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1,724 results on '"Beroukhim, Rameen"'

4. Analysis of germline-driven ancestry-associated gene expression in cancers

Author

Chambwe, Nyasha, Sayaman, Rosalyn W, Hu, Donglei, Huntsman, Scott, Network, The Cancer Genome Analysis, Carrot-Zhang, Jian, Berger, Ashton C, Han, Seunghun, Meyerson, Matthew, Damrauer, Jeffrey S, Hoadley, Katherine A, Felau, Ina, Demchok, John A, Mensah, Michael KA, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Knijnenburg, Theo A, Robertson, A Gordon, Yau, Christina, Benz, Christopher, Huang, Kuan-lin, Newberg, Justin Y, Frampton, Garrett M, Mashl, R Jay, Ding, Li, Romanel, Alessandro, Demichelis, Francesca, Zhou, Wanding, Laird, Peter W, Shen, Hui, Wong, Christopher K, Stuart, Joshua M, Lazar, Alexander J, Le, Xiuning, Oak, Ninad, Kemal, Anab, Caesar-Johnson, Samantha, Zenklusen, Jean C, Ziv, Elad, Beroukhim, Rameen, and Cherniack, Andrew D

Subjects
Biological Sciences, Health Sciences, Genetics, Human Genome, Biotechnology, Cancer, Good Health and Well Being, Gene Expression, Germ Cells, Humans, Neoplasms, Quantitative Trait Loci, RNA, Messenger, Cancer Genome Analysis Network, Bioinformatics, Computer sciences, Genomics, RNAseq, Sequence analysis
Abstract

Differential mRNA expression between ancestry groups can be explained by both genetic and environmental factors. We outline a computational workflow to determine the extent to which germline genetic variation explains cancer-specific molecular differences across ancestry groups. Using multi-omics datasets from The Cancer Genome Atlas (TCGA), we enumerate ancestry-informative markers colocalized with cancer-type-specific expression quantitative trait loci (e-QTLs) at ancestry-associated genes. This approach is generalizable to other settings with paired germline genotyping and mRNA expression data for a multi-ethnic cohort. For complete details on the use and execution of this protocol, please refer to Carrot-Zhang et al. (2020), Robertson et al. (2021), and Sayaman et al. (2021).

Published
2022

5. A Molecularly Integrated Grade for Meningioma

Author

Driver, Joseph, Hoffman, Samantha E, Tavakol, Sherwin, Woodward, Eleanor, Maury, Eduardo A, Bhave, Varun, Greenwald, Noah F, Nassiri, Farshad, Aldape, Kenneth, Zadeh, Gelareh, Choudhury, Abrar, Vasudevan, Harish N, Magill, Stephen T, Raleigh, David R, Abedalthagafi, Malak, Aizer, Ayal A, Alexander, Brian M, Ligon, Keith L, Reardon, David A, Wen, Patrick Y, Al-Mefty, Ossama, Ligon, Azra H, Dubuc, Adrian M, Beroukhim, Rameen, Claus, Elizabeth B, Dunn, Ian F, Santagata, Sandro, and Bi, Wenya Linda

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Brain Disorders, Brain Cancer, Rare Diseases, Human Genome, Cancer, Genetics, Good Health and Well Being, Adult, Cohort Studies, Humans, Meningeal Neoplasms, Meningioma, Neoplasm Grading, Neoplasm Recurrence, Local, Prognosis, Retrospective Studies, World Health Organization, meningioma, copy-number alterations, Neurosciences, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundMeningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management.MethodsWe evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms.ResultsWe developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score.ConclusionWe propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.

Published
2022

7. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.

Author

Dentro, Stefan C, Leshchiner, Ignaty, Haase, Kerstin, Tarabichi, Maxime, Wintersinger, Jeff, Deshwar, Amit G, Yu, Kaixian, Rubanova, Yulia, Macintyre, Geoff, Demeulemeester, Jonas, Vázquez-García, Ignacio, Kleinheinz, Kortine, Livitz, Dimitri G, Malikic, Salem, Donmez, Nilgun, Sengupta, Subhajit, Anur, Pavana, Jolly, Clemency, Cmero, Marek, Rosebrock, Daniel, Schumacher, Steven E, Fan, Yu, Fittall, Matthew, Drews, Ruben M, Yao, Xiaotong, Watkins, Thomas BK, Lee, Juhee, Schlesner, Matthias, Zhu, Hongtu, Adams, David J, McGranahan, Nicholas, Swanton, Charles, Getz, Gad, Boutros, Paul C, Imielinski, Marcin, Beroukhim, Rameen, Sahinalp, S Cenk, Ji, Yuan, Peifer, Martin, Martincorena, Inigo, Markowetz, Florian, Mustonen, Ville, Yuan, Ke, Gerstung, Moritz, Spellman, Paul T, Wang, Wenyi, Morris, Quaid D, Wedge, David C, Van Loo, Peter, and PCAWG Evolution and Heterogeneity Working Group and the PCAWG Consortium

Subjects
PCAWG Evolution and Heterogeneity Working Group and the PCAWG Consortium, branching evolution, cancer driver genes, cancer evolution, intra-tumor heterogeneity, pan-cancer genomics, subclonal reconstruction, tumor phylogeny, whole-genome sequencing, Genetics, Cancer, Human Genome, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

Published
2021

8. Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway.

Author

Carrot-Zhang, Jian, Yao, Xiaotong, Devarakonda, Siddhartha, Deshpande, Aditya, Damrauer, Jeffrey S, Silva, Tiago Chedraoui, Wong, Christopher K, Choi, Hyo Young, Felau, Ina, Robertson, A Gordon, Castro, Mauro AA, Bao, Lisui, Rheinbay, Esther, Liu, Eric Minwei, Trieu, Tuan, Haan, David, Yau, Christina, Hinoue, Toshinori, Liu, Yuexin, Shapira, Ofer, Kumar, Kiran, Mungall, Karen L, Zhang, Hailei, Lee, Jake June-Koo, Berger, Ashton, Gao, Galen F, Zhitomirsky, Binyamin, Liang, Wen-Wei, Zhou, Meng, Moorthi, Sitapriya, Berger, Alice H, Collisson, Eric A, Zody, Michael C, Ding, Li, Cherniack, Andrew D, Getz, Gad, Elemento, Olivier, Benz, Christopher C, Stuart, Josh, Zenklusen, JC, Beroukhim, Rameen, Chang, Jason C, Campbell, Joshua D, Hayes, D Neil, Yang, Lixing, Laird, Peter W, Weinstein, John N, Kwiatkowski, David J, Tsao, Ming S, Travis, William D, Khurana, Ekta, Berman, Benjamin P, Hoadley, Katherine A, Robine, Nicolas, TCGA Research Network, Meyerson, Matthew, Govindan, Ramaswamy, and Imielinski, Marcin

Subjects
TCGA Research Network, TCGA, driver, genome analysis, lung adenocarcinoma, noncoding, oncogene, precision oncology, structural variation, tumor suppressor, whole genome sequencing, Biochemistry and Cell Biology, Medical Physiology
Abstract

RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.

Published
2021

9. Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer

Author

Carrot-Zhang, Jian, Chambwe, Nyasha, Damrauer, Jeffrey S, Knijnenburg, Theo A, Robertson, A Gordon, Yau, Christina, Zhou, Wanding, Berger, Ashton C, Huang, Kuan-lin, Newberg, Justin Y, Mashl, R Jay, Romanel, Alessandro, Sayaman, Rosalyn W, Demichelis, Francesca, Felau, Ina, Frampton, Garrett M, Han, Seunghun, Hoadley, Katherine A, Kemal, Anab, Laird, Peter W, Lazar, Alexander J, Le, Xiuning, Oak, Ninad, Shen, Hui, Wong, Christopher K, Zenklusen, Jean C, Ziv, Elad, Network, Cancer Genome Atlas Analysis, Aguet, Francois, Ding, Li, Demchok, John A, Mensah, Michael KA, Caesar-Johnson, Samantha, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Alfoldi, Jessica, Karczewski, Konrad J, MacArthur, Daniel G, Meyerson, Matthew, Benz, Christopher, Stuart, Joshua M, Cherniack, Andrew D, and Beroukhim, Rameen

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Human Genome, Clinical Research, Cancer, Biotechnology, DNA Methylation, DNA-Binding Proteins, Ethnicity, F-Box-WD Repeat-Containing Protein 7, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genetics, Population, Genome, Human, Genomics, High-Throughput Nucleotide Sequencing, Humans, MicroRNAs, Mutation, Neoplasm Proteins, Neoplasms, Transcription Factors, Von Hippel-Lindau Tumor Suppressor Protein, Cancer Genome Atlas Analysis Network, TCGA, admixture, ancestry, cancer, eQTL, genomics, mRNA, methylation, miRNA, mutation, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

We evaluated ancestry effects on mutation rates, DNA methylation, and mRNA and miRNA expression among 10,678 patients across 33 cancer types from The Cancer Genome Atlas. We demonstrated that cancer subtypes and ancestry-related technical artifacts are important confounders that have been insufficiently accounted for. Once accounted for, ancestry-associated differences spanned all molecular features and hundreds of genes. Biologically significant differences were usually tissue specific but not specific to cancer. However, admixture and pathway analyses suggested some of these differences are causally related to cancer. Specific findings included increased FBXW7 mutations in patients of African origin, decreased VHL and PBRM1 mutations in renal cancer patients of African origin, and decreased immune activity in bladder cancer patients of East Asian origin.

