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7 results on '"Murray, Bradley"'

1. Integrated Molecular Characterization of Uterine Carcinosarcoma

Author

Cherniack, Andrew D, Shen, Hui, Walter, Vonn, Stewart, Chip, Murray, Bradley A, Bowlby, Reanne, Hu, Xin, Ling, Shiyun, Soslow, Robert A, Broaddus, Russell R, Zuna, Rosemary E, Robertson, Gordon, Laird, Peter W, Kucherlapati, Raju, Mills, Gordon B, Network, The Cancer Genome Atlas Research, Akbani, Rehan, Ally, Adrian, Auman, J Todd, Balasundaram, Miruna, Balu, Saianand, Baylin, Stephen B, Beroukhim, Rameen, Bodenheimer, Tom, Bogomolniy, Faina, Boice, Lori, Bootwalla, Moiz S, Bowen, Jay, Broaddus, Russell, Brooks, Denise, Carlsen, Rebecca, Cho, Juok, Chuah, Eric, Chudamani, Sudha, Cibulskis, Kristian, Cline, Melissa, Dao, Fanny, David, Mutch, Demchok, John A, Dhalla, Noreen, Dowdy, Sean, Felau, Ina, Ferguson, Martin L, Frazer, Scott, Frick, Jessica, Gabriel, Stacey, Gastier-Foster, Julie M, Gehlenborg, Nils, Gerken, Mark, Getz, Gad, Gupta, Manaswi, Haussler, David, Hayes, D Neil, Heiman, David I, Hess, Julian, Hoadley, Katherine A, Hoffmann, Robert, Holt, Robert A, Hoyle, Alan P, Huang, Mei, Hutter, Carolyn M, Jefferys, Stuart R, Jones, Steven JM, Jones, Corbin D, Kanchi, Rupa S, Kandoth, Cyriac, Kasaian, Katayoon, Kerr, Sarah, Kim, Jaegil, Lai, Phillip H, Lander, Eric, Lawrence, Michael S, Lee, Darlene, Leraas, Kristen M, Leshchiner, Ignaty, Levine, Douglas A, Lichtenberg, Tara M, Lin, Pei, Liu, Jia, Liu, Wenbin, Liu, Yuexin, Lolla, Laxmi, Lu, Yiling, Ma, Yussanne, Maglinte, Dennis T, Marra, Marco A, Mayo, Michael, Meng, Shaowu, Meyerson, Matthew, Mieczkowski, Piotr A, Moore, Richard A, Mose, Lisle E, Mungall, Andrew J, and Mungall, Karen

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Reproductive Medicine, Human Genome, Cancer, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Carcinosarcoma, DNA Copy Number Variations, Epithelial-Mesenchymal Transition, Female, Humans, Mutation, Uterine Neoplasms, Cancer Genome Atlas Research Network, EMT, TGGA, The Cancer Genome Atlas, UCS, endometrial cancer, epithelial-to-mesenchymal transition, gynecologic cancer, gynecologic oncology, translational science, uterine carcinosarcoma, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified.

