, Structural variant, Computational biology, DNA, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 030104 developmental biology, Molecular Probes, Genetics, Nucleic acid, Humans, Digital polymerase chain reaction, Lower cost, Biological Assay, Genetics (clinical)
Abstract

We describe a variation of droplet digital PCR (ddPCR) for DNA structural variant analysis, where expensive fluorescent probes are replaced by low-cost EvaGreen, a DNA binding dye, hence reducing cost without reducing sensitivity. ddPCR is a method that employs water-oil microfluidics and fluorescence technology to quantify target nucleic acids with extreme precision and sensitivity. Traditional ddPCR uses standard Taqman probe assays to determine target DNA concentrations, however these two-color fluorescent oligonucleotide probes are expensive and require extensive optimization. EvaGreen’s DNA binding properties allow target products to be effectively quantified at a significantly lower cost. This protocol employs the EvaGreen ddPCR assay to confirm structural variants on a ddPCR system and produces results comparable to the standard, far more expensive Taqman approach.

Published
2018

7. A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy

Author

Anne Keogh, Christopher S. Hayward, Claire Horvat, Paul J.R. Barton, Barbara McDonough, Alireza Haghighi, Jonathan G. Seidman, Leanne E. Felkin, Diane Fatkin, Francesco Mazzarotto, Peter S. Macdonald, Michael Parfenov, Christine E. Seidman, Steven R. DePalma, Daniel S. Herman, Angharad M. Roberts, Eleni Giannoulatou, Jacob E Munro, Amy E. Roberts, Stuart A. Cook, Renee Johnson, Lien Lam, British Heart Foundation, Fondation Leducq, and Royal Brompton & Harefield NHS Foundation Trust

Subjects
0301 basic medicine, Proband, Cardiomyopathy, Dilated, Male, Dilated cardiomyopathy, Cardiomyopathy, Mutation, Missense, Disease, TITIN, 030204 cardiovascular system & hematology, Biology, Article, 03 medical and health sciences, pathogenic variant, 0302 clinical medicine, Rare Diseases, medicine, SCN5A MUTATION, Missense mutation, Humans, Genetic Predisposition to Disease, Genetic Testing, Gene, Genetics (clinical), Genetic testing, SERVER, Genetics, Genetics & Heredity, 0604 Genetics, Science & Technology, medicine.diagnostic_test, BAG3, High-Throughput Nucleotide Sequencing, 1103 Clinical Sciences, ASSOCIATION, Middle Aged, medicine.disease, SODIUM-CHANNEL NA(V)1.5, Human genetics, Pedigree, pathogenic variant Genetic testing, 030104 developmental biology, Next-generation sequencing, HEART-FAILURE, Female, Life Sciences & Biomedicine
Abstract

© 2018, American College of Medical Genetics and Genomics. Purpose: We evaluated strategies for identifying disease-causing variants in genetic testing for dilated cardiomyopathy (DCM). Methods: Cardiomyopathy gene panel testing was performed in 532 DCM patients and 527 healthy control subjects. Rare variants in 41 genes were stratified using variant-level and gene-level characteristics. Results: A majority of DCM cases and controls carried rare protein-altering cardiomyopathy gene variants. Variant-level characteristics alone had limited discriminative value. Differentiation between groups was substantially improved by addition of gene-level information that incorporated ranking of genes based on literature evidence for disease association. The odds of DCM were increased to nearly 9-fold for truncating variants or high-impact missense variants in the subset of 14 genes that had the strongest biological links to DCM (P

Published
2018

8. Robust identification of deletions in exome and genome sequence data based on clustering of Mendelian errors

Author

Wendy K. Chung, Jonathan G. Seidman, Bruce D. Gelb, Nihir Patel, Michael Parfenov, Kathryn B. Manheimer, Elizabeth Goldmuntz, Joshua M. Gorham, Christine E. Seidman, Marko T. Boskovski, Andrew J. Sharp, Deepak Srivastava, Felix Richter, Martina Brueckner, Martin Tristani-Firouzi, Angela C. Tai, and Jason Homsy

Subjects
0301 basic medicine, Heart Defects, Congenital, Male, DNA Copy Number Variations, UPD, Clinical Sciences, DNA Mutational Analysis, copy number variant identification, Genomics, Computational biology, Biology, Genome, Whole Exome Sequencing, Article, 03 medical and health sciences, symbols.namesake, Congenital, 0302 clinical medicine, Exome Sequencing, medicine, Genetics, Humans, Exome, Copy-number variation, Cluster analysis, Genetics (clinical), Exome sequencing, 030304 developmental biology, Heart Defects, Sequence Deletion, Whole genome sequencing, Genetics & Heredity, 0303 health sciences, whole genome sequencing, Whole Genome Sequencing, Genome, Human, Chromosome Mapping, medicine.disease, Uniparental disomy, 030104 developmental biology, Mendelian inheritance, symbols, Human genome, Female, 030217 neurology & neurosurgery, Human
Abstract

Multiple tools have been developed to identify copy number variants (CNVs) from whole exome (WES) and whole genome sequencing (WGS) data. Current tools such as XHMM for WES and CNVnator for WGS identify CNVs based on changes in read depth. For WGS, other methods to identify CNVs include utilizing discordant read pairs and split reads and genome-wide local assembly with tools such as Lumpy and SvABA, respectively. Here, we introduce a new method to identify deletion CNVs from WES and WGS trio data based on the clustering of Mendelian errors (MEs). Using our Mendelian Error Method (MEM), we identified 127 deletions (inherited and de novo) in 2,601 WES trios from the Pediatric Cardiac Genomics Consortium, with a validation rate of 88% by digital droplet PCR. MEM identified additional de novo deletions compared to XHMM, and also identified sample switches, DNA contamination, a significant enrichment of 15q11.2 deletions compared to controls and eight cases of uniparental disomy. We applied MEM to WGS data from the Genome In A Bottle Ashkenazi trio and identified deletions with 97% specificity. MEM provides a robust, computationally inexpensive method for identifying deletions, and an orthogonal approach for verifying deletions called by other tools.

Published
2018

9. ViroFind: A novel target-enrichment deep-sequencing platform reveals a complex JC virus population in the brain of PML patients

Author

Michael Parfenov, Spyros Chalkias, Igor J. Koralnik, Joshua M. Gorham, Erica Mazaika, Christine E. Seidman, Xin Dang, Steve Depalma, Jonathan G. Seidman, and David M. McKean

Subjects
0301 basic medicine, Genes, Viral, viruses, JC virus, lcsh:Medicine, medicine.disease_cause, Database and Informatics Methods, Genome Sequencing, lcsh:Science, Pathology and laboratory medicine, Viral Genomics, Multidisciplinary, Progressive multifocal leukoencephalopathy, Leukoencephalopathy, Progressive Multifocal, Microbial Genetics, Brain, High-Throughput Nucleotide Sequencing, Genomics, Medical microbiology, 3. Good health, Viruses, Viral Genome, Pathogens, Sequence Analysis, Research Article, Bioinformatics, Nucleotide Sequencing, Microbial Genomics, Computational biology, Biology, Research and Analysis Methods, Microbiology, DNA sequencing, Deep sequencing, 03 medical and health sciences, Virology, Genetics, medicine, Humans, Human virome, Molecular Biology Techniques, Sequencing Techniques, Molecular Biology, Medicine and health sciences, Biology and life sciences, lcsh:R, Organisms, Viral pathogens, Computational Biology, Genome Analysis, medicine.disease, Polyomaviruses, Microbial pathogens, 030104 developmental biology, Tissue tropism, Human genome, lcsh:Q, DNA viruses, Sequence Alignment
Abstract

Deep nucleotide sequencing enables the unbiased, broad-spectrum detection of viruses in clinical samples without requiring an a priori hypothesis for the source of infection. However, its use in clinical research applications is limited by low cost-effectiveness given that most of the sequencing information from clinical samples is related to the human genome, which renders the analysis of viral genomes challenging. To overcome this limitation we developed ViroFind, an in-solution target-enrichment platform for virus detection and discovery in clinical samples. ViroFind comprises 165,433 viral probes that cover the genomes of 535 selected DNA and RNA viruses that infect humans or could cause zoonosis. The ViroFind probes are used in a hybridization reaction to enrich viral sequences and therefore enhance the detection of viral genomes via deep sequencing. We used ViroFind to detect and analyze all viral populations in the brain of 5 patients with progressive multifocal leukoencephalopathy (PML) and of 18 control subjects with no known neurological disease. Compared to direct deep sequencing, by using ViroFind we enriched viral sequences present in the clinical samples up to 127-fold. We discovered highly complex polyoma virus JC populations in the PML brain samples with a remarkable degree of genetic divergence among the JC virus variants of each PML brain sample. Specifically for the viral capsid protein VP1 gene, we identified 24 single nucleotide substitutions, 12 of which were associated with amino acid changes. The most frequent (4 of 5 samples, 80%) amino acid change was D66H, which is associated with enhanced tissue tropism, and hence likely a viral fitness advantage, compared to other variants. Lastly, we also detected sparse JC virus sequences in 10 of 18 (55.5%) of control samples and sparse human herpes virus 6B (HHV6B) sequences in the brain of 11 of 18 (61.1%) control subjects. In sum, ViroFind enabled the in-depth analysis of all viral genomes in PML and control brain samples and allowed us to demonstrate a high degree of JC virus genetic divergence in vivo that has been previously underappreciated. ViroFind can be used to investigate the structure of the virome with unprecedented depth in health and disease state.