Published
2020

10. Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer

Author

Akdemir, Kadir C, Le, Victoria T, Chandran, Sahaana, Li, Yilong, Verhaak, Roel G, Beroukhim, Rameen, Campbell, Peter J, Chin, Lynda, Dixon, Jesse R, and Futreal, P Andrew

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Cancer, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Chromatin, Gene Expression Regulation, Neoplastic, Gene Rearrangement, Genome, Human, Genomic Structural Variation, Humans, Neoplasms, PCAWG Structural Variation Working Group, PCAWG Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.

Published
2020

11. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition.

Author

Rodriguez-Martin, Bernardo, Alvarez, Eva G, Baez-Ortega, Adrian, Zamora, Jorge, Supek, Fran, Demeulemeester, Jonas, Santamarina, Martin, Ju, Young Seok, Temes, Javier, Garcia-Souto, Daniel, Detering, Harald, Li, Yilong, Rodriguez-Castro, Jorge, Dueso-Barroso, Ana, Bruzos, Alicia L, Dentro, Stefan C, Blanco, Miguel G, Contino, Gianmarco, Ardeljan, Daniel, Tojo, Marta, Roberts, Nicola D, Zumalave, Sonia, Edwards, Paul A, Weischenfeldt, Joachim, Puiggròs, Montserrat, Chong, Zechen, Chen, Ken, Lee, Eunjung Alice, Wala, Jeremiah A, Raine, Keiran M, Butler, Adam, Waszak, Sebastian M, Navarro, Fabio CP, Schumacher, Steven E, Monlong, Jean, Maura, Francesco, Bolli, Niccolo, Bourque, Guillaume, Gerstein, Mark, Park, Peter J, Wedge, David C, Beroukhim, Rameen, Torrents, David, Korbel, Jan O, Martincorena, Iñigo, Fitzgerald, Rebecca C, Van Loo, Peter, Kazazian, Haig H, Burns, Kathleen H, PCAWG Structural Variation Working Group, Campbell, Peter J, Tubio, Jose MC, and PCAWG Consortium

Subjects
PCAWG Structural Variation Working Group, PCAWG Consortium, Humans, Neoplasms, Retroelements, Gene Rearrangement, Long Interspersed Nucleotide Elements, Genome, Human, Carcinogenesis, Genetics, Digestive Diseases, Human Genome, Cancer, Rare Diseases, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.

Published
2020

12. Patterns of somatic structural variation in human cancer genomes

Author

Li, Yilong, Roberts, Nicola D, Wala, Jeremiah A, Shapira, Ofer, Schumacher, Steven E, Kumar, Kiran, Khurana, Ekta, Waszak, Sebastian, Korbel, Jan O, Haber, James E, Imielinski, Marcin, Weischenfeldt, Joachim, Beroukhim, Rameen, and Campbell, Peter J

Subjects
Cancer, Human Genome, Genetics, Biotechnology, Gene Rearrangement, Genetic Variation, Genome, Human, Genomics, Humans, Mutagenesis, Insertional, Neoplasms, Telomerase, PCAWG Structural Variation Working Group, PCAWG Consortium, General Science & Technology
Abstract

A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes1-7. Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types8. Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions-as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2-7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and-in liver cancer-frequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.

Published
2020

13. The evolutionary history of 2,658 cancers

Author

Gerstung, Moritz, Jolly, Clemency, Leshchiner, Ignaty, Dentro, Stefan C, Gonzalez, Santiago, Rosebrock, Daniel, Mitchell, Thomas J, Rubanova, Yulia, Anur, Pavana, Yu, Kaixian, Tarabichi, Maxime, Deshwar, Amit, Wintersinger, Jeff, Kleinheinz, Kortine, Vázquez-García, Ignacio, Haase, Kerstin, Jerman, Lara, Sengupta, Subhajit, Macintyre, Geoff, Malikic, Salem, Donmez, Nilgun, Livitz, Dimitri G, Cmero, Marek, Demeulemeester, Jonas, Schumacher, Steven, Fan, Yu, Yao, Xiaotong, Lee, Juhee, Schlesner, Matthias, Boutros, Paul C, Bowtell, David D, Zhu, Hongtu, Getz, Gad, Imielinski, Marcin, Beroukhim, Rameen, Sahinalp, S Cenk, Ji, Yuan, Peifer, Martin, Markowetz, Florian, Mustonen, Ville, Yuan, Ke, Wang, Wenyi, Morris, Quaid D, Spellman, Paul T, Wedge, David C, and Van Loo, Peter

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Bioinformatics and Computational Biology, Genetics, Oncology and Carcinogenesis, Rare Diseases, Brain Cancer, Brain Disorders, Human Genome, Cancer, 2.1 Biological and endogenous factors, Aetiology, DNA Repair, Evolution, Molecular, Gene Dosage, Genes, Tumor Suppressor, Genetic Variation, Genome, Human, Humans, Mutagenesis, Insertional, Neoplasms, PCAWG Evolution & Heterogeneity Working Group, PCAWG Consortium, General Science & Technology
Abstract

Cancer develops through a process of somatic evolution1,2. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes3. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)4, we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.

Published
2020

14. Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

Author

Rheinbay, Esther, Nielsen, Morten Muhlig, Abascal, Federico, Wala, Jeremiah A, Shapira, Ofer, Tiao, Grace, Hornshøj, Henrik, Hess, Julian M, Juul, Randi Istrup, Lin, Ziao, Feuerbach, Lars, Sabarinathan, Radhakrishnan, Madsen, Tobias, Kim, Jaegil, Mularoni, Loris, Shuai, Shimin, Lanzós, Andrés, Herrmann, Carl, Maruvka, Yosef E, Shen, Ciyue, Amin, Samirkumar B, Bandopadhayay, Pratiti, Bertl, Johanna, Boroevich, Keith A, Busanovich, John, Carlevaro-Fita, Joana, Chakravarty, Dimple, Chan, Calvin Wing Yiu, Craft, David, Dhingra, Priyanka, Diamanti, Klev, Fonseca, Nuno A, Gonzalez-Perez, Abel, Guo, Qianyun, Hamilton, Mark P, Haradhvala, Nicholas J, Hong, Chen, Isaev, Keren, Johnson, Todd A, Juul, Malene, Kahles, Andre, Kahraman, Abdullah, Kim, Youngwook, Komorowski, Jan, Kumar, Kiran, Kumar, Sushant, Lee, Donghoon, Lehmann, Kjong-Van, Li, Yilong, Liu, Eric Minwei, Lochovsky, Lucas, Park, Keunchil, Pich, Oriol, Roberts, Nicola D, Saksena, Gordon, Schumacher, Steven E, Sidiropoulos, Nikos, Sieverling, Lina, Sinnott-Armstrong, Nasa, Stewart, Chip, Tamborero, David, Tubio, Jose MC, Umer, Husen M, Uusküla-Reimand, Liis, Wadelius, Claes, Wadi, Lina, Yao, Xiaotong, Zhang, Cheng-Zhong, Zhang, Jing, Haber, James E, Hobolth, Asger, Imielinski, Marcin, Kellis, Manolis, Lawrence, Michael S, von Mering, Christian, Nakagawa, Hidewaki, Raphael, Benjamin J, Rubin, Mark A, Sander, Chris, Stein, Lincoln D, Stuart, Joshua M, Tsunoda, Tatsuhiko, Wheeler, David A, Johnson, Rory, Reimand, Jüri, Gerstein, Mark, Khurana, Ekta, Campbell, Peter J, López-Bigas, Núria, PCAWG Drivers and Functional Interpretation Working Group, PCAWG Structural Variation Working Group, Weischenfeldt, Joachim, Beroukhim, Rameen, Martincorena, Iñigo, Pedersen, Jakob Skou, Getz, Gad, and PCAWG Consortium

Subjects
PCAWG Drivers and Functional Interpretation Working Group, PCAWG Structural Variation Working Group, PCAWG Consortium, Humans, Neoplasms, Gene Expression Regulation, Neoplastic, Mutation, Genome, Human, Databases, Genetic, DNA Breaks, INDEL Mutation, Genome-Wide Association Study, Gene Expression Regulation, Neoplastic, Genome, Human, Databases, Genetic, General Science & Technology
Abstract

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

Published
2020

15. Early TP53 alterations engage environmental exposures to promote gastric premalignancy in an integrative mouse model.