Published
2017

2. Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

Author

Fishbein, Lauren, Leshchiner, Ignaty, Walter, Vonn, Danilova, Ludmila, Robertson, A Gordon, Johnson, Amy R, Lichtenberg, Tara M, Murray, Bradley A, Ghayee, Hans K, Else, Tobias, Ling, Shiyun, Jefferys, Stuart R, de Cubas, Aguirre A, Wenz, Brandon, Korpershoek, Esther, Amelio, Antonio L, Makowski, Liza, Rathmell, W Kimryn, Gimenez-Roqueplo, Anne-Paule, Giordano, Thomas J, L., Sylvia, Tischler, Arthur S, Network, The Cancer Genome Atlas Research, Akbani, Rehan, Ally, Adrian, Amar, Laurence, Arachchi, Harindra, Auchus, Richard J, Auman, J Todd, Baertsch, Robert, Balasundaram, Miruna, Balu, Saianand, Bartsch, Detlef K, Baudin, Eric, Bauer, Thomas, Beaver, Allison, Benz, Christopher, Beroukhim, Rameen, Beuschlein, Felix, Bodenheimer, Tom, Boice, Lori, Bowen, Jay, Bowlby, Reanne, Brooks, Denise, Carlsen, Rebecca, Carter, Suzie, Cassol, Clarissa A, Cherniack, Andrew D, Chin, Lynda, Cho, Juok, Chuah, Eric, Chudamani, Sudha, Cope, Leslie, Crain, Daniel, Curley, Erin, de Krijger, Ronald R, Demchok, John A, Deutschbein, Timo, Dhalla, Noreen, Dimmock, David, Dinjens, Winand NM, Eng, Charis, Eschbacher, Jennifer, Fassnacht, Martin, Felau, Ina, Feldman, Michael, Ferguson, Martin L, Fiddes, Ian, Frazer, Scott, Gabriel, Stacey B, Gardner, Johanna, Gastier-Foster, Julie M, Gehlenborg, Nils, Gerken, Mark, Getz, Gad, Geurts, Jennifer, Goldman, Mary, Graim, Kiley, Gupta, Manaswi, Haan, David, Hahner, Stefanie, Hantel, Constanze, Haussler, David, Hayes, D Neil, Heiman, David I, Hoadley, Katherine A, Holt, Robert A, Hoyle, Alan P, Huang, Mei, Hunt, Bryan, and Hutter, Carolyn M

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Neurosciences, Precision Medicine, Cancer, Human Genome, Cancer Genomics, Biotechnology, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Adult, Aged, Aged, 80 and over, DNA-Binding Proteins, Female, Gene Fusion, Humans, Male, Middle Aged, Mutation, Nuclear Proteins, Paraganglioma, Pheochromocytoma, Pol1 Transcription Initiation Complex Proteins, Proto-Oncogene Proteins c-ret, RNA-Binding Proteins, Trans-Activators, Transcription Factors, Cancer Genome Atlas Research Network, CSDE1, MAML3, TCGA, expression subtypes, genomics, metastasis, molecular profiling, paraganglioma, pheochromocytoma, sequencing, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.

Published
2017

3. Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

Author

Zheng, Siyuan, Cherniack, Andrew D, Dewal, Ninad, Moffitt, Richard A, Danilova, Ludmila, Murray, Bradley A, Lerario, Antonio M, Else, Tobias, Knijnenburg, Theo A, Ciriello, Giovanni, Kim, Seungchan, Assie, Guillaume, Morozova, Olena, Akbani, Rehan, Shih, Juliann, Hoadley, Katherine A, Choueiri, Toni K, Waldmann, Jens, Mete, Ozgur, Robertson, A Gordon, Wu, Hsin-Ta, Raphael, Benjamin J, Shao, Lina, Meyerson, Matthew, Demeure, Michael J, Beuschlein, Felix, Gill, Anthony J, Sidhu, Stan B, Almeida, Madson Q, Fragoso, Maria CBV, Cope, Leslie M, Kebebew, Electron, Habra, Mouhammed A, Whitsett, Timothy G, Bussey, Kimberly J, Rainey, William E, L., Sylvia, Bertherat, Jérôme, Fassnacht, Martin, Wheeler, David A, Network, The Cancer Genome Atlas Research, Verhaak, Roel GW, Giordano, Thomas J, Hammer, Gary D, Assié, Guillaume, Wu, Hsin-Tu, Almeida, Madson, Fragoso, Maria Candida Barisson, Habra, Mouhammed Amir, Benz, Christopher, Ally, Adrian, Balasundaram, Miruna, Bowlby, Reanne, Brooks, Denise, Butterfield, Yaron SN, Carlsen, Rebecca, Dhalla, Noreen, Guin, Ranabir, Holt, Robert A, Jones, Steven JM, Kasaian, Katayoon, Lee, Darlene, Li, Haiyan I, Lim, Lynette, Ma, Yussanne, and Marra, Marco A

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Human Genome, Cancer, Rare Diseases, Biotechnology, Clinical Research, Adolescent, Adrenal Cortex Neoplasms, Adrenocortical Carcinoma, Adult, Aged, Aged, 80 and over, Child, DNA Methylation, Disease-Free Survival, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genome, Human, Genomics, Humans, Male, Middle Aged, Mutation, Outcome Assessment, Health Care, Prognosis, Young Adult, Cancer Genome Atlas Research Network, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

We describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers.