Published
2018

10. 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

11. Comprehensive genomic characterization of head and neck squamous cell carcinomas

Author

Ni Zhao, Carter Van Waes, Lori Boice, Ashley H. Salazar, Petar Stojanov, Michael B. Prystowsky, Akinyemi I. Ojesina, Tara M. Lichtenberg, Nikolaus Schultz, Joshua M. Stuart, Mitchell J. Frederick, Julie M. Gastier-Foster, Jeffrey N. Myers, Bradley A. Ozenberger, Margaret L. Gulley, Jean C. Zenklusen, Inanc Birol, Christina Yau, Mark E. Sherman, Saianand Balu, Angela Hadjipanayis, Barry S. Taylor, Piotr A. Mieczkowski, Anthony Saleh, Carol G. Shores, Ezra E.W. Cohen, Joonil Jung, Ari B. Kahn, Lisa Wise, Peter S. Hammerman, Pei Lin, Marc Ladanyi, Mark C. Weissler, Scott L. Carter, Michele C. Hayward, Rehan Akbani, Todd Pihl, J. Jack Lee, Sophie C. Egea, Harshad S. Mahadeshwar, Leigh B. Thorne, Matthew G. Soloway, Troy Shelton, Andrea Haddad, William N. William, Wiktoria Maria Suchorska, Johanna Gardner, Marco A. Marra, Julie Ahn, Travis I. Zack, Lihua Zou, Bayardo Perez-Ordonez, David A. Wheeler, Daniel Crain, Adrian Ally, Deepak Srinivasan, Jay Bowen, Aaron D. Black, Jing Wang, Ludmila Danilova, Roy Tarnuzzer, Brenda Diergaarde, Tod D. Casasent, Dean Cheng, Giovanni Ciriello, Ken Burnett, Jeff Bruce, Wojciech Golusiński, Jonathan G. Seidman, Corbin D. Jones, Daniel J. Weisenberger, Lisa A. Peterson, Thomas M. Harris, Angeliki Pantazi, Nina Thiessen, Curtis R. Pickering, Chandra Sekhar Pedamallu, Yingchun Liu, William Lee, Andrzej Mackiewicz, Hailei Zhang, Ronglai Shen, B. Arman Aksoy, Lixing Yang, Jeffrey Roach, Simion I. Chiosea, John Waldron, David Van Den Berg, James Stephen Marron, Tanja Davidsen, Liming Yang, Maciej Wiznerowicz, Benjamin Gross, Paul M. Weinberger, Yufeng Liu, Reanne Bowlby, Zhixiang Zuo, Bartosz Szybiak, Roni J. Bollag, Samuel S. Freeman, Heather M. Walline, Gad Getz, Scott Morris, Michael S. Noble, Charles Saller, Sahil Seth, Richard A. Gibbs, Jonathan C. Irish, Hollie A. Harper, George E. Sandusky, S. Onur Sumer, Trevor Hackman, Gordon B. Mills, Carol R. Bradford, Payal Sipahimalani, Nipun Kakkar, Robert Penny, Jennifer Drummond, Adam M. Zanation, Rebecca Carlsen, Andrew J. Mungall, Harshavardhan Doddapaneni, James G. Herman, Sylvia Wrenn, Andy Chu, Nilsa C. Ramirez, Patrick Kwok Shing Ng, Patrick K. Kimes, Tina Wong, Mark E. Prince, Han Si, Kristian Cibulskis, Katherine Tarvin, Peter W. Laird, Jiabin Tang, Raja R. Seethala, Michael Parfenov, Jan F. Prins, Erin Curley, Hui Cheng, Donna M. Muzny, Lynda Chin, D. Neil Hayes, Margi Sheth, Carmen Gomez-Fernandez, Jessica Walton, Paul C. Boutros, Ariane Nguyen, Kristen M. Leraas, Robert L. Ferris, Greg Eley, Christopher C. Benz, Jaegil Kim, Thomas E. Carey, Douglas B. Chepeha, Janae V. Simons, Jiexin Zhang, Laura S. Rozek, Maureen A. Sartor, Christopher A. Bristow, Justin A. Bishop, Adel K. El-Naggar, Nishant Agrawal, Yiling Lu, Carrie Sougnez, Evan G. Taylor, Raju Kucherlapati, Scott M. Lippman, Colleen Mitchell, Wendell G. Yarbrough, Chu Chen, Donghui Tan, Bhishamjit S. Chera, Michael Mayo, Wenbin Liu, Ranabir Guin, W. Kimryn Rathmell, Mayya Malakh, Jessica Frick, John N. Weinstein, Kevin Lau, Michelle Q. Pham, Gideon Dresdner, Luc G. T. Morris, David Mallery, Zhining Wang, Yichao Sun, Lynn M. Herbert, Christine M. Komarck, Lauren Averett Byers, Angela Tam, Thomas Bodenheimer, Doug Voet, Christie Kovar, Junyuan Wu, Walker Hale, Charles M. Perou, Angela B.Y. Hui, Kenna R. Mills Shaw, Timothy J. Triche, Dong Zeng, Steven J.M. Jones, Matthew D. Wilkerson, Jinze Liu, Yan Guo, Hsu Chao, Tamara R. Jones, Katherine A. Hoadley, Stuart R. Jefferys, Thomas C. Motter, Matthew Meyerson, Konstanty Korski, Timothy A. Chan, Mark A. Jensen, Julien Baboud, Alexei Protopopov, David I. Heiman, Nils Gehlenborg, Heidi J. Sofia, Aaron D. Tward, Eric S. Lander, Yunhu Wan, Scot Waring, Peggy Yena, Robert I. Haddad, Daniel DiCara, Gordon Saksena, Juok Cho, Richard A. Moore, Darshan Singh, Peter J. Park, Matthew Ibbs, Robert A. Holt, Andrew D. Cherniack, Tanguy Y. Seiwert, Lee Lichtenstein, Anders Jacobsen, Rameen Beroukhim, Brandee T. Brown, Stephen C. Benz, Paweł Golusiński, Vonn Walter, Lixia Diao, Erik Zmuda, Scott Frazer, Michael S. Lawrence, Nils Weinhold, Jacqueline E. Schein, Xiaojia Ren, Denise Brooks, Elizabeth Buda, Jianjiong Gao, Jianhua Zhang, William W. Shockley, J. Todd Auman, Xingzhi Song, Jennifer R. Grandis, Jonathan B. McHugh, Stacey Gabriel, Martin L. Ferguson, Jeffrey S. Reid, Joseph Paulauskis, Umadevi Veluvolu, John A. Demchok, Moiz S. Bootwalla, Fei-Fei Liu, Alan P. Hoyle, Shaowu Meng, Mei Huang, Ann Marie Egloff, Christina Beard, Liu Xi, Ricardo Ramirez, Donna Morton, Lisle E. Mose, Leslie Cope, Marjorie Romkes, Zubair Khan, Noreen Dhalla, Candace Shelton, Boris Reva, Stephen B. Baylin, Miruna Balasundaram, Psalm Haseley, Andrew Wei Xu, Yan Shi, A. Gordon Robertson, Gregory T. Wolf, Darlene Lee, Steven E. Schumacher, Semin Lee, Rileen Sinha, Dennis T. Maglinte, Haiyan I. Li, William K. Funkhouser, Yi Han, Sam Ng, Joel S. Parker, Kai Wang, Zhong Chen, You Hong Fan, Yaron S.N. Butterfield, Jeffrey S. Moyer, Robert A. Burton, David Pot, Chris Sander, Daryl Waggott, Joseph A. Califano, Netty Santoso, and Kyle Chang

Subjects
Male, DNA Copy Number Variations, Somatic cell, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, CDKN2A, Humans, HRAS, Molecular Targeted Therapy, RNA, Neoplasm, Gene, neoplasms, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Oncogene, Genome, Human, Squamous Cell Carcinoma of Head and Neck, Wnt signaling pathway, DNA, Neoplasm, Genomics, Oncogenes, Cell cycle, 3. Good health, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Mutation, Cancer research, Carcinoma, Squamous Cell, Female, FAT1, Signal Transduction, Transcription Factors
Abstract

The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.

Published
2015

12. Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Author

A. Gordon Robertson, Juliann Shih, Christina Yau, Ewan A. Gibb, Junna Oba, Karen L. Mungall, Julian M. Hess, Vladislav Uzunangelov, Vonn Walter, Ludmila Danilova, Tara M. Lichtenberg, Melanie Kucherlapati, Patrick K. Kimes, Ming Tang, Alexander Penson, Ozgun Babur, Rehan Akbani, Christopher A. Bristow, Katherine A. Hoadley, Lisa Iype, Matthew T. Chang, Andrew D. Cherniack, Christopher Benz, Gordon B. Mills, Roel G.W. Verhaak, Klaus G. Griewank, Ina Felau, Jean C. Zenklusen, Jeffrey E. Gershenwald, Lynn Schoenfield, Alexander J. Lazar, Mohamed H. Abdel-Rahman, Sergio Roman-Roman, Marc-Henri Stern, Colleen M. Cebulla, Michelle D. Williams, Martine J. Jager, Sarah E. Coupland, Bita Esmaeli, Cyriac Kandoth, Scott E. Woodman, Adrian Ally, J. Todd Auman, Miruna Balasundaram, Saianand Balu, Rameen Beroukhim, Inanc Birol, Tom Bodenheimer, Jay Bowen, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Lynda Chin, Juok Cho, Eric Chuah, Sudha Chudamani, Carrie Cibulskis, Kristian Cibulskis, Leslie Cope, Timothy Defreitas, John A. Demchok, Laurence Desjardins, Noreen Dhalla, Martin L. Ferguson, Scott Frazer, Stacey B. Gabriel, Julie M. Gastier-Foster, Nils Gehlenborg, Mark Gerken, Gad Getz, Elizabeth A. Grimm, D. Neil Hayes, Apurva M. Hegde, David I. Heiman, Carmen Helsel, Shital Hobensack, Robert A. Holt, Alan P. Hoyle, Xin Hu, Carolyn M. Hutter, Stuart R. Jefferys, Corbin D. Jones, Steven J.M. Jones, Katayoon Kasaian, Jaegil Kim, Raju Kucherlapati, Eric Lander, Michael S. Lawrence, Semin Lee, Kristen M. Leraas, Pei Lin, Jia Liu, Wenbin Liu, Laxmi Lolla, Yiling Lu, Yussanne Ma, Harshad S. Mahadeshwar, Odette Mariani, Marco A. Marra, Michael Mayo, Sam Meier, Shaowu Meng, Matthew Meyerson, Piotr A. Mieczkowski, Richard A. Moore, Lisle E. Mose, Andrew J. Mungall, Bradley A. Murray, Rashi Naresh, Michael S. Noble, Angeliki Pantazi, Michael Parfenov, Peter J. Park, Joel S. Parker, Charles M. Perou, Todd Pihl, Robert Pilarski, Alexei Protopopov, Amie Radenbaugh, Karan Rai, Nilsa C. Ramirez, Xiaojia Ren, Sheila M. Reynolds, Jeffrey Roach, Jason Roszik, Sara Sadeghi, Gordon Saksena, Xavier Sastre, Dirk Schadendorf, Jacqueline E. Schein, Steven E. Schumacher, Jonathan Seidman, Sahil Seth, Geetika Sethi, Margi Sheth, Yan Shi, Carol Shields, Ilya Shmulevich, Janae V. Simons, Arun D. Singh, Payal Sipahimalani, Tara Skelly, Heidi Sofia, Matthew G. Soloway, Xingzhi Song, Joshua Stuart, Qiang Sun, Huandong Sun, Angela Tam, Donghui Tan, Jiabin Tang, Roy Tarnuzzer, Barry S. Taylor, Nina Thiessen, Vesteinn Thorsson, Kane Tse, Umadevi Veluvolu, Doug Voet, Yunhu Wan, Zhining Wang, John N. Weinstein, Matthew D. Wilkerson, Lisa Wise, Tina Wong, Ye Wu, Liming Yang, Lixing Yang, Jiashan Zhang, Hailei Zhang, and Erik Zmuda

Subjects
0301 basic medicine, Uveal Neoplasms, Cancer Research, Medizin, Eukaryotic Initiation Factor-1, Uveal Neoplasm, medicine.disease_cause, 0302 clinical medicine, Monosomy, Medicine, Melanoma, Cancer, Genetics, BAP1, Mutation, molecular subtypes, Tumor, Serine-Arginine Splicing Factors, SF3B1, Prognosis, Gene Expression Regulation, Neoplastic, SRSF2, Oncology, 030220 oncology & carcinogenesis, EIF1AX, DNA methylation, RNA Splicing Factors, uveal melanoma, Ubiquitin Thiolesterase, DNA Copy Number Variations, Oncology and Carcinogenesis, TCGA Research Network, monosomy 3, GNA11, Biology, noncoding RNA, Article, 03 medical and health sciences, Rare Diseases, GNAQ, Biomarkers, Tumor, Humans, Oncology & Carcinogenesis, Eye Disease and Disorders of Vision, Neoplastic, business.industry, Tumor Suppressor Proteins, Human Genome, Neurosciences, Cell Biology, DNA Methylation, TCGA, medicine.disease, Phosphoproteins, 030104 developmental biology, Gene Expression Regulation, Cancer research, business, Biomarkers
Abstract

Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.