Author

Sethi, Nilay S, Kikuchi, Osamu, Duronio, Gina N, Stachler, Matthew D, McFarland, James M, Ferrer-Luna, Ruben, Zhang, Yanxi, Bao, Chunyang, Bronson, Roderick, Patil, Deepa, Sanchez-Vega, Francisco, Liu, Jie-Bin, Sicinska, Ewa, Lazaro, Jean-Bernard, Ligon, Keith L, Beroukhim, Rameen, and Bass, Adam J

Subjects
Organoids, Cell Line, Tumor, Animals, Mice, Inbred C57BL, Mice, Transgenic, Mice, Knockout, Humans, Adenocarcinoma, Esophageal Neoplasms, Stomach Neoplasms, Neoplasms, Experimental, Precancerous Conditions, Barrett Esophagus, Methylnitrosourea, Environmental Exposure, Mutation, Tumor Suppressor Protein p53, Cyclin-Dependent Kinase Inhibitor p16, Cell Line, Tumor, Mice, Inbred C57BL, Transgenic, Knockout, Neoplasms, Experimental, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Somatic alterations in cancer genes are being detected in normal and premalignant tissue, thus placing greater emphasis on gene-environment interactions that enable disease phenotypes. By combining early genetic alterations with disease-relevant exposures, we developed an integrative mouse model to study gastric premalignancy. Deletion of Trp53 in gastric cells confers a selective advantage and promotes the development of dysplasia in the setting of dietary carcinogens. Organoid derivation from dysplastic lesions facilitated genomic, transcriptional and functional evaluation of gastric premalignancy. Cell cycle regulators, most notably Cdkn2a, were upregulated by p53 inactivation in gastric premalignancy, serving as a barrier to disease progression. Co-deletion of Cdkn2a and Trp53 in dysplastic gastric organoids promoted cancer phenotypes but also induced replication stress, exposing a susceptibility to DNA damage response inhibitors. These findings demonstrate the utility of mouse models that integrate genomic alterations with relevant exposures and highlight the importance of gene-environment interactions in shaping the premalignant state.

Published
2020

16. Longitudinal molecular trajectories of diffuse glioma in adults

Author

Barthel, Floris P, Johnson, Kevin C, Varn, Frederick S, Moskalik, Anzhela D, Tanner, Georgette, Kocakavuk, Emre, Anderson, Kevin J, Abiola, Olajide, Aldape, Kenneth, Alfaro, Kristin D, Alpar, Donat, Amin, Samirkumar B, Ashley, David M, Bandopadhayay, Pratiti, Barnholtz-Sloan, Jill S, Beroukhim, Rameen, Bock, Christoph, Brastianos, Priscilla K, Brat, Daniel J, Brodbelt, Andrew R, Bruns, Alexander F, Bulsara, Ketan R, Chakrabarty, Aruna, Chakravarti, Arnab, Chuang, Jeffrey H, Claus, Elizabeth B, Cochran, Elizabeth J, Connelly, Jennifer, Costello, Joseph F, Finocchiaro, Gaetano, Fletcher, Michael N, French, Pim J, Gan, Hui K, Gilbert, Mark R, Gould, Peter V, Grimmer, Matthew R, Iavarone, Antonio, Ismail, Azzam, Jenkinson, Michael D, Khasraw, Mustafa, Kim, Hoon, Kouwenhoven, Mathilde CM, LaViolette, Peter S, Li, Meihong, Lichter, Peter, Ligon, Keith L, Lowman, Allison K, Malta, Tathiane M, Mazor, Tali, McDonald, Kerrie L, Molinaro, Annette M, Nam, Do-Hyun, Nayyar, Naema, Ng, Ho Keung, Ngan, Chew Yee, Niclou, Simone P, Niers, Johanna M, Noushmehr, Houtan, Noorbakhsh, Javad, Ormond, D Ryan, Park, Chul-Kee, Poisson, Laila M, Rabadan, Raul, Radlwimmer, Bernhard, Rao, Ganesh, Reifenberger, Guido, Sa, Jason K, Schuster, Michael, Shaw, Brian L, Short, Susan C, Smitt, Peter A Sillevis, Sloan, Andrew E, Smits, Marion, Suzuki, Hiromichi, Tabatabai, Ghazaleh, Van Meir, Erwin G, Watts, Colin, Weller, Michael, Wesseling, Pieter, Westerman, Bart A, Widhalm, Georg, Woehrer, Adelheid, Yung, WK Alfred, Zadeh, Gelareh, Huse, Jason T, De Groot, John F, Stead, Lucy F, and Verhaak, Roel GW

Subjects
Neurosciences, Brain Disorders, Cancer, Rare Diseases, Brain Cancer, Genetics, Adult, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 19, Disease Progression, Glioma, Humans, Isocitrate Dehydrogenase, Mutation, Polymorphism, Single Nucleotide, Recurrence, GLASS Consortium, General Science & Technology
Abstract

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

Published
2019

18. Structural variants shape driver combinations and outcomes in pediatric high-grade glioma

Author

Dubois, Frank P. B., Shapira, Ofer, Greenwald, Noah F., Zack, Travis, Wala, Jeremiah, Tsai, Jessica W., Crane, Alexander, Baguette, Audrey, Hadjadj, Djihad, Harutyunyan, Ashot S., Kumar, Kiran H., Blattner-Johnson, Mirjam, Vogelzang, Jayne, Sousa, Cecilia, Kang, Kyung Shin, Sinai, Claire, Wang, Dayle K., Khadka, Prasidda, Lewis, Kathleen, Nguyen, Lan, Malkin, Hayley, Ho, Patricia, O’Rourke, Ryan, Zhang, Shu, Gold, Rose, Deng, Davy, Serrano, Jonathan, Snuderl, Matija, Jones, Chris, Wright, Karen D., Chi, Susan N., Grill, Jacques, Kleinman, Claudia L., Goumnerova, Liliana C., Jabado, Nada, Jones, David T. W., Kieran, Mark W., Ligon, Keith L., Beroukhim, Rameen, and Bandopadhayay, Pratiti

Published
2022
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19. Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial

Author

Wen, Patrick Y, Touat, Mehdi, Alexander, Brian M, Mellinghoff, Ingo K, Ramkissoon, Shakti, McCluskey, Christine S, Pelton, Kristine, Haidar, Sam, Basu, Sankha S, Gaffey, Sarah C, Brown, Loreal E, Martinez-Ledesma, Juan Emmanuel, Wu, Shaofang, Kim, Jungwoo, Wei, Wei, Park, Mi-Ae, Huse, Jason T, Kuhn, John G, Rinne, Mikael L, Colman, Howard, Agar, Nathalie YR, Omuro, Antonio M, DeAngelis, Lisa M, Gilbert, Mark R, de Groot, John F, Cloughesy, Timothy F, S., Andrew, Roberts, Thomas M, Zhao, Jean J, Lee, Eudocia Q, Nayak, Lakshmi, Heath, James R, Horky, Laura L, Batchelor, Tracy T, Beroukhim, Rameen, Chang, Susan M, Ligon, Azra H, Dunn, Ian F, Koul, Dimpy, Young, Geoffrey S, Prados, Michael D, Reardon, David A, Yung, WK Alfred, and Ligon, Keith L

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Cancer, Brain Cancer, Brain Disorders, Rare Diseases, Clinical Trials and Supportive Activities, Neurosciences, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adult, Aged, Aged, 80 and over, Aminopyridines, Antineoplastic Agents, Brain Neoplasms, Chemotherapy, Adjuvant, Disease Progression, Enzyme Activation, Female, Glioblastoma, Humans, Male, Middle Aged, Morpholines, Neoadjuvant Therapy, Neoplasm Recurrence, Local, Phosphatidylinositol 3-Kinase, Phosphoinositide-3 Kinase Inhibitors, Progression-Free Survival, Time Factors, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

PurposePhosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation.MethodsThis study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2.ResultsSixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKTS473 immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6S235/236 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]).ConclusionBuparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.