Published
2016

4. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma

Author

Linehan, W Marston, Spellman, Paul T, Ricketts, Christopher J, Creighton, Chad J, Fei, Suzanne S, Davis, Caleb, Wheeler, David A, Murray, Bradley A, Schmidt, Laura, Vocke, Cathy D, Peto, Myron, Al Mamun, Abu Amar M, Shinbrot, Eve, Sethi, Anurag, Brooks, Samira, Rathmell, W Kimryn, Brooks, Angela N, Hoadley, Katherine A, Robertson, A Gordon, Brooks, Denise, Bowlby, Reanne, Sadeghi, Sara, Shen, Hui, Weisenberger, Daniel J, Bootwalla, Moiz, Baylin, Stephen B, Laird, Peter W, Cherniack, Andrew D, Saksena, Gordon, Haake, Scott, Li, Jun, Liang, Han, Lu, Yiling, Mills, Gordon B, Akbani, Rehan, Leiserson, Mark DM, Raphael, Benjamin J, Anur, Pavana, Bottaro, Donald, Albiges, Laurence, Barnabas, Nandita, Choueiri, Toni K, Czerniak, Bogdan, Godwin, Andrew K, Hakimi, A Ari, Ho, Thai H, Hsieh, James, Ittmann, Michael, Kim, William Y, Krishnan, Bhavani, Merino, Maria J, Mills Shaw, Kenna R, Reuter, Victor E, Reznik, Ed, Shelley, Carl S, Shuch, Brian, Signoretti, Sabina, Srinivasan, Ramaprasad, Tamboli, Pheroze, Thomas, George, Tickoo, Satish, Burnett, Kenneth, Crain, Daniel, Gardner, Johanna, Lau, Kevin, Mallery, David, Morris, Scott, Paulauskis, Joseph D, Penny, Robert J, Shelton, Candace, Shelton, W Troy, Sherman, Mark, Thompson, Eric, Yena, Peggy, Avedon, Melissa T, Bowen, Jay, Gastier-Foster, Julie M, Gerken, Mark, Leraas, Kristen M, Lichtenberg, Tara M, Ramirez, Nilsa C, Santos, Tracie, Wise, Lisa, Zmuda, Erik, Demchok, John A, Felau, Ina, Hutter, Carolyn M, Sheth, Margi, Sofia, Heidi J, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean C, Zhang, Jiashan, Ayala, Brenda, Baboud, Julien, Chudamani, Sudha, Liu, Jia, Lolla, Laxmi, and Naresh, Rashi

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Genetics, Biotechnology, Digestive Diseases, Kidney Disease, Good Health and Well Being, Carcinoma, Papillary, CpG Islands, DNA Methylation, Humans, Kidney Neoplasms, MicroRNAs, Mutation, NF-E2-Related Factor 2, Phenotype, Proto-Oncogene Proteins c-met, RNA, Messenger, RNA, Neoplasm, Sequence Analysis, RNA, Signal Transduction, Cancer Genome Atlas Research Network, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundPapillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.MethodsWe performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis.ResultsType 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH).ConclusionsType 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).