Published
2017

13. Increased Burden of Cardiovascular Disease in Carriers of APOL1 Genetic Variants

Author

Steven R. DePalma, Kaoru Ito, Christopher Newton-Cheh, Jason Flannick, Jonathan G. Seidman, Namrata Gupta, David J. Friedman, Sekar Kathiresan, James G. Wilson, Alexander G. Bick, Martin R. Pollak, Giulio Genovese, Christine E. Seidman, Stacey Gabriel, Michael Parfenov, David Altshuler, Ervin R. Fox, Joel N. Hirschhorn, and Herman A. Taylor

Subjects
Genetics, education.field_of_study, medicine.medical_specialty, biology, Physiology, Apolipoprotein L1, business.industry, Population, Disease, medicine.disease, Internal medicine, Genotype, Genetic variation, Epidemiology, biology.protein, Medicine, Allele, Cardiology and Cardiovascular Medicine, education, business, Kidney disease
Abstract

Rationale: Two distinct alleles in the gene encoding apolipoprotein L1 ( APOL1 ), a major component of high-density lipoprotein, confer protection against Trypanosoma brucei rhodesiense infection and also increase risk for chronic kidney disease. Approximately 14% of Americans with African ancestry carry 2 APOL1 risk alleles, accounting for the high chronic kidney disease burden in this population. Objective: We tested whether APOL1 risk alleles significantly increase risk for atherosclerotic cardiovascular disease (CVD) in African Americans. Methods and Results: We sequenced APOL1 in 1959 randomly selected African American participants in the Jackson Heart Study (JHS) and evaluated associations between APOL1 genotypes and renal and cardiovascular phenotypes. Previously identified association between APOL1 genotypes and chronic kidney disease was confirmed ( P =2.4×10 −6 ). Among JHS participants with 2 APOL1 risk alleles, we observed increased risk for CVD (50/763 events among participants without versus 37/280 events among participants with 2 risk alleles; odds ratio, 2.17; P =9.4×10 −4 ). We replicated this novel association of APOL1 genotype with CVD in Women’s Health Initiative (WHI) participants (66/292 events among participants without versus 37/101 events among participants with 2 risk alleles; odds ratio, 1.98; P =8.37×10 −3 ; JHS and WHI combined, P =8.5×10 −5 ; odds ratio, 2.12). The increased risk for CVD conferred by APOL1 alleles was robust to correction for both traditional CVD risk factors and chronic kidney disease. Conclusions: APOL1 variants contribute to atherosclerotic CVD risk, indicating a genetic component to cardiovascular health disparities in individuals of African ancestry. The considerable population of African Americans with 2 APOL1 risk alleles may benefit from intensive interventions to reduce CVD.

Published
2014

14. Abstract 5206: Role of super-enhancers in HPV+ head and neck squamous cell carcinoma

Author

Fernando T. Zamuner, Ilya Vorontsov, Emily Flam, Vera Mukhina, Ludmila Danilova, Tingting Ou, Elena Stavrovskaya, Theresa Guo, Eric Windsor, Dylan Z. Kelley, Michael Parfenov, Michael Considine, Elana J. Fertig, Alexander Favorov, and Daria A. Gaykalova

Subjects
Cancer Research, Oncology
Abstract

Head and neck squamous cell carcinomas (HNSCC) are the sixth leading cause of cancer worldwide with different incidences, mortalities, and prognosis for different subsites. Infection by Human Papilloma Viral (HPV) can cause the development of HPV+ HNSCC, the most rapidly growing population of cancer patients. The molecular biology of HPV+ HNSCC is related to abnormal transcriptional regulation. Super-enhancers (SEs) were recently identified as critical regulators of gene expression during cell differentiation and disease development. SEs are long clusters of enhancers that recruit master transcription factors (TFs) and coactivators to regulate the expression of target genes. We have recently developed a new whole-genome analytical pipeline to optimize ChIP-Seq procedures on primary surgical samples, and this protocol helped us to define the whole-genome distribution of H3K27ac, the hallmark of SEs, in HPV+ HNSCC samples. To detect SEs, we used a novel LILY algorithm that corrects the ChIP-Seq signal for copy number variation and CpG density. The analysis revealed that HPV+ HNSCC-specific SEs regulate genes critical for head and neck cancer development, such as EGFR, TP63, JAG1, IRF6, SMAD3, MAP4K2, SNAI1, TNFAIP3, ANO2, and TNFRSF1A. These genes are located in the vicinity of HNSCC-specific SEs, and the expression of those genes was altered by JQ1, the inhibitor of BRD4, the main component of SE machinery, supporting the role of SE in their regulation. The following Cistrome analysis allowed us to elucidate the TF composition of the SE machinery. Thus, we have found out that P63, P53, SOX2, FOSL1, SMAD3, and SNAI2 are TFs that are the most overrepresented in the HPV+ HNSCC-specific SEs. These comprehensive analyses have revealed novel insight into the HPV+ HNSCC biology and paved the basis for the implications for epigenetic therapeutics for this tumor types, and potentially other virus-related malignancies. Citation Format: Fernando T. Zamuner, Ilya Vorontsov, Emily Flam, Vera Mukhina, Ludmila Danilova, Tingting Ou, Elena Stavrovskaya, Theresa Guo, Eric Windsor, Dylan Z. Kelley, Michael Parfenov, Michael Considine, Elana J. Fertig, Alexander Favorov, Daria A. Gaykalova. Role of super-enhancers in HPV+ head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5206.

Published
2019

15. Molecular profiling of dilated cardiomyopathy that progresses to heart failure

Author

Michael A. Burke, Michael Parfenov, Danos C. Christodoulou, David A. Conner, Jonathan G. Seidman, Stephen Chang, Seda Eminaga, Tetsuo Konno, Hiroko Wakimoto, Joshua M. Gorham, Christine E. Seidman, and Steve Depalma

Subjects
0301 basic medicine, medicine.medical_specialty, Hypertrophic cardiomyopathy, Cardiomyopathy, Dilated cardiomyopathy, General Medicine, 030204 cardiovascular system & hematology, Biology, medicine.disease, Proinflammatory cytokine, Phospholamban, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Endocrinology, Downregulation and upregulation, Heart failure, Internal medicine, Genetic model, cardiovascular system, medicine, cardiovascular diseases, Research Article
Abstract

Dilated cardiomyopathy (DCM) is defined by progressive functional and structural changes. We performed RNA-seq at different stages of disease to define molecular signaling in the progression from pre-DCM hearts to DCM and overt heart failure (HF) using a genetic model of DCM (phospholamban missense mutation, PLNR9C/+). Pre-DCM hearts were phenotypically normal yet displayed proliferation of nonmyocytes (59% relative increase vs. WT, P = 8 × 10–4) and activation of proinflammatory signaling with notable cardiomyocyte-specific induction of a subset of profibrotic cytokines including TGFβ2 and TGFβ3. These changes progressed through DCM and HF, resulting in substantial fibrosis (17.6% of left ventricle [LV] vs. WT, P = 6 × 10–33). Cardiomyocytes displayed a marked shift in metabolic gene transcription: downregulation of aerobic respiration and subsequent upregulation of glucose utilization, changes coincident with attenuated expression of PPARα and PPARγ coactivators -1α (PGC1α) and -1β, and increased expression of the metabolic regulator T-box transcription factor 15 (Tbx15). Comparing DCM transcriptional profiles with those in hypertrophic cardiomyopathy (HCM) revealed similar and distinct molecular mechanisms. Our data suggest that cardiomyocyte-specific cytokine expression, early fibroblast activation, and the shift in metabolic gene expression are hallmarks of cardiomyopathy progression. Notably, key components of these profibrotic and metabolic networks were disease specific and distinguish DCM from HCM.