Published
2019

20. Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author

Hmeljak, Julija, Sanchez-Vega, Francisco, Hoadley, Katherine A, Shih, Juliann, Stewart, Chip, Heiman, David, Tarpey, Patrick, Danilova, Ludmila, Drill, Esther, Gibb, Ewan A, Bowlby, Reanne, Kanchi, Rupa, Osmanbeyoglu, Hatice U, Sekido, Yoshitaka, Takeshita, Jumpei, Newton, Yulia, Graim, Kiley, Gupta, Manaswi, Gay, Carl M, Diao, Lixia, Gibbs, David L, Thorsson, Vesteinn, Iype, Lisa, Kantheti, Havish, Severson, David T, Ravegnini, Gloria, Desmeules, Patrice, Jungbluth, Achim A, Travis, William D, Dacic, Sanja, Chirieac, Lucian R, Galateau-Sallé, Françoise, Fujimoto, Junya, Husain, Aliya N, Silveira, Henrique C, Rusch, Valerie W, Rintoul, Robert C, Pass, Harvey, Kindler, Hedy, Zauderer, Marjorie G, Kwiatkowski, David J, Bueno, Raphael, Tsao, Anne S, Creaney, Jenette, Lichtenberg, Tara, Leraas, Kristen, Bowen, Jay, Felau, Ina, Zenklusen, Jean Claude, Akbani, Rehan, Cherniack, Andrew D, Byers, Lauren A, Noble, Michael S, Fletcher, Jonathan A, Robertson, A Gordon, Shen, Ronglai, Aburatani, Hiroyuki, Robinson, Bruce W, Campbell, Peter, Ladanyi, Marc, Ally, Adrian, Anur, Pavana, Armenia, Joshua, Auman, J Todd, Balasundaram, Miruna, Balu, Saianand, Baylin, Stephen B, Becich, Michael, Behrens, Carmen, Beroukhim, Rameen, Bielski, Craig, Bodenheimer, Tom, Bootwalla, Moiz S, Brooks, Denise, Byers, Lauren Averett, Cárcano, Flávio M, Carlsen, Rebecca, Carvalho, Andre L, Cheung, Dorothy, Chirieac, Lucian, Cho, Juok, Chuah, Eric, Chudamani, Sudha, Cibulskis, Carrie, Cope, Leslie, Crain, Daniel, Curley, Erin, Rienzo, Assunta De, DeFreitas, Timothy, Demchok, John A, and Dhalla, Noreen

Subjects
Rare Diseases, Lung Cancer, Biotechnology, Lung, Cancer, Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Aged, Biomarkers, Tumor, Female, Histone-Lysine N-Methyltransferase, Humans, Kaplan-Meier Estimate, Lung Neoplasms, Male, Mesothelioma, Middle Aged, Mutation, Pleural Neoplasms, Prognosis, Protein Methyltransferases, Tumor Suppressor Proteins, Ubiquitin Thiolesterase, TCGA Research Network, Oncology and Carcinogenesis
Abstract

Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. SIGNIFICANCE: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.See related commentary by Aggarwal and Albelda, p. 1508.This article is highlighted in the In This Issue feature, p. 1494.

Published
2018

21. Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling

Author

Iniguez, Amanda Balboni, Alexe, Gabriela, Wang, Emily Jue, Roti, Giovanni, Patel, Sarvagna, Chen, Liying, Kitara, Samuel, Conway, Amy, Robichaud, Amanda L, Stolte, Björn, Bandopadhayay, Pratiti, Goodale, Amy, Pantel, Sasha, Lee, Yenarae, Cheff, Dorian M, Hall, Matthew D, Guha, Rajarshi, Davis, Mindy I, Menard, Marie, Nasholm, Nicole, Weiss, William A, Qi, Jun, Beroukhim, Rameen, Piccioni, Federica, Johannessen, Cory, and Stegmaier, Kimberly

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Genetics, Human Genome, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Animals, Azepines, Cell Line, Tumor, Disease-Free Survival, Drug Resistance, Neoplasm, Epigenesis, Genetic, Female, Humans, Indazoles, Mice, Nude, Molecular Targeted Therapy, Neuroblastoma, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Proteins, Signal Transduction, Sulfonamides, Triazoles, Xenograft Model Antitumor Assays, BET inhibition, MYCN, PI3K signaling, drug resistance, enhancer remodeling, neuroblastoma, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Drug resistance represents a major challenge to achieving durable responses to cancer therapeutics. Resistance mechanisms to epigenetically targeted drugs remain largely unexplored. We used bromodomain and extra-terminal domain (BET) inhibition in neuroblastoma as a prototype to model resistance to chromatin modulatory therapeutics. Genome-scale, pooled lentiviral open reading frame (ORF) and CRISPR knockout rescue screens nominated the phosphatidylinositol 3-kinase (PI3K) pathway as promoting resistance to BET inhibition. Transcriptomic and chromatin profiling of resistant cells revealed that global enhancer remodeling is associated with upregulation of receptor tyrosine kinases (RTKs), activation of PI3K signaling, and vulnerability to RTK/PI3K inhibition. Large-scale combinatorial screening with BET inhibitors identified PI3K inhibitors among the most synergistic upfront combinations. These studies provide a roadmap to elucidate resistance to epigenetic-targeted therapeutics and inform efficacious combination therapies.

Published
2018

22. PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation

Author

Khadka, Prasidda, Reitman, Zachary J., Lu, Sophie, Buchan, Graham, Gionet, Gabrielle, Dubois, Frank, Carvalho, Diana M., Shih, Juliann, Zhang, Shu, Greenwald, Noah F., Zack, Travis, Shapira, Ofer, Pelton, Kristine, Hartley, Rachel, Bear, Heather, Georgis, Yohanna, Jarmale, Spandana, Melanson, Randy, Bonanno, Kevin, Schoolcraft, Kathleen, Miller, Peter G., Condurat, Alexandra L., Gonzalez, Elizabeth M., Qian, Kenin, Morin, Eric, Langhnoja, Jaldeep, Lupien, Leslie E., Rendo, Veronica, Digiacomo, Jeromy, Wang, Dayle, Zhou, Kevin, Kumbhani, Rushil, Guerra Garcia, Maria E., Sinai, Claire E., Becker, Sarah, Schneider, Rachel, Vogelzang, Jayne, Krug, Karsten, Goodale, Amy, Abid, Tanaz, Kalani, Zohra, Piccioni, Federica, Beroukhim, Rameen, Persky, Nicole S., Root, David E., Carcaboso, Angel M., Ebert, Benjamin L., Fuller, Christine, Babur, Ozgun, Kieran, Mark W., Jones, Chris, Keshishian, Hasmik, Ligon, Keith L., Carr, Steven A., Phoenix, Timothy N., and Bandopadhayay, Pratiti

Published
2022
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25. Author Correction: Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

Author

Rodriguez-Martin, Bernardo, Alvarez, Eva G., Baez-Ortega, Adrian, Zamora, Jorge, Supek, Fran, Demeulemeester, Jonas, Santamarina, Martin, Ju, Young Seok, Temes, Javier, Garcia-Souto, Daniel, Detering, Harald, Li, Yilong, Rodriguez-Castro, Jorge, Dueso-Barroso, Ana, Bruzos, Alicia L., Dentro, Stefan C., Blanco, Miguel G., Contino, Gianmarco, Ardeljan, Daniel, Tojo, Marta, Roberts, Nicola D., Zumalave, Sonia, Edwards, Paul A., Weischenfeldt, Joachim, Puiggròs, Montserrat, Chong, Zechen, Chen, Ken, Lee, Eunjung Alice, Wala, Jeremiah A., Raine, Keiran M., Butler, Adam, Waszak, Sebastian M., Navarro, Fabio C. P., Schumacher, Steven E., Monlong, Jean, Maura, Francesco, Bolli, Niccolo, Bourque, Guillaume, Gerstein, Mark, Park, Peter J., Wedge, David C., Beroukhim, Rameen, Torrents, David, Korbel, Jan O., Martincorena, Iñigo, Fitzgerald, Rebecca C., Van Loo, Peter, Kazazian, Haig H., Burns, Kathleen H., Campbell, Peter J., and Tubio, Jose M. C.

Published
2023
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27. Glioma through the looking GLASS: molecular evolution of diffuse gliomas and the Glioma Longitudinal Analysis Consortium

Author

Aldape, Kenneth, Amin, Samirkumar B, Ashley, David M, Barnholtz-Sloan, Jill S, Bates, Amanda J, Beroukhim, Rameen, Bock, Christoph, Brat, Daniel J, Claus, Elizabeth B, Costello, Joseph F, de Groot, John F, Finocchiaro, Gaetano, French, Pim J, Gan, Hui K, Griffith, Brent, Herold-Mende, Christel C, Horbinski, Craig, Iavarone, Antonio, Kalkanis, Steven N, Karabatsou, Konstantina, Kim, Hoon, Kouwenhoven, Mathilde CM, McDonald, Kerrie L, Miletic, Hrvoje, Nam, Do-Hyun, Ng, Ho Keung, Niclou, Simone P, Noushmehr, Houtan, Ormond, D Ryan, Poisson, Laila M, Reifenberger, Guido, Roncaroli, Federico, Sa, Jason K, Smitt, Peter AE Sillevis, Smits, Marion, Souza, Camila F, Tabatabai, Ghazaleh, Van Meir, Erwin G, Verhaak, Roel GW, Watts, Colin, Wesseling, Pieter, Woehrer, Adelheid, Yung, WK Alfred, Jungk, Christine, Hau, Ann-Christin, van Dyck, Eric, Westerman, Bart A, Yin, Julia, Abiola, Olajide, Zeps, Nikolaj, Grimmond, Sean, Buckland, Michael, Khasraw, Mustafa, Sulman, Erik P, Muscat, Andrea M, and Stead, Lucy

Subjects
Cancer, Human Genome, Brain Cancer, Rare Diseases, Orphan Drug, Brain Disorders, Neurosciences, Genetics, Brain Neoplasms, Evolution, Molecular, Genomics, Glioma, Humans, Longitudinal Studies, characterization, evolution, glioma, sequencing, subtypes, GLASS Consortium, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Adult diffuse gliomas are a diverse group of brain neoplasms that inflict a high emotional toll on patients and their families. The Cancer Genome Atlas and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant cellular and molecular evolution during disease progression. We review the current knowledge on the genomic and epigenetic abnormalities in primary tumors and after disease recurrence, highlight the gaps in the literature, and elaborate on the need for a new multi-institutional effort to bridge these knowledge gaps and how the Glioma Longitudinal Analysis Consortium (GLASS) aims to systemically catalog the longitudinal changes in gliomas. The GLASS initiative will provide essential insights into the evolution of glioma toward a lethal phenotype, with the potential to reveal targetable vulnerabilities and, ultimately, improved outcomes for a patient population in need.