Published
2016

5. Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma

Author

Ceccarelli, Michele, Barthel, Floris P, Malta, Tathiane M, Sabedot, Thais S, Salama, Sofie R, Murray, Bradley A, Morozova, Olena, Newton, Yulia, Radenbaugh, Amie, Pagnotta, Stefano M, Anjum, Samreen, Wang, Jiguang, Manyam, Ganiraju, Zoppoli, Pietro, Ling, Shiyun, Rao, Arjun A, Grifford, Mia, Cherniack, Andrew D, Zhang, Hailei, Poisson, Laila, Carlotti, Carlos Gilberto, da Cunha Tirapelli, Daniela Pretti, Rao, Arvind, Mikkelsen, Tom, Lau, Ching C, Yung, WK Alfred, Rabadan, Raul, Huse, Jason, Brat, Daniel J, Lehman, Norman L, Barnholtz-Sloan, Jill S, Zheng, Siyuan, Hess, Kenneth, Rao, Ganesh, Meyerson, Matthew, Beroukhim, Rameen, Cooper, Lee, Akbani, Rehan, Wrensch, Margaret, Haussler, David, Aldape, Kenneth D, Laird, Peter W, Gutmann, David H, Network, TCGA Research, Arachchi, Harindra, Auman, J Todd, Balasundaram, Miruna, Balu, Saianand, Barnett, Gene, Baylin, Stephen, Bell, Sue, Benz, Christopher, Bir, Natalie, Black, Keith L, Bodenheimer, Tom, Boice, Lori, Bootwalla, Moiz S, Bowen, Jay, Bristow, Christopher A, Butterfield, Yaron SN, Chen, Qing-Rong, Chin, Lynda, Cho, Juok, Chuah, Eric, Chudamani, Sudha, Coetzee, Simon G, Cohen, Mark L, Colman, Howard, Couce, Marta, D’Angelo, Fulvio, Davidsen, Tanja, Davis, Amy, Demchok, John A, Devine, Karen, Ding, Li, Duell, Rebecca, Elder, J Bradley, Eschbacher, Jennifer M, Fehrenbach, Ashley, Ferguson, Martin, Frazer, Scott, Fuller, Gregory, Fulop, Jordonna, Gabriel, Stacey B, Garofano, Luciano, Gastier-Foster, Julie M, Gehlenborg, Nils, Gerken, Mark, Getz, Gad, Giannini, Caterina, Gibson, William J, Hadjipanayis, Angela, Hayes, D Neil, Heiman, David I, Hermes, Beth, Hilty, Joe, Hoadley, Katherine A, Hoyle, Alan P, and Huang, Mei

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Bioinformatics and Computational Biology, Genetics, Oncology and Carcinogenesis, Orphan Drug, Brain Cancer, Brain Disorders, Biotechnology, Human Genome, Rare Diseases, Neurosciences, Cancer, Adult, Brain Neoplasms, Cell Proliferation, Cluster Analysis, DNA Helicases, DNA Methylation, Epigenesis, Genetic, Glioma, Humans, Isocitrate Dehydrogenase, Middle Aged, Mutation, Nuclear Proteins, Promoter Regions, Genetic, Signal Transduction, Telomerase, Telomere, Transcriptome, X-linked Nuclear Protein, TCGA Research Network, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
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

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

Author

Brat, Daniel J, Verhaak, Roel GW, Aldape, Kenneth D, Yung, WK Alfred, Salama, Sofie R, Cooper, Lee AD, Rheinbay, Esther, Miller, C Ryan, Vitucci, Mark, Morozova, Olena, Robertson, A Gordon, Noushmehr, Houtan, Laird, Peter W, Cherniack, Andrew D, Akbani, Rehan, Huse, Jason T, Ciriello, Giovanni, Poisson, Laila M, Barnholtz-Sloan, Jill S, Berger, Mitchel S, Brennan, Cameron, Colen, Rivka R, Colman, Howard, Flanders, Adam E, Giannini, Caterina, Grifford, Mia, Iavarone, Antonio, Jain, Rajan, Joseph, Isaac, Kim, Jaegil, Kasaian, Katayoon, Mikkelsen, Tom, Murray, Bradley A, O'Neill, Brian Patrick, Pachter, Lior, Parsons, Donald W, Sougnez, Carrie, Sulman, Erik P, Vandenberg, Scott R, Van Meir, Erwin G, von Deimling, Andreas, Zhang, Hailei, Crain, Daniel, Lau, Kevin, Mallery, David, Morris, Scott, Paulauskis, Joseph, Penny, Robert, Shelton, Troy, Sherman, Mark, Yena, Peggy, Black, Aaron, Bowen, Jay, Dicostanzo, Katie, Gastier-Foster, Julie, Leraas, Kristen M, Lichtenberg, Tara M, Pierson, Christopher R, Ramirez, Nilsa C, Taylor, Cynthia, Weaver, Stephanie, Wise, Lisa, Zmuda, Erik, Davidsen, Tanja, Demchok, John A, Eley, Greg, Ferguson, Martin L, Hutter, Carolyn M, Mills Shaw, Kenna R, Ozenberger, Bradley A, Sheth, Margi, Sofia, Heidi J, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean Claude, Ayala, Brenda, Baboud, Julien, Chudamani, Sudha, Jensen, Mark A, Liu, Jia, Pihl, Todd, Raman, Rohini, Wan, Yunhu, Wu, Ye, Ally, Adrian, Auman, J Todd, Balasundaram, Miruna, Balu, Saianand, Baylin, Stephen B, Beroukhim, Rameen, Bootwalla, Moiz S, Bowlby, Reanne, Bristow, Christopher A, Brooks, Denise, Butterfield, Yaron, Carlsen, Rebecca, Carter, Scott, Chin, Lynda, and Chu, Andy