Published
2016

16. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma

Author

Michele Ceccarelli, Floris P. Barthel, Tathiane M. Malta, Thais S. Sabedot, Sofie R. Salama, Bradley A. Murray, Olena Morozova, Yulia Newton, Amie Radenbaugh, Stefano M. Pagnotta, Samreen Anjum, Jiguang Wang, Ganiraju Manyam, Pietro Zoppoli, Shiyun Ling, Arjun A. Rao, Mia Grifford, Andrew D. Cherniack, Hailei Zhang, Laila Poisson, Carlos Gilberto Carlotti, Daniela Pretti da Cunha Tirapelli, Arvind Rao, Tom Mikkelsen, Ching C. Lau, W.K. Alfred Yung, Raul Rabadan, Jason Huse, Daniel J. Brat, Norman L. Lehman, Jill S. Barnholtz-Sloan, Siyuan Zheng, Kenneth Hess, Ganesh Rao, Matthew Meyerson, Rameen Beroukhim, Lee Cooper, Rehan Akbani, Margaret Wrensch, David Haussler, Kenneth D. Aldape, Peter W. Laird, David H. Gutmann, Houtan Noushmehr, Antonio Iavarone, Roel G.W. Verhaak, Harindra Arachchi, J. Todd Auman, Miruna Balasundaram, Saianand Balu, Gene Barnett, Stephen Baylin, Sue Bell, Christopher Benz, Natalie Bir, Keith L. Black, Tom Bodenheimer, Lori Boice, Moiz S. Bootwalla, Jay Bowen, Christopher A. Bristow, Yaron S.N. Butterfield, Qing-Rong Chen, Lynda Chin, Juok Cho, Eric Chuah, Sudha Chudamani, Simon G. Coetzee, Mark L. Cohen, Howard Colman, Marta Couce, Fulvio D’Angelo, Tanja Davidsen, Amy Davis, John A. Demchok, Karen Devine, Li Ding, Rebecca Duell, J. Bradley Elder, Jennifer M. Eschbacher, Ashley Fehrenbach, Martin Ferguson, Scott Frazer, Gregory Fuller, Jordonna Fulop, Stacey B. Gabriel, Luciano Garofano, Julie M. Gastier-Foster, Nils Gehlenborg, Mark Gerken, Gad Getz, Caterina Giannini, William J. Gibson, Angela Hadjipanayis, D. Neil Hayes, David I. Heiman, Beth Hermes, Joe Hilty, Katherine A. Hoadley, Alan P. Hoyle, Mei Huang, Stuart R. Jefferys, Corbin D. Jones, Steven J.M. Jones, Zhenlin Ju, Alison Kastl, Ady Kendler, Jaegil Kim, Raju Kucherlapati, Phillip H. Lai, Michael S. Lawrence, Semin Lee, Kristen M. Leraas, Tara M. Lichtenberg, Pei Lin, Yuexin Liu, Jia Liu, Julia Y. Ljubimova, Yiling Lu, Yussanne Ma, Dennis T. Maglinte, Harshad S. Mahadeshwar, Marco A. Marra, Mary McGraw, Christopher McPherson, Shaowu Meng, Piotr A. Mieczkowski, C. Ryan Miller, Gordon B. Mills, Richard A. Moore, Lisle E. Mose, Andrew J. Mungall, Rashi Naresh, Theresa Naska, Luciano Neder, Michael S. Noble, Ardene Noss, Brian Patrick O’Neill, Quinn T. Ostrom, Cheryl Palmer, Angeliki Pantazi, Michael Parfenov, Peter J. Park, Joel S. Parker, Charles M. Perou, Christopher R. Pierson, Todd Pihl, Alexei Protopopov, Nilsa C. Ramirez, W. Kimryn Rathmell, Xiaojia Ren, Jeffrey Roach, A. Gordon Robertson, Gordon Saksena, Jacqueline E. Schein, Steven E. Schumacher, Jonathan Seidman, Kelly Senecal, Sahil Seth, Hui Shen, Yan Shi, Juliann Shih, Kristen Shimmel, Hugues Sicotte, Suzanne Sifri, Tiago Silva, Janae V. Simons, Rosy Singh, Tara Skelly, Andrew E. Sloan, Heidi J. Sofia, Matthew G. Soloway, Xingzhi Song, Carrie Sougnez, Camila Souza, Susan M. Staugaitis, Huandong Sun, Charlie Sun, Donghui Tan, Jiabin Tang, Yufang Tang, Leigh Thorne, Felipe Amstalden Trevisan, Timothy Triche, David J. Van Den Berg, Umadevi Veluvolu, Doug Voet, Yunhu Wan, Zhining Wang, Ronald Warnick, John N. Weinstein, Daniel J. Weisenberger, Matthew D. Wilkerson, Felicia Williams, Lisa Wise, Yingli Wolinsky, Junyuan Wu, Andrew W. Xu, Lixing Yang, Liming Yang, Travis I. Zack, Jean C. Zenklusen, Jianhua Zhang, Wei Zhang, Jiashan Zhang, Erik Zmuda, Ceccarelli, M, Barthel, Fp, Malta, Tm, Sabedot, T, Salama, Sr, Murray, Ba, Morozova, O, Newton, Y, Radenbaugh, A, Pagnotta, Sm, Anjum, S, Wang, Jg, Manyam, G, Zoppoli, P, Ling, S, Rao, Aa, Grifford, M, Cherniack, Ad, Zhang, Hl, Poisson, L, Carlotti, Cg, Tirapelli, Dpd, Rao, A, Mikkelsen, T, Lau, Cc, Yung, Wka, Rabadan, R, Huse, J, Brat, Dj, Lehman, Nl, Barnholtz-Sloan, J, Zheng, S, Hess, K, Rao, G, Meyerson, M, Beroukhim, R, Cooper, L, Akbani, R, Wrensch, M, Haussler, D, Aldape, Kd, Laird, Pw, Gutmann, Dh, Noushmehr, H, Iavarone, A, Verhaak, Rgw, and Neurosurgery

Subjects
0301 basic medicine, Adult, X-linked Nuclear Protein, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Epigenesis, Genetic, Transcriptome, 03 medical and health sciences, Diffuse Glioma, Glioma, medicine, Cluster Analysis, Humans, Promoter Regions, Genetic, Gene, Telomerase, ATRX, Cell Proliferation, Pilocytic astrocytoma, Biochemistry, Genetics and Molecular Biology(all), Brain Neoplasms, MUTAÇÃO GENÉTICA, DNA Helicases, Nuclear Proteins, DNA Methylation, Middle Aged, Telomere, medicine.disease, Isocitrate Dehydrogenase, 3. Good health, 030104 developmental biology, DNA demethylation, DNA methylation, Mutation, Cancer research, Signal Transduction
Abstract

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

Published
2016

17. Burden of Rare Sarcomere Gene Variants in the Framingham and Jackson Heart Study Cohorts

Author

Sekar Kathiresan, James G. Wilson, Jonathan G. Seidman, Heidi L. Rehm, Ramachandran S. Vasan, Jayashri Aragam, Michael Parfenov, Joel N. Hirschhorn, Susan Cheng, Ervin R. Fox, Birgit Funke, Christine E. Seidman, Steven R. DePalma, Daniel S. Herman, Jason Flannick, Christopher J. O'Donnell, Stacey Gabriel, Kaoru Ito, Christopher Newton-Cheh, Emelia J. Benjamin, Namrata Gupta, Alexander G. Bick, David Altshuler, and Herman A. Taylor

Subjects
Adult, Cardiomyopathy, Dilated, Male, Sarcomeres, medicine.medical_specialty, Population, Cardiomyopathy, 030204 cardiovascular system & hematology, Biology, Sarcomere, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Framingham Heart Study, Risk Factors, Report, Internal medicine, Genetics, medicine, Humans, Genetics(clinical), education, Genetics (clinical), Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, education.field_of_study, Framingham Risk Score, Models, Cardiovascular, Hypertrophic cardiomyopathy, Genetic Variation, Cardiomyopathy, Hypertrophic, Middle Aged, medicine.disease, 3. Good health, Cardiovascular Diseases, Cohort, Cardiology, Female, Cohort study
Abstract

Rare sarcomere protein variants cause dominant hypertrophic and dilated cardiomyopathies. To evaluate whether allelic variants in eight sarcomere genes are associated with cardiac morphology and function in the community, we sequenced 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts. Out of the total, 11.2% of individuals had one or more rare nonsynonymous sarcomere variants. The prevalence of likely pathogenic sarcomere variants was 0.6%, twice the previous estimates; however, only four of the 22 individuals had clinical manifestations of hypertrophic cardiomyopathy. Rare sarcomere variants were associated with an increased risk for adverse cardiovascular events (hazard ratio: 2.3) in the FHS cohort, suggesting that cardiovascular risk assessment in the general population can benefit from rare variant analysis.

Published
2012

18. The molecular taxonomy of primary prostate cancer

Author

Piotr A. Mieczkowski, Jianhua Zhang, Saianand Balu, Marc Ladanyi, Victor E. Reuter, Johanna Gardner, Junyuan Wu, Troy Shelton, Simone Chevalier, Marco A. Marra, Anuradha Gopalan, Roy Tarnuzzer, Pei Lin, Joel S. Parker, Umadevi Veluvolu, Lisle E. Mose, Rebecca Carlsen, Michel Carmel, Shalini S. Yadav, Joseph Paulauskis, Fadi Brimo, Sheila Reynolds, Scott Frazer, Natalya Dyakova, Christopher A. Bristow, Brian D. Robinson, Lucie Hamel, Yaron S.N. Butterfield, Yao Fu, Syed Haider, Christopher J. Logothetis, Michael Parfenov, Jeff Boyd, Katherine Tarvin, Kjong-Van Lehmann, Stuart R. Jefferys, Alan P. Hoyle, Arshi Arora, A. Gordon Robertson, Matti Annala, Thomas L. Bauer, Jianhua Luo, Rodolfo Borges Dos Reis, Louis Lacombe, Andrew Salner, Matti Nykter, Alexandre Doueik, Mei Huang, Alireza Moinzadeh, Joshua Armenia, Andre Kahles, Rehan Akbani, Todd Pihl, Gordon Saksena, Robert A. Holt, Felipe Amstalden Trevisan, Mario Berrios, Nina Thiessen, Ronglai Shen, Carrie Sougnez, Xiaojia Ren, Matthew G. Soloway, Lixing Yang, W. Marston Linehan, Chip Stewart, Angeliki Pantazi, Alain Bergeron, Andrea Sboner, Angela Hadjipanayis, Xingzhi Song, Carlos Gilberto Carlotti, Manaswi Gupta, Rashi Naresh, Yiling Lu, Hartmut Juhl, Mark Gerstein, Robert Leung, Sahil Seth, Teri A. Longacre, Ignaty Leshchiner, Chris Sander, Andrew Wei Xu, Anne Marie Mes-Masson, Patrick Teebagy, Julian M. Hess, Matthew Meyerson, Adrian Ally, Jiabin Tang, Ye Wu, Janae V. Simons, David Van Den Berg, Kenna R. Mills Shaw, Patricia Troncoso, Thomas Gribbin, Shannon J. McCall, Andrew K. Godwin, Daniel J. Weisenberger, Kimberly Rieger-Christ, Nilsa C. Ramirez, Peter J. Park, Margi Sheth, Mark E. Sherman, Eric S. Lander, Yunhu Wan, Lisa Iype, Robert Penny, J. Todd Auman, Ekta Khurana, Stephen J. Freedland, Jeffry Simko, Nils Weinhold, Bradley M. Broom, Angela Tam, Nikolaus Schultz, Erik Zmuda, Wei Zhang, Wenyi Wang, Jeffrey Roach, Christopher E. Barbieri, Alan H. Bryce, Qingguo Wang, Lawrence D. True, Christopher C. Benz, Mathieu Latour, Richard A. Moore, Michael Mayo, Yi Zhong, Tara M. Lichtenberg, Jacqueline E. Schein, Svitlana Tyekucheva, Ranabir Guin, Scott L. Carter, Michael Kerger, David Canes, Scott M. Lippman, Alexei Protopopov, Katayoon Kasaian, Peter A. Pinto, Peter S. Nelson, W. Kimryn Rathmell, David Mallery, Brett S. Carver, David I. Heiman, Juok Cho, Doug Voet, Thorsten Schlomm, Janet E. Cowan, Heidi J. Sofia, Peggy Yena, Matthew D. Wilkerson, Glenn Bubley, Tucker W. LeBien, Yan Shi, Lucas Lochovsky, Gordon B. Mills, Hailei Zhang, Andrea Holbrook, Christopher M. Hovens, Christina Yau, Jonathan G. Seidman, Samirkumar B. Amin, Corbin D. Jones, Andrew D. Cherniack, Lori Boice, Laxmi Lolla, Kristen M. Leraas, Denise Brooks, Francesca Demichelis, Maria Christina Tsourlakis, Katherine A. Hoadley, Charles Saller, Leigh B. Thorne, Julie M. Gastier-Foster, Jaegil Kim, Rameen Beroukhim, Peter R. Carroll, John A. Demchok, Christopher J. Kane, Jay Bowen, Massimo Loda, Richard Cartun, Ina Felau, Carl Morrison, Kerstin David, Eliezer M. Van Allen, Laura S. Schmidt, D. Neil Hayes, Adrian Bivol, Michael S. Lawrence, Raju Kucherlapati, Kelsey Zhu, Wen-Bin Liu, Matthew R. Cooperberg, Houtan Noushmehr, Daniel Crain, Luciano Neder, Lynda Chin, Barry S. Taylor, Jiashan Zhang, Bradley A. Murray, Ginette McKercher, Miruna Balasundaram, Chia Chin Wu, Peter T. Scardino, Suhn K. Rhie, Mark A. Rubin, Jean C. Zenklusen, Ronald Simon, Jaeil Ahn, Markus Graefen, Phillip H. Lai, Michael Ittmann, June M. Chan, Maria J. Merino, Andy Chu, Liming Yang, Charles M. Perou, Steven J.M. Jones, Gad Getz, Stacey Gabriel, Martin L. Ferguson, Jianjiong Gao, Payal Sipahimalani, Lisa Wise, Serghei Stepa, Arvind Rao, Bettina F. Drake, Antonia H. Holway, Armaz Mariamidze, Kiley Graim, Juliann Shih, Guido Sauter, Sarah Minner, Amanda Clarke, Harshad S. Mahadeshwar, Andrew J. Mungall, Alain Piché, Cathy D. Vocke, Sudha Chudamani, Yulia Newton, Davide Prandi, Roeland Verhaak, Ilya Shmulevich, Matthew T. Chang, Sara Sadeghi, Michael Button, Joshua M. Stuart, Anne Breggia, Kristian Cibulskis, Giovanni Ciriello, Paul C. Boutros, Yu Chen, Zhining Wang, Jerome Myers, Heidi Dvinge, Ashutosh Tewari, Scott Morris, Andrea Sorcini, Tara Skelly, Niall M. Corcoran, Michael S. Noble, Anthony J. Costello, Timothy C. Thompson, Eric Chuah, Carolyn M. Hutter, Robert K. Bradley, Fred Saad, John A. Libertino, Reanne Bowlby, John A. Stewart, Shiyun Ling, Gunnar Rätsch, George E. Sandusky, Alexis Sharp, Eric J. Burks, Thomas Zeng, Erin Curley, Charlie Sun, Rajiv Dhir, Yussanne Ma, Huihui Ye, Hui Shen, Nils Gehlenborg, Imelda Tenggara, Travis Sullivan, Tom Bodenheimer, Jia Liu, Christopher D. Andry, Adam Abeshouse, Daniela P. Tirapelli, John N. Weinstein, Kevin Lau, Francisco Sanchez-Vega, Armen Aprikian, Peter W. Laird, Noreen Dhalla, Candace Shelton, Joel Nelson, Bernard Têtu, Darlene Lee, Eleonora Scarlata, Mark Nelson, Steven E. Schumacher, Robert J. Klein, Mark Gerken, Donghui Tan, Semin Lee, John S. Witte, Shaowu Meng, Huandong Sun, Moiz S. Bootwalla, Scott A. Tomlins, Institute for Medical Engineering and Science, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Biology, Bradley, Robert K, Carmell, Michelle, Carter, Scott, Chin, Lynda, Cibulskis, Kristian, Getz, Gad Asher, Heiman, David, Lander, Eric Steven, Lin, Pei, Loda, Massimo, Meyerson, Matthew L, Park, Peter J, Seidman, Jonathan, Sougnez, Carrie L, Verhaak, Roel, and Voet, Douglas