Published
2018

28. The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Author

Ricketts, Christopher J, De Cubas, Aguirre A, Fan, Huihui, Smith, Christof C, Lang, Martin, Reznik, Ed, Bowlby, Reanne, Gibb, Ewan A, Akbani, Rehan, Beroukhim, Rameen, Bottaro, Donald P, Choueiri, Toni K, Gibbs, Richard A, Godwin, Andrew K, Haake, Scott, Hakimi, A Ari, Henske, Elizabeth P, Hsieh, James J, Ho, Thai H, Kanchi, Rupa S, Krishnan, Bhavani, Kwiatkowski, David J, Lui, Wembin, Merino, Maria J, Mills, Gordon B, Myers, Jerome, Nickerson, Michael L, Reuter, Victor E, Schmidt, Laura S, Shelley, C Simon, Shen, Hui, Shuch, Brian, Signoretti, Sabina, Srinivasan, Ramaprasad, Tamboli, Pheroze, Thomas, George, Vincent, Benjamin G, Vocke, Cathy D, Wheeler, David A, Yang, Lixing, Kim, William Y, Robertson, A Gordon, Spellman, Paul, Rathmell, W Kimryn, Linehan, W Marston, Caesar-Johnson, Samantha J, Demchok, John A, Felau, Ina, Kasapi, Melpomeni, Ferguson, Martin L, Hutter, Carolyn M, Sofia, Heidi J, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean C, Zhang, Jiashan, Chudamani, Sudha, Liu, Jia, Lolla, Laxmi, Naresh, Rashi, Pihl, Todd, Sun, Qiang, Wan, Yunhu, Wu, Ye, Cho, Juok, DeFreitas, Timothy, Frazer, Scott, Gehlenborg, Nils, Getz, Gad, Heiman, David I, Kim, Jaegil, Lawrence, Michael S, Lin, Pei, Meier, Sam, Noble, Michael S, Saksena, Gordon, Voet, Doug, Zhang, Hailei, Bernard, Brady, Chambwe, Nyasha, Dhankani, Varsha, Knijnenburg, Theo, Kramer, Roger, Leinonen, Kalle, Liu, Yuexin, Miller, Michael, Reynolds, Sheila, Shmulevich, Ilya, Thorsson, Vesteinn, Zhang, Wei, Broom, Bradley M, Hegde, Apurva M, Ju, Zhenlin, Korkut, Anil, Li, Jun, Liang, Han, and Ling, Shiyun

Subjects
Biological Sciences, Cancer Genome Atlas Research Network, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

(Cell Reports 23, 313–326; April 3, 2018) In the originally published version of this article, the author list contained two errors. Specifically, David J. Kwiatkowski was misspelled as David J. Kwaitkowski, and William Y. Kim was inadvertently written as William T. Kim. Both names have been corrected online. The authors regret this error.

Published
2018

29. Integrated Molecular Characterization of Testicular Germ Cell Tumors

Author

Shen, Hui, Shih, Juliann, Hollern, Daniel P, Wang, Linghua, Bowlby, Reanne, Tickoo, Satish K, Thorsson, Vésteinn, Mungall, Andrew J, Newton, Yulia, Hegde, Apurva M, Armenia, Joshua, Sánchez-Vega, Francisco, Pluta, John, Pyle, Louise C, Mehra, Rohit, Reuter, Victor E, Godoy, Guilherme, Jones, Jeffrey, Shelley, Carl S, Feldman, Darren R, Vidal, Daniel O, Lessel, Davor, Kulis, Tomislav, Cárcano, Flavio M, Leraas, Kristen M, Lichtenberg, Tara M, Brooks, Denise, Cherniack, Andrew D, Cho, Juok, Heiman, David I, Kasaian, Katayoon, Liu, Minwei, Noble, Michael S, Xi, Liu, Zhang, Hailei, Zhou, Wanding, ZenKlusen, Jean C, Hutter, Carolyn M, Felau, Ina, Zhang, Jiashan, Schultz, Nikolaus, Getz, Gad, Meyerson, Matthew, Stuart, Joshua M, Akbani, Rehan, Wheeler, David, Laird, Peter W, Nathanson, Katherine L, Cortessis, Victoria K, Hoadley, Katherine A, Wheeler, David A, Hughes, Daniel, Covington, Kyle, Jayaseelan, Joy C, Korchina, Viktoriya, Lewis, Lora, Hu, Jianhong, Doddapaneni, HarshaVardhan, Muzny, Donna, Gibbs, Richard, Hollern, Daniel, Vincent, Benjamin G, Chai, Shengjie, Smith, Christof C, Auman, J Todd, Shi, Yan, Meng, Shaowu, Skelly, Tara, Tan, Donghui, Veluvolu, Umadevi, Mieczkowski, Piotr A, Jones, Corbin D, Wilkerson, Matthew D, Balu, Saianand, Bodenheimer, Tom, Hoyle, Alan P, Jefferys, Stuart R, Mose, Lisle E, Simons, Janae V, Soloway, Matthew G, Roach, Jeffrey, Parker, Joel S, Hayes, D Neil, Perou, Charles M, Saksena, Gordon, Cibulskis, Carrie, Schumacher, Steven E, Beroukhim, Rameen, Gabriel, Stacey B, and Ally, Adrian

Subjects
Urologic Diseases, Rare Diseases, Human Genome, Cancer, Biotechnology, Genetics, DNA Copy Number Variations, DNA Methylation, Gene Expression Regulation, Neoplastic, Humans, Male, MicroRNAs, Neoplasms, Germ Cell and Embryonal, Proto-Oncogene Proteins c-kit, Seminoma, Testicular Neoplasms, ras Proteins, Cancer Genome Atlas Research Network, DNA methylation, KIT, The Cancer Genome Atlas, copy number, exome sequencing, miR-375, nonseminoma, seminoma, testicular germ cell tumors, Biochemistry and Cell Biology, Medical Physiology
Abstract

We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance-KIT, KRAS, and NRAS-exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas.

Published
2018

30. The Integrated Genomic Landscape of Thymic Epithelial Tumors

Author

Radovich, Milan, Pickering, Curtis R, Felau, Ina, Ha, Gavin, Zhang, Hailei, Jo, Heejoon, Hoadley, Katherine A, Anur, Pavana, Zhang, Jiexin, McLellan, Mike, Bowlby, Reanne, Matthew, Thomas, Danilova, Ludmila, Hegde, Apurva M, Kim, Jaegil, Leiserson, Mark DM, Sethi, Geetika, Lu, Charles, Ryan, Michael, Su, Xiaoping, Cherniack, Andrew D, Robertson, Gordon, Akbani, Rehan, Spellman, Paul, Weinstein, John N, Hayes, D Neil, Raphael, Ben, Lichtenberg, Tara, Leraas, Kristen, Zenklusen, Jean Claude, Network, The Cancer Genome Atlas, Ally, Adrian, Appelbaum, Elizabeth L, Auman, J Todd, Balasundaram, Miruna, Balu, Saianand, Behera, Madhusmita, Beroukhim, Rameen, Berrios, Mario, Blandino, Giovanni, Bodenheimer, Tom, Bootwalla, Moiz S, Bowen, Jay, Brooks, Denise, Carcano, Flavio M, Carlsen, Rebecca, Carvalho, Andre L, Castro, Patricia, Chalabreysse, Lara, Chin, Lynda, Cho, Juok, Choe, Gina, Chuah, Eric, Chudamani, Sudha, Cibulskis, Carrie, Cope, Leslie, Cordes, Matthew G, Crain, Daniel, Curley, Erin, Defreitas, Timothy, Demchok, John A, Detterbeck, Frank, Dhalla, Noreen, Dienemann, Hendrik, Edenfield, W Jeff, Facciolo, Francesco, Ferguson, Martin L, Frazer, Scott, Fronick, Catrina C, Fulton, Lucinda A, Fulton, Robert S, Gabriel, Stacey B, Gardner, Johanna, Gastier-Foster, Julie M, Gehlenborg, Nils, Gerken, Mark, Getz, Gad, Heiman, David I, Hobensack, Shital, Holbrook, Andrea, Holt, Robert A, Hoyle, Alan P, Hutter, Carolyn M, Ittmann, Michael, Jefferys, Stuart R, Jones, Corbin D, Jones, Steven JM, Kasaian, Katayoon, Kimes, Patrick K, Lai, Phillip H, Laird, Peter W, Lawrence, Michael S, Lin, Pei, Liu, Jia, Lolla, Laxmi, Lu, Yiling, Ma, Yussanne, Maglinte, Dennis T, and Mallery, David