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Human Genome, Brain Cancer, Rare Diseases, Neurosciences, Biotechnology, Cancer Genomics, Genetics, Cancer, Brain Disorders, Adolescent, Adult, Aged, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 19, Cluster Analysis, DNA, Neoplasm, Female, Genes, p53, Glioblastoma, Glioma, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Mutation, Neoplasm Grading, Proportional Hazards Models, Sequence Analysis, DNA, Signal Transduction, Cancer Genome Atlas Research Network, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundDiffuse 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.MethodsWe 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.ResultsUnsupervised 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.ConclusionsThe 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

7. The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

Author

Davis, Caleb F, Ricketts, Christopher J, Wang, Min, Yang, Lixing, Cherniack, Andrew D, Shen, Hui, Buhay, Christian, Kang, Hyojin, Kim, Sang Cheol, Fahey, Catherine C, Hacker, Kathryn E, Bhanot, Gyan, Gordenin, Dmitry A, Chu, Andy, Gunaratne, Preethi H, Biehl, Michael, Seth, Sahil, Kaipparettu, Benny A, Bristow, Christopher A, Donehower, Lawrence A, Wallen, Eric M, Smith, Angela B, Tickoo, Satish K, Tamboli, Pheroze, Reuter, Victor, Schmidt, Laura S, Hsieh, James J, Choueiri, Toni K, Hakimi, A Ari, Network, The Cancer Genome Atlas Research, Creighton, Chad J, Morgan, Margaret, Wheeler, David A, Gibbs, Richard A, Signoretti, Sabina, Robertson, A Gordon, Henske, Elizabeth P, Kwiatkowski, David J, Ricketts, Christopher, Linehan, W Marston, Seiler, Michael, Rathmell, W Kimryn, Laird, Peter W, Shuch, Brian, Muzny, Donna, Chao, Hsu, Dahdouli, Mike, Xi, Liu, Kakkar, Nipun, Reid, Jeffrey G, Downs, Brittany, Drummond, Jennifer, Morton, Donna, Doddapaneni, Harsha, Lewis, Lora, English, Adam, Meng, Qingchang, Kovar, Christie, Wang, Qiaoyan, Hale, Walker, Hawes, Alicia, Kalra, Divya, Walker, Kimberly, Murray, Bradley A, Sougnez, Carrie, Saksena, Gordon, Carter, Scott L, Schumacher, Steven E, Tabak, Barbara, Zack, Travis I, Getz, Gad, Beroukhim, Rameen, Gabriel, Stacey B, Meyerson, Matthew, Ally, Adrian, Balasundaram, Miruna, Birol, Inanc, and Brooks, Denise

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Bioinformatics and Computational Biology, Genetics, Oncology and Carcinogenesis, Biotechnology, Rare Diseases, Kidney Disease, Cancer, Cancer Genomics, Human Genome, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Base Sequence, Carcinoma, Renal Cell, Chromosome Breakpoints, Chromosome Deletion, Chromosomes, Human, DNA Copy Number Variations, DNA Methylation, DNA Mutational Analysis, DNA, Mitochondrial, Exome, Genome, Human, Humans, Kidney Neoplasms, Molecular Sequence Data, Promoter Regions, Genetic, Telomerase, Transcriptome, The Cancer Genome Atlas Research Network, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with 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 upregulation in cancer distinct from previously observed amplifications and point mutations.

Published
2014

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