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, DNA Repair, DNA repair, Urology, MEDLINE, Biology, SPOP, Bioinformatics, Molecular taxonomy, General Biochemistry, Genetics and Molecular Biology, Article, Epigenesis, Genetic, Fusion gene, 03 medical and health sciences, Prostate cancer, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Prostate, Internal medicine, medicine, Humans, Neoplasm Metastasis, Gene, 030304 developmental biology, Gynecology, 0303 health sciences, Primary (chemistry), business.industry, Prostatic Neoplasms, medicine.disease, 3. Good health, Androgen receptor, Gene Expression Regulation, Neoplastic, GENÉTICA, 030104 developmental biology, medicine.anatomical_structure, Receptors, Androgen, 030220 oncology & carcinogenesis, DNA methylation, Mutation, Cancer research, ras Proteins, Gene Fusion, business, Signal Transduction
Abstract

There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects., National Institutes of Health (U.S.). (grant 5U24CA143799), National Institutes of Health (U.S.). (grant 5U24CA143835), National Institutes of Health (U.S.). (grant 5U24CA143840), National Institutes of Health (U.S.). (grant 5U24CA143843), National Institutes of Health (U.S.). (grant 5U24CA143845), National Institutes of Health (U.S.). (grant 5U24CA143848), National Institutes of Health (U.S.). (grant 5U24CA143858), National Institutes of Health (U.S.). (grant 5U24CA143866), National Institutes of Health (U.S.). (grant 5U24CA143867), National Institutes of Health (U.S.). (grant 5U24CA143882), National Institutes of Health (U.S.). (grant 5U24CA143883), National Institutes of Health (U.S.). (grant 5U24CA144025), National Institutes of Health (U.S.). (grant U54HG003067), National Institutes of Health (U.S.). (grant U54HG003079), National Institutes of Health (U.S.). (grant U54HG003273), National Institutes of Health (U.S.). (grant P30CA16672)

Published
2015

19. Finding Pathogenic Nucleic Acid Sequences in Next Generation Sequencing Data

Author

Jonathan G. Seidman and Michael Parfenov

Subjects
Genetics, Base Sequence, Computational Biology, High-Throughput Nucleotide Sequencing, RNA, Genomics, Sequence Analysis, DNA, Biology, biology.organism_classification, Genome, DNA sequencing, Transcriptome Sequencing, Genome, Microbial, chemistry.chemical_compound, chemistry, Nucleic acid, Humans, Databases, Nucleic Acid, Genes, Microbial, Pathogen, Software, Genetics (clinical), Bacteria, DNA
Abstract

Viruses and bacteria are established as one of the main causes of human diseases from hepatitis to cancer. Recently, the presence of such pathogens has been extensively studied using human whole genome and transcriptome sequencing data. However, detecting and studying pathogens via next generation sequencing data is a challenging task in terms of time and computational resources. In this protocol we give instructions for a simple and quick method to find pathogenic DNA or RNA and detect possible integration of the pathogen genome into the host genome. © 2015 by John Wiley & Sons, Inc. Keywords: next generation sequencing; pathogens; viruses; bacteria; integration; detection

Published
2015

20. 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

21. Characterization of HPV and host genome interactions in primary head and neck cancers

Author

J. Jack Lee, Carter Van Waes, Michael B. Prystowsky, Akinyemi I. Ojesina, Joshua M. Stuart, Mitchell J. Frederick, Angela By Hui, Saianand Balu, Scot Waring, Inanc Birol, Bayardo Perez-Ordonez, Aaron D. Black, Payal Sipahimalani, Wiktoria Maria Suchorska, Michele C. Hayward, Jeffrey Roach, Adrian Ally, Ranabir Guin, Samuel S. Freeman, J. Todd Auman, Hollie A. Harper, Mark E. Prince, David Van Den Berg, Nipun Kakkar, James G. Herman, Adam M. Zanation, Nilsa C. Ramirez, Daniel DiCara, Carol R. Bradford, Paul C. Boutros, Peter W. Laird, Evan G. Taylor, Yan Shi, Jonathan M. Irish, Kristian Cibulskis, Junyuan Wu, Darlene Lee, Katherine A. Hoadley, Jeff Bruce, Yingchun Liu, Heather M. Walline, Carol G. Shores, Raju Kucherlapati, Scott M. Lippman, Colleen Mitchell, Steven E. Schumacher, Wendell G. Yarbrough, Tanguy Y. Seiwert, Sophie C. Egea, Elena Ivanova, Troy Shelton, Jiexin Zhang, Patrick K. Kimes, Nikolaus Schultz, Noreen Dhalla, Maciej Wiznerowicz, Daniel J. Weisenberger, Martin L. Ferguson, Tamara R. Jones, Haiyan I. Li, Nishant Agrawal, Yiling Lu, Lixing Yang, Brandee T. Brown, Julie M. Gastier-Foster, Nils Weinhold, Harshad S. Mahadeshwar, Angela Tam, Lihua Zou, Tom Bodenheimer, Gordon B. Mills, W. Kimryn Rathmell, David Mallery, Semin Lee, Scott J. Morris, Lynn M. Herbert, Hailei Zhang, Thomas C. Motter, Walker Hale, Tina Wong, Yichao Sun, Heidi J. Sofia, Rileen Sinha, Dennis T. Maglinte, Robert I. Haddad, Matthew D. Wilkerson, Jinze Liu, Julien Baboud, Brenda Diergaarde, Michelle Q. Pham, Tanja M. Davidsen, Maureen A. Sartor, Robert A. Holt, Angela Hadjipanayis, Pei Lin, Anders Jacobsen, Stephen C. Benz, Dean Cheng, Matthew Meyerson, Andy Chu, Ezra E.W. Cohen, Joonil Jung, Ari B. Kahn, Scott Frazer, Leigh B. Thorne, Andrew J. Mungall, David A. Wheeler, Nina Thiessen, Jay Bowen, Hui Cheng, D. Neil Hayes, Jennifer Drummond, Patrick Kwok Shing Ng, Harshavardhan Doddapaneni, S. Onur Sumer, Katherine Tarvin, John W.F. Waldron, Nils Gehlenborg, Douglas B. Chepeha, Janae V. Simons, Robert L. Ferris, Paweł Golusiński, Christina Beard, Donna Morton, Boris Reva, Psalm Haseley, Andrew Wei Xu, Giovanni Ciriello, Gregory T. Wolf, Ken Burnett, Lisa A. Peterson, Sylvia Wrenn, Mark A. Jensen, Travis I. Zack, Deepak Srinivasan, Thomas E. Carey, Lisle E. Mose, Mark E. Sherman, Leslie Cope, Adel K. El-Naggar, Marjorie Romkes, D Wheeler, Christopher A. Bristow, Andrea Haddad, Mayya Malakh, Ludmila Danilova, Jean C. Zenklusen, Jiabin Tang, Laura S. Rozek, Jon G. Seidman, Steven J.M. Jones, Hsu Chao, Candance Shelton, Carmen Gomez-Fernandez, Carrie Sougnez, Piotr A. Mieczkowski, Lee Lichtenstein, Erik Zmuda, Johanna Gardner, Jianjiong Gao, Marco A. Marra, Juok Cho, Alexei Protopopov, Roy Tarnuzzer, Tod D. Casasent, Timothy M. Chan, Michael Parfenov, Jing Wang, Christine M. Komarck, Lauren Averett Byers, Rehan Akbani, Todd Pihl, Curtis R. Pickering, Aaron D. Tward, Chandra Sekhar Pedamallu, Han Si, Jan F. Prins, Vonn Walter, Simion I. Chiosea, Jacqueline E. Schein, James Stephen Marron, Ariane Nguyen, William W. Shockley, Jennifer R. Grandis, Zhining Wang, Jeffrey N. Myers, Konstanty Korski, Bradley A. Ozenberger, Margaret L. Gulley, Barry S. Taylor, B. Arman Aksoy, Ni Zhao, Ashley H. Salazar, Petar Stojanov, Tara M. Lichtenberg, Chu Chen, Donghui Tan, Bhishamjit S. Chera, Andrzej Mackiewicz, A. Gordon Robertson, Ronglai Shen, Lisa Wise, Charles M. Perou, Michael Mayo, Charles Saller, Timothy J. Triche, Dong Zeng, Yan Guo, Lixia Diao, Jonathan B. McHugh, Zhixiang Zuo, Gad Getz, John A. Demchok, Raja R. Seethala, Gordon Saksena, Liu Xi, Liming Yang, Justin A. Bishop, Jessica Walton, Greg Eley, Jessica Frick, John N. Weinstein, Kevin Lau, Jianhua Zhang, Kenna R. Mills Shaw, Miruna Balasundaram, Zubair Khan, Umadevi Veluvolu, Stuart R. Jefferys, Christie Kovar, Moiz S. Bootwalla, Rebecca Carlsen, Daniel Crain, Fei-Fei Liu, Matthiew Ibbs, Michael S. Noble, William K. Funkhouser, Shaowu Meng, Mei Huang, Ann Marie Egloff, George E. Sandusky, Yi Han, Eric S. Lander, Sam Ng, William Lee, Christina Yau, Reanne Bowlby, Erin Curley, Donna M. Muzny, Lynda Chin, Joel S. Parker, Stephen B. Baylin, Peter S. Hammerman, Julie Ahn, Christopher C. Benz, Benjamin Gross, Paul M. Weinberger, Gideon Dresdner, Luc G. T. Morris, Zhong Chen, You Hong Fan, Angeliki Pantazi, David I. Heiman, Bartosz Szybiak, Sahil Seth, Richard A. Gibbs, Trevor Hackman, Peggy Yena, Richard A. Moore, Darshan Singh, Yaron S.N. Butterfield, Andrew D. Cherniack, Jeffrey S. Moyer, Robert A. Burton, Peter J. Park, Rameen Beroukhim, Ricardo Ramirez, Natalia Issaeva, Michael S. Lawrence, Wen-Bin Liu, Xiaojia Ren, Chris Sander, Yunhu Wan, Daryl Waggott, Joseph A. Califano, David A. Pot, Mathew G. Soloway, Roni J. Bollag, Stacey Gabriel, Jeffrey S. Reid, Netty Santoso, Elizabeth Buda, Doug Voet, Xingzhi Song, Kyle Chang, Joseph Paulauskis, Thomas M. Harris, Jaegil Kim, Alan P. Hoyle, Marc Ladanyi, Anthony Saleh, Mark C. Weissler, Scott L. Carter, Kai Wang, Jonathan G. Seidman, Corbin D. Jones, Wojciech Golusiński, Robert Penny, Margi Sheth, and Lori Boice