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Autoimmune Disease, Biotechnology, Human Genome, Cancer, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Adult, Aged, Aged, 80 and over, Female, Genomics, Humans, Male, Middle Aged, Mutation, Neoplasms, Glandular and Epithelial, Thymoma, Thymus Neoplasms, Transcription Factors, TFII, Young Adult, Cancer Genome Atlas Network, TCGA, autoimmunity, genomics, myasthenia gravis, proteomics, thymic carcinoma, thymic epithelial tumors, thymoma, transcriptomics, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral overexpression of muscle autoantigens, and increased aneuploidy.

Published
2018

31. Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Author

Network, The Cancer Genome Atlas Research, Abeshouse, Adam, Adebamowo, Clement, Adebamowo, Sally N, Akbani, Rehan, Akeredolu, Teniola, Ally, Adrian, Anderson, Matthew L, Anur, Pavana, Appelbaum, Elizabeth L, Armenia, Joshua, Auman, J Todd, Bailey, Matthew H, Baker, Laurence, Balasundaram, Miruna, Balu, Saianand, Barthel, Floris P, Bartlett, John, Baylin, Stephen B, Behera, Madhusmita, Belyaev, Dmitry, Bennett, Joesph, Benz, Christopher, Beroukhim, Rameen, Birrer, Michael, Bocklage, Thèrése, Bodenheimer, Tom, Boice, Lori, Bootwalla, Moiz S, Bowen, Jay, Bowlby, Reanne, Boyd, Jeff, Brohl, Andrew S, Brooks, Denise, Byers, Lauren, Carlsen, Rebecca, Castro, Patricia, Chen, Hsiao-Wei, Cherniack, Andrew D, Chibon, Fréderic, Chin, Lynda, Cho, Juok, Chuah, Eric, Chudamani, Sudha, Cibulskis, Carrie, Cooper, Lee AD, Cope, Leslie, Cordes, Matthew G, Crain, Daniel, Curley, Erin, Danilova, Ludmila, Dao, Fanny, Davis, Ian J, Davis, Lara E, Defreitas, Timothy, Delman, Keith, Demchok, John A, Demetri, George D, Demicco, Elizabeth G, Dhalla, Noreen, Diao, Lixia, Ding, Li, DiSaia, Phil, Dottino, Peter, Doyle, Leona A, Drill, Esther, Dubina, Michael, Eschbacher, Jennifer, Fedosenko, Konstantin, Felau, Ina, Ferguson, Martin L, Frazer, Scott, Fronick, Catrina C, Fulidou, Victoria, Fulton, Lucinda A, Fulton, Robert S, Gabriel, Stacey B, Gao, Jianjiong, Gao, Qingsong, Gardner, Johanna, Gastier-Foster, Julie M, Gay, Carl M, Gehlenborg, Nils, Gerken, Mark, Getz, Gad, Godwin, Andrew K, Godwin, Eryn M, Gordienko, Elena, Grilley-Olson, Juneko E, Gutman, David A, Gutmann, David H, Hayes, D Neil, Hegde, Apurva M, Heiman, David I, Heins, Zachary, Helsel, Carmen, Hepperla, Austin J, Higgins, Kelly, Hoadley, Katherine A, and Hobensack, Shital

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Cancer, Human Genome, Digestive Diseases, Rare Diseases, Adult, Aged, Aged, 80 and over, Cluster Analysis, DNA Copy Number Variations, Epigenomics, Genome, Human, Genome-Wide Association Study, Humans, Middle Aged, Mutation, Sarcoma, Young Adult, Cancer Genome Atlas Research Network. Electronic address: elizabeth.demicco@sinaihealthsystem.ca, Cancer Genome Atlas Research Network, DNA methylation, The Cancer Genome Atlas, dedifferentiated liposarcoma, genomics, immune infiltration, leiomyosarcoma, molecular subtype, myxofibrosarcoma, pleomorphism, undifferentiated pleomorphic sarcoma, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.

Published
2017

32. Supplementary Table S3 from Clinical and Genomic Predictors of Adverse Events in Newly Diagnosed Glioblastoma

Author

Lim-Fat, Mary Jane, primary, Iorgulescu, J. Bryan, primary, Rahman, Rifaquat, primary, Bhave, Varun, primary, Muzikansky, Alona, primary, Woodward, Eleanor, primary, Whorral, Sydney, primary, Allen, Marie, primary, Touat, Mehdi, primary, Li, Xiaomei, primary, Xy, Gongwen, primary, Patel, Jay, primary, Gerstner, Elizabeth R., primary, Kalpathy-Cramer, Jayashree, primary, Youssef, Gilbert, primary, Chukwueke, Ugonma, primary, McFaline-Figueroa, J. Ricardo, primary, Nayak, Lakshmi, primary, Lee, Eudocia Q., primary, Reardon, David A., primary, Beroukhim, Rameen, primary, Huang, Raymond Y., primary, Bi, Wenya Linda, primary, Ligon, Keith L., primary, and Wen, Patrick Y., primary

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2024
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33. Supplementary Figure S1 from Clinical and Genomic Predictors of Adverse Events in Newly Diagnosed Glioblastoma

Author

Lim-Fat, Mary Jane, primary, Iorgulescu, J. Bryan, primary, Rahman, Rifaquat, primary, Bhave, Varun, primary, Muzikansky, Alona, primary, Woodward, Eleanor, primary, Whorral, Sydney, primary, Allen, Marie, primary, Touat, Mehdi, primary, Li, Xiaomei, primary, Xy, Gongwen, primary, Patel, Jay, primary, Gerstner, Elizabeth R., primary, Kalpathy-Cramer, Jayashree, primary, Youssef, Gilbert, primary, Chukwueke, Ugonma, primary, McFaline-Figueroa, J. Ricardo, primary, Nayak, Lakshmi, primary, Lee, Eudocia Q., primary, Reardon, David A., primary, Beroukhim, Rameen, primary, Huang, Raymond Y., primary, Bi, Wenya Linda, primary, Ligon, Keith L., primary, and Wen, Patrick Y., primary

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2024
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35. Table S1 from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author

Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary

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2024
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36. Supp Figures from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author

Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary

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2024
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37. Supplemental Figures Legends from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author

Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary

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2024
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38. Data from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author

Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary

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2024
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39. Supplementary Appendix from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author

Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary

Published
2024
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40. Author Correction: Analyses of non-coding somatic drivers in 2,658 cancer whole genomes

Author

Rheinbay, Esther, Nielsen, Morten Muhlig, Abascal, Federico, Wala, Jeremiah A., Shapira, Ofer, Tiao, Grace, Hornshøj, Henrik, Hess, Julian M., Juul, Randi Istrup, Lin, Ziao, Feuerbach, Lars, Sabarinathan, Radhakrishnan, Madsen, Tobias, Kim, Jaegil, Mularoni, Loris, Shuai, Shimin, Lanzós, Andrés, Herrmann, Carl, Maruvka, Yosef E., Shen, Ciyue, Amin, Samirkumar B., Bandopadhayay, Pratiti, Bertl, Johanna, Boroevich, Keith A., Busanovich, John, Carlevaro-Fita, Joana, Chakravarty, Dimple, Chan, Calvin Wing Yiu, Craft, David, Dhingra, Priyanka, Diamanti, Klev, Fonseca, Nuno A., Gonzalez-Perez, Abel, Guo, Qianyun, Hamilton, Mark P., Haradhvala, Nicholas J., Hong, Chen, Isaev, Keren, Johnson, Todd A., Juul, Malene, Kahles, Andre, Kahraman, Abdullah, Kim, Youngwook, Komorowski, Jan, Kumar, Kiran, Kumar, Sushant, Lee, Donghoon, Lehmann, Kjong-Van, Li, Yilong, Liu, Eric Minwei, Lochovsky, Lucas, Park, Keunchil, Pich, Oriol, Roberts, Nicola D., Saksena, Gordon, Schumacher, Steven E., Sidiropoulos, Nikos, Sieverling, Lina, Sinnott-Armstrong, Nasa, Stewart, Chip, Tamborero, David, Tubio, Jose M. C., Umer, Husen M., Uusküla-Reimand, Liis, Wadelius, Claes, Wadi, Lina, Yao, Xiaotong, Zhang, Cheng-Zhong, Zhang, Jing, Haber, James E., Hobolth, Asger, Imielinski, Marcin, Kellis, Manolis, Lawrence, Michael S., von Mering, Christian, Nakagawa, Hidewaki, Raphael, Benjamin J., Rubin, Mark A., Sander, Chris, Stein, Lincoln D., Stuart, Joshua M., Tsunoda, Tatsuhiko, Wheeler, David A., Johnson, Rory, Reimand, Jüri, Gerstein, Mark, Khurana, Ekta, Campbell, Peter J., López-Bigas, Núria, Weischenfeldt, Joachim, Beroukhim, Rameen, Martincorena, Iñigo, Pedersen, Jakob Skou, and Getz, Gad

Published
2023
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41. Author Correction: The evolutionary history of 2,658 cancers

Author

Gerstung, Moritz, Jolly, Clemency, Leshchiner, Ignaty, Dentro, Stefan C., Gonzalez, Santiago, Rosebrock, Daniel, Mitchell, Thomas J., Rubanova, Yulia, Anur, Pavana, Yu, Kaixian, Tarabichi, Maxime, Deshwar, Amit, Wintersinger, Jeff, Kleinheinz, Kortine, Vázquez-García, Ignacio, Haase, Kerstin, Jerman, Lara, Sengupta, Subhajit, Macintyre, Geoff, Malikic, Salem, Donmez, Nilgun, Livitz, Dimitri G., Cmero, Marek, Demeulemeester, Jonas, Schumacher, Steven, Fan, Yu, Yao, Xiaotong, Lee, Juhee, Schlesner, Matthias, Boutros, Paul C., Bowtell, David D., Zhu, Hongtu, Getz, Gad, Imielinski, Marcin, Beroukhim, Rameen, Sahinalp, S. Cenk, Ji, Yuan, Peifer, Martin, Markowetz, Florian, Mustonen, Ville, Yuan, Ke, Wang, Wenyi, Morris, Quaid D., Spellman, Paul T., Wedge, David C., and Van Loo, Peter

Published
2023
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43. Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Author

Robertson, A Gordon, Shih, Juliann, Yau, Christina, Gibb, Ewan A, Oba, Junna, Mungall, Karen L, Hess, Julian M, Uzunangelov, Vladislav, Walter, Vonn, Danilova, Ludmila, Lichtenberg, Tara M, Kucherlapati, Melanie, Kimes, Patrick K, Tang, Ming, Penson, Alexander, Babur, Ozgun, Akbani, Rehan, Bristow, Christopher A, Hoadley, Katherine A, Iype, Lisa, Chang, Matthew T, Network, TCGA Research, Abdel-Rahman, Mohamed H, Ally, Adrian, Auman, J Todd, Balasundaram, Miruna, Balu, Saianand, Benz, Christopher, Beroukhim, Rameen, Birol, Inanc, Bodenheimer, Tom, Bowen, Jay, Bowlby, Reanne, Brooks, Denise, Carlsen, Rebecca, Cebulla, Colleen M, Cherniack, Andrew D, Chin, Lynda, Cho, Juok, Chuah, Eric, Chudamani, Sudha, Cibulskis, Carrie, Cibulskis, Kristian, Cope, Leslie, Coupland, Sarah E, Defreitas, Timothy, Demchok, John A, Desjardins, Laurence, Dhalla, Noreen, Esmaeli, Bita, Felau, Ina, Ferguson, Martin L, Frazer, Scott, Gabriel, Stacey B, Gastier-Foster, Julie M, Gehlenborg, Nils, Gerken, Mark, Gershenwald, Jeffrey E, Getz, Gad, Griewank, Klaus G, Grimm, Elizabeth A, Hayes, D Neil, Hegde, Apurva M, Heiman, David I, Helsel, Carmen, Hobensack, Shital, Holt, Robert A, Hoyle, Alan P, Hu, Xin, Hutter, Carolyn M, Jager, Martine J, Jefferys, Stuart R, Jones, Corbin D, Jones, Steven JM, Kandoth, Cyriac, Kasaian, Katayoon, Kim, Jaegil, Kucherlapati, Raju, Lander, Eric, Lawrence, Michael S, Lazar, Alexander J, Lee, Semin, Leraas, Kristen M, Lin, Pei, Liu, Jia, Liu, Wenbin, Lolla, Laxmi, and Lu, Yiling

Subjects
Eye Disease and Disorders of Vision, Cancer, Human Genome, Rare Diseases, Genetics, Biomarkers, Tumor, DNA Copy Number Variations, DNA Methylation, Eukaryotic Initiation Factor-1, Gene Expression Regulation, Neoplastic, Humans, Melanoma, Monosomy, Mutation, Phosphoproteins, Prognosis, RNA Splicing Factors, Serine-Arginine Splicing Factors, Tumor Suppressor Proteins, Ubiquitin Thiolesterase, Uveal Neoplasms, TCGA Research Network, EIF1AX, GNA11, GNAQ, SF3B1, SRSF2, TCGA, molecular subtypes, monosomy 3, noncoding RNA, uveal melanoma, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
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

44. The whole-genome landscape of medulloblastoma subtypes

Author

Northcott, Paul A, Buchhalter, Ivo, Morrissy, A Sorana, Hovestadt, Volker, Weischenfeldt, Joachim, Ehrenberger, Tobias, Gröbner, Susanne, Segura-Wang, Maia, Zichner, Thomas, Rudneva, Vasilisa A, Warnatz, Hans-Jörg, Sidiropoulos, Nikos, Phillips, Aaron H, Schumacher, Steven, Kleinheinz, Kortine, Waszak, Sebastian M, Erkek, Serap, Jones, David TW, Worst, Barbara C, Kool, Marcel, Zapatka, Marc, Jäger, Natalie, Chavez, Lukas, Hutter, Barbara, Bieg, Matthias, Paramasivam, Nagarajan, Heinold, Michael, Gu, Zuguang, Ishaque, Naveed, Jäger-Schmidt, Christina, Imbusch, Charles D, Jugold, Alke, Hübschmann, Daniel, Risch, Thomas, Amstislavskiy, Vyacheslav, Gonzalez, Francisco German Rodriguez, Weber, Ursula D, Wolf, Stephan, Robinson, Giles W, Zhou, Xin, Wu, Gang, Finkelstein, David, Liu, Yanling, Cavalli, Florence MG, Luu, Betty, Ramaswamy, Vijay, Wu, Xiaochong, Koster, Jan, Ryzhova, Marina, Cho, Yoon-Jae, Pomeroy, Scott L, Herold-Mende, Christel, Schuhmann, Martin, Ebinger, Martin, Liau, Linda M, Mora, Jaume, McLendon, Roger E, Jabado, Nada, Kumabe, Toshihiro, Chuah, Eric, Ma, Yussanne, Moore, Richard A, Mungall, Andrew J, Mungall, Karen L, Thiessen, Nina, Tse, Kane, Wong, Tina, Jones, Steven JM, Witt, Olaf, Milde, Till, Von Deimling, Andreas, Capper, David, Korshunov, Andrey, Yaspo, Marie-Laure, Kriwacki, Richard, Gajjar, Amar, Zhang, Jinghui, Beroukhim, Rameen, Fraenkel, Ernest, Korbel, Jan O, Brors, Benedikt, Schlesner, Matthias, Eils, Roland, Marra, Marco A, Pfister, Stefan M, Taylor, Michael D, and Lichter, Peter

Subjects
Cancer, Human Genome, Brain Disorders, Pediatric Cancer, Brain Cancer, Genetics, Biotechnology, Rare Diseases, Neurosciences, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Good Health and Well Being, Carcinogenesis, Carrier Proteins, Cohort Studies, DNA Methylation, DNA Mutational Analysis, Datasets as Topic, Epistasis, Genetic, Genome, Human, Genomics, Humans, Medulloblastoma, Molecular Targeted Therapy, Muscle Proteins, Mutation, Oncogenes, Transcription Factors, Whole Genome Sequencing, Wnt Proteins, General Science & Technology
Abstract