Subjects
Cervical Cancer, Genome, head and neck, Cancer Genome Atlas Network, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Papillomaviridae, Aetiology, Genetics, Multidisciplinary, biology, HPV infection, virus diseases, Biological Sciences, integration sites, female genital diseases and pregnancy complications, Gene Expression Regulation, Neoplastic, Infectious Diseases, Head and Neck Neoplasms, DNA methylation, Host-Pathogen Interactions, HIV/AIDS, Infection, Human, Virus Integration, Molecular Sequence Data, DNA sequencing, Rare Diseases, medicine, Humans, cancer, Dental/Oral and Craniofacial Disease, Gene, genome rearrangement, Neoplastic, Base Sequence, Genome, Human, Human Genome, DNA Methylation, biology.organism_classification, medicine.disease, Human genetics, Gene Expression Regulation, Genes, Neoplasm, Sexually Transmitted Infections, Human genome, Genes, Neoplasm, papilloma virus
Abstract

Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.

Published
2014

22. 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

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

Author

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

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

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

Published
2014

24. Loss of FHL1 induces an age-dependent skeletal muscle myopathy associated with myofibrillar and intermyofibrillar disorganization in mice

Author

Danos C. Christodoulou, Ju Chen, Michael Parfenov, Angela K. Peter, David S. Gokhin, Aldrin V. Gomes, Indroneal Banerjee, Ziyou Cui, G. Diane Shelton, Ling T. Guo, Richard L. Lieber, Andrea A. Domenighetti, Frank A. Witzmann, Xianyin Lai, Jonathan G. Seidman, Farah Sheikh, Daniel Y. Li, Tongbin Wu, Pao-Hsien Chu, Joshua M. Gorham, and Christine E. Seidman

Subjects
Male, Muscle Proteins, Medical and Health Sciences, Transgenic, Muscular Dystrophies, Myoblasts, Mice, Myofibrils, Myocyte, 2.1 Biological and endogenous factors, Muscular Dystrophy, Muscular dystrophy, Aetiology, Genetics (clinical), Genetics & Heredity, Emery-Dreifuss, Intracellular Signaling Peptides and Proteins, Age Factors, Cell Differentiation, Articles, General Medicine, Skeletal, LIM Domain Proteins, Biological Sciences, Muscular Dystrophy, Emery-Dreifuss, medicine.anatomical_structure, Muscle, Female, medicine.symptom, ITGA7, medicine.medical_specialty, Myoblasts, Skeletal, Intellectual and Developmental Disabilities (IDD), Mice, Transgenic, Biology, Motor Activity, Rare Diseases, Internal medicine, medicine, Genetics, Animals, Humans, Muscle, Skeletal, Myopathy, Molecular Biology, Loss function, Skeletal muscle, medicine.disease, FHL1, Brain Disorders, Endocrinology, Musculoskeletal, Myofibril
Abstract

Recent human genetic studies have provided evidences that sporadic or inherited missense mutations in four-and-a-half LIM domain protein 1 (FHL1), resulting in alterations in FHL1 protein expression, are associated with rare congenital myopathies, including reducing body myopathy and Emery–Dreifuss muscular dystrophy. However, it remains to be clarified whether mutations in FHL1 cause skeletal muscle remodeling owing to gain- or loss of FHL1 function. In this study, we used FHL1-null mice lacking global FHL1 expression to evaluate loss-of-function effects on skeletal muscle homeostasis. Histological and functional analyses of soleus, tibialis anterior and sternohyoideus muscles demonstrated that FHL1-null mice develop an age-dependent myopathy associated with myofibrillar and intermyofibrillar (mitochondrial and sarcoplasmic reticulum) disorganization, impaired muscle oxidative capacity and increased autophagic activity. A longitudinal study established decreased survival rates in FHL1-null mice, associated with age-dependent impairment of muscle contractile function and a significantly lower exercise capacity. Analysis of primary myoblasts isolated from FHL1-null muscles demonstrated early muscle fiber differentiation and maturation defects, which could be rescued by re-expression of the FHL1A isoform, highlighting that FHL1A is necessary for proper muscle fiber differentiation and maturation in vitro. Overall, our data show that loss of FHL1 function leads to myopathy in vivo and suggest that loss of function of FHL1 may be one of the mechanisms underlying muscle dystrophy in patients with FHL1 mutations.

Published
2014

25. 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

26. Comprehensive molecular characterization of urothelial bladder carcinoma

Author

Elizabeth Buda, Nikolaus Schultz, Donghui Tan, Pat Swanson, Xingzhi Song, Jennifer Owens, Carmelo Gaudioso, Liming Yang, Kenna R. Mills Shaw, Sophie C. Egea, John N. Weinstein, Lihua Zou, Dmitry A. Gordenin, Gad Getz, Stuart R. Jefferys, Wiam Bshara, David Haussler, Ari B. Kahn, Mary Iacocca, Brady Bernard, Charles M. Perou, Leigh B. Thorne, Kimberly R. Christ, Eric S. Lander, Yunhu Wan, Timothy J. Triche, Dong Zeng, Bogdan Czerniak, Wenbin Liu, Jianhua Zhang, David Mallery, B. Arman Aksoy, Lynn M. Herbert, Hailei Zhang, Jennifer DiPiero, Tod D. Casasent, Sugy Kodeeswaran, Daniel DiCara, Jacqueline E. Schein, Scott L. Carter, Umadevi Veluvolu, John M. S. Bartlett, Theresa M. Koppie, Ji Yeon Yang, Ronglai Shen, Yingchun Liu, Daniel J. Weisenberger, Ranabir Guin, Myra M. George, Marc Ladanyi, J. Todd Auman, Moiz S. Bootwalla, Shaowu Meng, Mark S. Soloway, Tatjana Antic, Greg Eley, Hikmat Al-Ahmadie, Carolyn M. Hutter, Jonathan G. Seidman, Corbin D. Jones, Lori Boice, Xiaoping Su, Jay Bowen, Raju Kucherlapati, Hui Shen, Benjamin Gross, Reanne Bowlby, Lawrence A. Donehower, Phan Thi Hanh, David J. McConkey, Saianand Balu, Jiexin Zhang, Tina Wong, Juok Cho, Alexei Protopopov, Carolyn L. Smith, Yuexin Liu, Angeliki Pantazi, Jason R. Gee, Xuan Van Le, Ricardo Ramirez, Ami S. Bhatt, Samuel S. Freeman, Jaegil Kim, Bui Duc Phu, Michael Ittman, Charles C. Guo, Carmen Gomez-Fernandez, Norm D. Smith, S. Onur Sumer, Bradley A. Ozenberger, Paul M. Weinberger, George E. Sandusky, Troy Shelton, Seth P. Lerner, Charles Saller, Nicholas J. Petrelli, Nguyen Van Bang, Sahil Seth, Richard A. Gibbs, Lisle E. Mose, Aaron D. Black, Yair Lotan, Carrie Sougnez, Jessie Au, Martin L. Ferguson, Ashley Marie Regazzi, Matthew Meyerson, Joel B. Nelson, Natasja Wye, Daniel E. Carlin, Nils Weinhold, Tom Bodenheimer, Nilsa C. Ramirez, Michael Ryan, Anders Jacobsen, Eric J. Burks, Lee Lichtenstein, Erin Curley, Angela Hadjipanayis, Nils Gehlenborg, Hector Rovira, Bernard Kohl, Jean C. Zenklusen, Travis Sullivan, Margaret Morgan, Rajiv Dhir, Julie M. Gastier-Foster, Gary D. Steinberg, Mathew G. Soloway, Nina Thiessen, Jianjiong Gao, Lisa Wise, Barry S. Taylor, Gordon Saksena, Hui Yao, David Van Den Berg, Jiabin Tang, Robert Penny, Nguyen Viet Tien, Jeffrey R. Gingrich, Jing Zhu, Ronald L. Hrebinko, Dick Kreisberg, Pei Lin, Christopher A. Bristow, Andrey Sivachenko, Andy Chu, Peter W. Laird, Thomas Barr, Junyuan Wu, Robert A. Holt, Harshad S. Mahadeshwar, Piotr A. Mieczkowski, Steven A. Roberts, Victor E. Reuter, Jeffrey S. Damrauer, Roni J. Bollag, Chad J. Creighton, Johanna Gardner, Michael Parfenov, Qiang Li, Phillip H. Lai, Thomas C. Motter, Alireza Moinzadeh, Jodi K. Maranchie, Christopher C. Benz, Lynda Chin, Angela Tam, Margi Sheth, David B. Solit, Erik Zmuda, Lixing Yang, Peter J. Park, Marco A. Marra, Katherine A. Hoadley, Eila C. Skinner, Scott Frazer, Roy Tarnuzzer, Heidi J. Sofia, Bradley M. Broom, Zhining Wang, David I. Heiman, Sebrina A Tello, Lori Huelsenbeck-Dill, Steven J.M. Jones, Antonia H. Holway, Ilana Rebecca Garcia-Grossman, Merce Jorda, Roeland Verhaak, Ilya Shmulevich, W.K. Rathmell, Bernard H. Bochner, Scot Waring, Kenneth Aldape, Richard A. Moore, Toshinori Hinoue, Carrie Hirst, Mark A. Jensen, Payal Kapur, Andrew D. Cherniack, Dean F. Bajorin, Evano Paull, Cheryl M. Lewis, William Y. Kim, Giovanni Ciriello, David C. Fargo, Gordon B. Mills, Michael S. Noble, Stephanie Weaver, Whitney D. McClenden, Benjamin Davies, Payal Sipahimalani, Vina Alexopoulou, Bo Peng, Stephen B. Baylin, Michael Mayo, Rameen Beroukhim, Boris Reva, Anil V. Parwani, Joshua M. Stuart, David J. Kwiatkowski, Stacey B. Gabrie, Janae V. Simons, Rehan Akbani, Todd Pihl, Nianxiang Zhang, Suzie Carter, Michael S. Lawrence, Carmen Helsel, Carl Morrison, Xiaojia Ren, Jeffrey Roach, Peter H. O'Donnell, Miruna Balasundaram, Yevgeniy Antipin, Gideon Dresdner, Cynthia McAllister, Tanja Davidsen, Brenda Rabeno, Jolanta Bondaruk, Kristian Cibulskis, Chip Stewart, Matthew D. Wilkerson, Jonathan E. Rosenberg, Brian D. Robinson, Patricia Castro, Wei Zhang, Chandra Sekhar Pedamallu, Allison Beaver, Andrew Wei Xu, Adrian Ally, Andrea Sorcini, Andrew J. Mungall, Katherine Tarvin, Christine Czerwinski, Petar Stojanov, Philip L. Lorenzi, Alan P. Hoyle, Jay Engel, Tara M. Lichtenberg, D. Neil Hayes, John A. Demchok, Eric Chuah, Benjamin Hanf, Deepak Srinivasan, Donna E. Hansel, Noreen Dhalla, Zhenlin Ju, Leszek J. Klimczak, Trevor J. Pugh, Richard Thorp, A. Gordon Robertson, Darlene Lee, Steven E. Schumacher, Semin Lee, Sheldon I. Bastacky, Rileen Sinha, Haiyan I. Li, William Lee, Sam Ng, Joel S. Parker, Sheila Reynolds, Teresa R. Tabler, Yaron S.N. Butterfield, David Pot, Chris Sander, Wenyi Wang, Weiguo Jian, Le Quang Vinh, Netty Santoso, Doug Voet, and Joonil Jung

Subjects
Metastatic Urothelial Carcinoma, Invasive urothelial carcinoma, Virus Integration, Down-Regulation, Disease, Bioinformatics, Malignancy, Article, Phosphatidylinositol 3-Kinases, Cancer genome, medicine, Carcinoma, Humans, Molecular Targeted Therapy, RNA, Messenger, Urothelial carcinoma, Multidisciplinary, business.industry, TOR Serine-Threonine Kinases, Cell Cycle, Creative commons, medicine.disease, Chromatin, 3. Good health, Gene Expression Regulation, Neoplastic, MicroRNAs, Oxidative Stress, Urinary Bladder Neoplasms, business, Protein Kinases, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.

Published
2013

27. Comprehensive molecular profiling of lung adenocarcinoma

Author

Amie Radenbaugh, Noreen Dhalla, Christina Williamson, Charles Saller, James Suh, Ramaswamy Govindan, Travis I. Zack, Paul T. Spellman, Daniel DiCara, Harvey I. Pass, Deepak Srinivasan, William G. Richards, Robert J. Cerfolio, Igor Letovanec, A. Gordon Robertson, Gabriel Sica, Chad J. Creighton, Hendrik Dienemann, Jeffrey A. Borgia, Boris Reva, Bryan F. Meyers, Yiling Lu, Nikolaus Schultz, Christopher I. Amos, Dante Trusty, Carmelo Gaudioso, Michael Meister, James T. Robinson, Lihua Zou, James Shin, Jeremy Parfitt, Darlene Lee, Junyuan Wu, Carl Morrison, Scott L. Carter, Giovanni Ciriello, Nils Weinhold, Elena Nemirovich-Danchenko, Andrew Wei Xu, Christopher G. Maher, Lori Boice, Irina Zaytseva, Dennis A. Wigle, Kenna R. Mills Shaw, Matthew G. Soloway, Matthew Meyerson, Peng Chieh Chen, Frank Schneider, Troy Shelton, Douglas Voet, Steven E. Schumacher, D L Rotin, Saianand Balu, Stuart R. Jefferys, Tom Bodenheimer, Bradley A. Ozenberger, Eric S. Lander, Edward Gabrielson, Konstantin V. Fedosenko, Rehan Akbani, William D. Travis, Ari B. Kahn, Marcin Imielinski, Jacqueline E. Schein, Thomas L. Bauer, Kai Ye, Samuel A. Yousem, Robert C. Onofrio, Thomas Muley, Ayesha S. Bryant, Michael K. Asiedu, Monique Albert, Pei Lin, Corbin D. Jones, Edwina Duhig, Jean C. Zenklusen, Lucinda Fulton, Christina Yau, J. Todd Auman, Leigh B. Thorne, Elena Helman, Richard T. Cheney, William Lee, Patrick K. Kimes, Juok Cho, Alexei Protopopov, Wenbin Liu, Lee Lichtenstein, Jing Wang, Lixing Yang, W. Kimryn Rathmell, Jo Ellen Weaver, David A. Wheeler, Leslie Cope, Mark A. Watson, Heidi J. Sofia, Angeliki Pantazi, Ronglai Shen, Jeffrey Roach, Eric A. Collisson, Patrick Kwok Shing Ng, Angela Hadjipanayis, Peter S. Hammerman, David Van Den Berg, Kwun M. Fong, Nils Gehlenborg, Natasha Rekhtman, William K. Funkhouser, D. Neil Hayes, Harshad S. Mahadeshwar, Semin Lee, Martin Peifer, David Mallery, Piotr A. Mieczkowski, Ranabir Guin, Madhusmita Behera, Philipp A. Schnabel, Jill M. Siegfried, Carmen Gomez-Fernandez, Johanna Gardner, Lynn M. Herbert, Hailei Zhang, Robert S. Fulton, Travis Sullivan, Sahil Seth, Sam Ng, Chandra Sekhar Pedamallu, Barry S. Taylor, Venkatraman E. Seshan, Valerie W. Rusch, Jinze Liu, Daniel P. Raymond, Jianjiong Gao, Nathan A. Pennell, Marco A. Marra, Jan F. Prins, Payal Sipahimalani, Janae V. Simons, Joel S. Parker, Rileen Sinha, Lindy Hunter, Raju Kucherlapati, Dennis T. Maglinte, Fedor Moiseenko, Eric E. Snyder, Roy Tarnuzzer, Beverly Lee, James Stephen Marron, Kristian Cibulskis, Jerome Myers, Haiyan I. Li, Robert Penny, Hartmut Juhl, Richard K. Wilson, Zhining Wang, Eran Hodis, Carrie Sougnez, Jiabin Tang, William Mallard, Bryan Hernandez, Liming Yang, Jennifer Brown, Gad Getz, Farhad Kosari, Catrina Fronick, Juliann Chmielecki, Jianhua Zhang, Suresh S. Ramalingam, Michael Parfenov, Peter J. Park, Tanja Davidsen, Philip H. Lai, Jeff Boyd, Dang Huy Quoc Thinh, Harmanjatinder S. Sekhon, Malcolm V. Brock, Mark Pool, Margi Sheth, Kimberly M. Rieger-Christ, Michael J. Liptay, E. Getz, S. Onur Sumer, Ian A. Yang, B. Arman Aksoy, Douglas B. Flieder, Bradley M. Broom, Carrie Hirst, Solange Peters, Joshua M. Stuart, Khurram Z. Khan, Scott Morris, Donghui Tan, Andrew J. Mungall, Ming-Sound Tsao, Gordon B. Mills, Stephen B. Baylin, Rebecca Carlsen, Sanja Dacic, Julien Baboud, Brenda Rabeno, Richard A. Hajek, Lauren Averett Byers, Yaron S.N. Butterfield, Miruna Balasundaram, Chip Stewart, Katherine Tarvin, Peter B. Illei, James G. Herman, David J. Kwiatkowski, Andy Chu, David Haussler, Natasja Wye, Charles M. Perou, Peter W. Laird, Timothy J. Triche, Yan Shi, Jill P. Mesirov, Angela N. Brooks, Lori Huelsenbeck-Dill, Steven J.M. Jones, Antonia H. Holway, Lixia Diao, Anthony A. Gal, David G. Beer, Angela Tam, Ashley H. Salazar, Mark A. Jensen, Robert A. Holt, Katherine A. Hoadley, John A. Demchok, Sandra McDonald, Chandra Goparaju, David Pot, Belinda E. Clarke, Gordon Robertson, Michael C. Wendl, Helga Thorvaldsdottir, Kristen Rogers, Joshua D. Campbell, Chris Sander, Rayleen V. Bowman, Marc Danie Nazaire, Michael Mayo, Olga Voronina, Ludmila Danilova, Paul Zippile, Netty Santoso, John V. Heymach, Matthew D. Wilkerson, John Eckman, Morgan Windsor, Cureline Oleg Dolzhanskiy, Nina Thiessen, Mara Rosenberg, Gideon Dresdner, Levi A. Garraway, Eric Chuah, Richard Varhol, Elizabeth Buda, Li Ding, Alice H. Berger, Xingzhi Song, John M. S. Bartlett, Michael D. McLellan, Olga Potapova, Joseph Paulauskis, Igor Jurisica, Benjamin Gross, Jaegil Kim, John N. Weinstein, Kevin Lau, Christopher R. Cabanski, Philip Bonomi, Michael S. Noble, Maureen F. Zakowski, George E. Sandusky, Mary Iacocca, Eric J. Burks, Erin Curley, Lynda Chin, Rajiv Dhir, Singer Ma, Sophie C. Egea, Umadevi Veluvolu, Sugy Kodeeswaran, Christopher A. Miller, Moiz S. Bootwalla, Daniel J. Weisenberger, Shaowu Meng, Mei Huang, Elaine R. Mardis, Gordon Saksena, Nicholas J. Petrelli, Yvonne Owusu-Sarpong, Christopher C. Benz, Bernard Kohl, Jingchun Zhu, David I. Heiman, Carol Farver, Scot Waring, Richard A. Moore, Darshan Singh, Andrew D. Cherniack, Rameen Beroukhim, Michael S. Lawrence, Xiaojia Ren, Marc Ladanyi, Stacey Gabriel, Christine Czerwinski, Alan P. Hoyle, Cancer Genome Atlas Research Network, Collisson, E. A., Campbell, J.D., Brooks, A.N., Berger, A.H., Lee, W., Chmielecki, J., Beer, D.G., Cope, L., Creighton, C.J., Danilova, L., Ding, L., Getz, G., Hammerman, P.S., Hayes, D.N., Hernandez, B., Herman, J.G., Heymach, J.V., Jurisica, I., Kucherlapati, R., Kwiatkowski, D., Ladanyi, M., Robertson, G., Schultz, N., Shen, R., Sinha, R., Sougnez, C., Tsao, M.S., Travis, W.D., Weinstein, J.N., Wigle, D.A., Wilkerson, M.D., Chu, A., Cherniack, A.D., Hadjipanayis, A., Rosenberg, M., Weisenberger, D.J., Laird, P.W., Radenbaugh, A., Ma, S., Stuart, J.M., Averett Byers, L., Baylin, S.B., Govindan, R., Meyerson, M., Gabriel, S.B., Cibulskis, K., Kim, J., Stewart, C., Lichtenstein, L., Lander, E.S., Lawrence, M.S., Kandoth, C., Fulton, R., Fulton, L.L., McLellan, M.D., Wilson, R.K., Ye, K., Fronick, C.C., Maher, C.A., Miller, C.A., Wendl, M.C., Cabanski, C., Mardis, E., Wheeler, D., Balasundaram, M., Butterfield, Y.S., Carlsen, R., Chuah, E., Dhalla, N., Guin, R., Hirst, C., Lee, D., Li, H.I., Mayo, M., Moore, R.A., Mungall, A.J., Schein, J.E., Sipahimalani, P., Tam, A., Varhol, R., Robertson, A., Wye, N., Thiessen, N., Holt, R.A., Jones, S.J., Marra, M.A., Imielinski, M., Onofrio, R.C., Hodis, E., Zack, T., Helman, E., Sekhar Pedamallu, C., Mesirov, J., Saksena, G., Schumacher, S.E., Carter, S.L., Garraway, L., Beroukhim, R., Lee, S., Mahadeshwar, H.S., Pantazi, A., Protopopov, A., Ren, X., Seth, S., Song, X., Tang, J., Yang, L., Zhang, J., Chen, P.C., Parfenov, M., Wei Xu, A., Santoso, N., Chin, L., Park, P.J., Hoadley, K.A., Auman, J.T., Meng, S., Shi, Y., Buda, E., Waring, S., Veluvolu, U., Tan, D., Mieczkowski, P.A., Jones, C.D., Simons, J.V., Soloway, M.G., Bodenheimer, T., Jefferys, S.R., Roach, J., Hoyle, A.P., Wu, J., Balu, S., Singh, D., Prins, J.F., Marron, J.S., Parker, J.S., Perou, C.M., Liu, J., Maglinte, D.T., Lai, P.H., Bootwalla, M.S., Van Den Berg, D.J., Triche, T., Cho, J., DiCara, D., Heiman, D., Lin, P., Mallard, W., Voet, D., Zhang, H., Zou, L., Noble, M.S., Gehlenborg, N., Thorvaldsdottir, H., Nazaire, M.D., Robinson, J., Aksoy, B.A., Ciriello, G., Taylor, B.S., Dresdner, G., Gao, J., Gross, B., Seshan, V.E., Reva, B., Sumer, S.O., Weinhold, N., Sander, C., Ng, S., Zhu, J., Benz, C.C., Yau, C., Haussler, D., Spellman, P.T., Kimes, P.K., Broom, B.M., Wang, J., Lu, Y., Kwok Shing Ng, P., Diao, L., Liu, W., Amos, C.I., Akbani, R., Mills, G.B., Curley, E., Paulauskis, J., Lau, K., Morris, S., Shelton, T., Mallery, D., Gardner, J., Penny, R., Saller, C., Tarvin, K., Richards, W.G., Cerfolio, R., Bryant, A., Raymond, D.P., Pennell, N.A., Farver, C., Czerwinski, C., Huelsenbeck-Dill, L., Iacocca, M., Petrelli, N., Rabeno, B., Brown, J., Bauer, T., Dolzhanskiy, O., Potapova, O., Rotin, D., Voronina, O., Nemirovich-Danchenko, E., Fedosenko, K.V., Gal, A., Behera, M., Ramalingam, S.S., Sica, G., Flieder, D., Boyd, J., Weaver, J., Kohl, B., Huy Quoc Thinh, D., Sandusky, G., Juhl, H., Duhig, E., Illei, P., Gabrielson, E., Shin, J., Lee, B., Rodgers, K., Trusty, D., Brock, M.V., Williamson, C., Burks, E., Rieger-Christ, K., Holway, A., Sullivan, T., Asiedu, M.K., Kosari, F., Rekhtman, N., Zakowski, M., Rusch, V.W., Zippile, P., Suh, J., Pass, H., Goparaju, C., Owusu-Sarpong, Y., Bartlett, J.M., Kodeeswaran, S., Parfitt, J., Sekhon, H., Albert, M., Eckman, J., Myers, J.B., Cheney, R., Morrison, C., Gaudioso, C., Borgia, J.A., Bonomi, P., Pool, M., Liptay, M.J., Moiseenko, F., Zaytseva, I., Dienemann, H., Meister, M., Schnabel, P.A., Muley, T.R., Peifer, M., Gomez-Fernandez, C., Herbert, L., Egea, S., Huang, M., Thorne, L.B., Boice, L., Hill Salazar, A., Funkhouser, W.K., Rathmell, W.K., Dhir, R., Yousem, S.A., Dacic, S., Schneider, F., Siegfried, J.M., Hajek, R., Watson, M.A., McDonald, S., Meyers, B., Clarke, B., Yang, I.A., Fong, K.M., Hunter, L., Windsor, M., Bowman, R.V., Peters, S., Letovanec, I., Khan, K.Z., Jensen, M.A., Snyder, E.E., Srinivasan, D., Kahn, A.B., Baboud, J., Pot, D.A., Mills Shaw, K.R., Sheth, M., Davidsen, T., Demchok, J.A., Wang, Z., Tarnuzzer, R., Zenklusen, J.C., Ozenberger, B.A., Sofia, H.J., Massachusetts Institute of Technology. Department of Biology, and Lander, Eric S.

Subjects
Male, Lung Neoplasms, Adenocarcinoma/genetics, Adenocarcinoma/pathology, Cell Cycle Proteins/genetics, Female, Gene Dosage, Gene Expression Regulation, Neoplastic, Genomics, Humans, Lung Neoplasms/genetics, Lung Neoplasms/pathology, Molecular Typing, Mutation/genetics, Oncogenes/genetics, Sex Factors, Transcriptome/genetics, Adenocarcinoma of Lung, Cell Cycle Proteins, Biology, Adenocarcinoma, Exon, Germline mutation, microRNA, Adenocarcinoma of the lung, medicine, Gene, Multidisciplinary, Oncogene, Oncogenes, medicine.disease, MET Exon 14 Skipping Mutation, Molecular biology, 3. Good health, Mutation, Transcriptome
Abstract

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

Published
2013

28. De novo mutations in histone-modifying genes in congenital heart disease

Author

Hiroko Wakimoto, Bruce D. Gelb, Stephen Sanders, Jennie Kline, Peter White, Khalid Adnan Mohamed A. Fakhro, Jonathan G. Seidman, Lijiang Ma, Michael Parfenov, Irina Tikhonova, Michael J. Italia, Robert D. Bjornson, Mathew W. State, Howard S. Seiden, Amy E. Roberts, George A. Porter, Samir Zaidi, Jeremy Leipzig, Wei Wang, Elizabeth Goldmuntz, Alexander Lopez, Jianming Jiang, Hongyu Zhao, Murim Choi, Christine E. Seidman, Steve Depalma, Sai Lakshmi Subramanian, Jonathan R. Kaltman, Jane W. Newburger, Richard B. Kim, Richard P. Lifton, Dorothy Warburton, Ravi Sachidanandam, Wendy K. Chung, Martina Brueckner, Shrikant Mane, John E. Deanfield, Kerry K. Brown, Juan Pablo Kaski, Nicholas Carriero, Angela Romano-Adesman, Teresa Lee, John D. Overton, Laura E. Mitchell, Hakon Hakonarson, Ismee A. Williams, Joseph T. Glessner, Yee Him Cheung, Itsik Pe'er, and Roger E. Breitbart

Subjects
Adult, Male, Heart Diseases, DNA Mutational Analysis, 030204 cardiovascular system & hematology, Biology, Bioinformatics, medicine.disease_cause, Methylation, Article, Frameshift mutation, Histones, 03 medical and health sciences, 0302 clinical medicine, medicine, Odds Ratio, Humans, Exome, Epigenetics, Genes, Developmental, Child, Promoter Regions, Genetic, Gene, Exome sequencing, 030304 developmental biology, Genetics, 0303 health sciences, Mutation, Multidisciplinary, Point mutation, Lysine, Chromatin, Histone, Enhancer Elements, Genetic, Case-Control Studies, biology.protein, Female
Abstract

Exome sequencing of patients with congenital heart disease (CHD) and their unaffected parents reveals an excess of strong-effect, protein-altering de novo mutations in genes expressed in the developing heart, many of which regulate chromatin modification in key developmental genes; collectively, these mutations are predicted to account for approximately 10% of severe CHD cases. This paper demonstrates that de novo mutations with large effect have a role in the pathogenesis of at least 10% of cases of congenital heart disease (CHD). Using exome sequence analysis in parent–offspring trios Richard Lifton and colleagues compared the frequency of de novo mutations, identified by exome sequencing, in 362 CHD parent–offspring trios and 264 control trios. Gene ontology analysis demonstrated significant enrichment of de novo protein-altering mutation of genes involved in chromatin modification, notably a marked enrichment of genes involved in the production, removal and reading of methylation of histone H3K4 and H3K27. Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births1. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent–offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation2,3,4. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left–right organizer5. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes ‘poised’ promoters and enhancers, which regulate expression of key developmental genes6. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.

Published
2013

29. 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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