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

Published
2017

45. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Author

Ally, Adrian, Balasundaram, Miruna, Carlsen, Rebecca, Chuah, Eric, Clarke, Amanda, Dhalla, Noreen, Holt, Robert A, Jones, Steven JM, Lee, Darlene, Ma, Yussanne, Marra, Marco A, Mayo, Michael, Moore, Richard A, Mungall, Andrew J, Schein, Jacqueline E, Sipahimalani, Payal, Tam, Angela, Thiessen, Nina, Cheung, Dorothy, Wong, Tina, Brooks, Denise, Robertson, A Gordon, Bowlby, Reanne, Mungall, Karen, Sadeghi, Sara, Xi, Liu, Covington, Kyle, Shinbrot, Eve, Wheeler, David A, Gibbs, Richard A, Donehower, Lawrence A, Wang, Linghua, Bowen, Jay, Gastier-Foster, Julie M, Gerken, Mark, Helsel, Carmen, Leraas, Kristen M, Lichtenberg, Tara M, Ramirez, Nilsa C, Wise, Lisa, Zmuda, Erik, Gabriel, Stacey B, Meyerson, Matthew, Cibulskis, Carrie, Murray, Bradley A, Shih, Juliann, Beroukhim, Rameen, Cherniack, Andrew D, Schumacher, Steven E, Saksena, Gordon, Pedamallu, Chandra Sekhar, Chin, Lynda, Getz, Gad, Noble, Michael, Zhang, Hailei, Heiman, David, Cho, Juok, Gehlenborg, Nils, Voet, Douglas, Lin, Pei, Frazer, Scott, Defreitas, Timothy, Meier, Sam, Lawrence, Michael, Kim, Jaegil, Creighton, Chad J, Muzny, Donna, Doddapaneni, HarshaVardhan, Hu, Jianhong, Wang, Min, Morton, Donna, Korchina, Viktoriya, Han, Yi, Dinh, Huyen, Lewis, Lora, Bellair, Michelle, Liu, Xiuping, Santibanez, Jireh, Glenn, Robert, Lee, Sandra, Hale, Walker, Parker, Joel S, Wilkerson, Matthew D, Hayes, D Neil, Reynolds, Sheila M, Shmulevich, Ilya, Zhang, Wei, Liu, Yuexin, Iype, Lisa, Makhlouf, Hala, Torbenson, Michael S, Kakar, Sanjay, Yeh, Matthew M, Jain, Dhanpat, Kleiner, David E, Dhanasekaran, Renumathy, El-Serag, Hashem B, and Yim, Sun Young

Subjects
Human Genome, Digestive Diseases, Biotechnology, Rare Diseases, Genetics, Liver Disease, Liver Cancer, Cancer, Aetiology, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, Carcinoma, Hepatocellular, DNA Methylation, Genomics, Humans, Isocitrate Dehydrogenase, Liver Neoplasms, MicroRNAs, Mutation, Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu, Cancer Genome Atlas Research Network, IDH1/2, TP53, cancer subtyping, expression profile, hepatocellular carcinoma, metabolic reprogramming, promoter hypermethylation, significantly mutated genes, sonic hedgehog signaling, stem cell phenotype, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.

Published
2017

46. Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas

Author

Shankar, Ganesh M, Abedalthagafi, Malak, Vaubel, Rachael A, Merrill, Parker H, Nayyar, Naema, Gill, Corey M, Brewster, Ryan, Bi, Wenya Linda, Agarwalla, Pankaj K, Thorner, Aaron R, Reardon, David A, Al-Mefty, Ossama, Wen, Patrick Y, Alexander, Brian M, van Hummelen, Paul, Batchelor, Tracy T, Ligon, Keith L, Ligon, Azra H, Meyerson, Matthew, Dunn, Ian F, Beroukhim, Rameen, Louis, David N, Perry, Arie, Carter, Scott L, Giannini, Caterina, Curry, William T, Cahill, Daniel P, Barker, Frederick G, Brastianos, Priscilla K, and Santagata, Sandro

Subjects
Cancer, Rare Diseases, Clinical Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Disease Progression, Germ-Line Mutation, Humans, Meningeal Neoplasms, Meningioma, Mutation, Neoplasm Grading, Rhabdoid Tumor, Survival Analysis, Tumor Suppressor Proteins, Ubiquitin Thiolesterase, BAP1, exome sequencing, rhabdoid meningiomas, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundPatients with meningiomas have widely divergent clinical courses. Some entirely recover following surgery alone, while others have relentless tumor recurrences. This clinical conundrum is exemplified by rhabdoid meningiomas, which are designated in the World Health Organization Classification of Tumours as high grade, despite only a subset following an aggressive clinical course. Patient management decisions are further exacerbated by high rates of interobserver variability, biased against missing possibly aggressive tumors. Objective molecular determinants are needed to guide classification and clinical decision making.MethodsTo define genomic aberrations of rhabdoid meningiomas, we performed sequencing of cancer-related genes in 27 meningiomas from 18 patients with rhabdoid features and evaluated breast cancer [BRCA]1-associated protein 1 (BAP1) expression by immunohistochemistry in 336 meningiomas. We assessed outcomes, germline status, and family history in patients with BAP1-negative rhabdoid meningiomas.ResultsThe tumor suppressor gene BAP1, a ubiquitin carboxy-terminal hydrolase, is inactivated in a subset of high-grade rhabdoid meningiomas. Patients with BAP1-negative rhabdoid meningiomas had reduced time to recurrence compared with patients with BAP1-retained rhabdoid meningiomas (Kaplan-Meier analysis, 26 mo vs 116 mo, P < .001; hazard ratio 12.89). A subset of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, indicating that rhabdoid meningiomas can be a harbinger of the BAP1 cancer predisposition syndrome.ConclusionWe define a subset of aggressive rhabdoid meningiomas that can be recognized using routine laboratory tests. We implicate ubiquitin deregulation in the pathogenesis of these high-grade malignancies. In addition, we show that familial and sporadic BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management.

Published
2017

47. 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

48. Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles

Author

Farshidfar, Farshad, Zheng, Siyuan, Gingras, Marie-Claude, Newton, Yulia, Shih, Juliann, Robertson, A Gordon, Hinoue, Toshinori, Hoadley, Katherine A, Gibb, Ewan A, Roszik, Jason, Covington, Kyle R, Wu, Chia-Chin, Shinbrot, Eve, Stransky, Nicolas, Hegde, Apurva, Yang, Ju Dong, Reznik, Ed, Sadeghi, Sara, Pedamallu, Chandra Sekhar, Ojesina, Akinyemi I, Hess, Julian M, Auman, J Todd, Rhie, Suhn K, Bowlby, Reanne, Borad, Mitesh J, Network, The Cancer Genome Atlas, Akbani, Rehan, Allotey, Loretta K, Ally, Adrian, Alvaro, Domenico, Andersen, Jesper B, Appelbaum, Elizabeth L, Arora, Arshi, Balasundaram, Miruna, Balu, Saianand, Bardeesy, Nabeel, Bathe, Oliver F, Baylin, Stephen B, Beroukhim, Rameen, Berrios, Mario, Bodenheimer, Tom, Boice, Lori, Bootwalla, Moiz S, Bowen, Jay, Bragazzi, Maria Consiglia, Brooks, Denise, Cardinale, Vincenzo, Carlsen, Rebecca, Carpino, Guido, Carvalho, Andre L, Chaiteerakij, Roongruedee, Chandan, Vishal C, Cherniack, Andrew D, Chin, Lynda, Cho, Juok, Choe, Gina, Chuah, Eric, Chudamani, Sudha, Cibulskis, Carrie, Cordes, Matthew G, Crain, Daniel, Curley, Erin, De Rose, Agostino Maria, Defreitas, Timothy, Demchok, John A, Deshpande, Vikram, Dhalla, Noreen, Ding, Li, Evason, Kimberley, Felau, Ina, Ferguson, Martin L, Foo, Wai Chin, Franchitto, Antonio, Frazer, Scott, Fronick, Catrina C, Fulton, Lucinda A, Fulton, Robert S, Gabriel, Stacey B, Gardner, Johanna, Gastier-Foster, Julie M, Gaudio, Eugenio, Gehlenborg, Nils, Genovese, Giannicola, Gerken, Mark, Getz, Gad, Giama, Nasra H, Gibbs, Richard A, Giuliante, Felice, Grazi, Gian Luca, Hayes, D Neil, Hegde, Apurva M, and Heiman, David I

Subjects
Liver Cancer, Digestive Diseases, Liver Disease, Biotechnology, Human Genome, Genetics, Cancer, Rare Diseases, Digestive Diseases - (Gallbladder), Adult, Aged, Aged, 80 and over, Bile Duct Neoplasms, Cholangiocarcinoma, Chromatin, DNA Methylation, DNA-Binding Proteins, Female, Gene Expression Regulation, Neoplastic, Genomics, Humans, Isocitrate Dehydrogenase, Liver, Liver Neoplasms, Male, Middle Aged, Mitochondria, Mutation, Nuclear Proteins, Pancreatic Neoplasms, Promoter Regions, Genetic, RNA, Long Noncoding, RNA, Messenger, Transcription Factors, Cancer Genome Atlas Network, ARID1A, DNA methylation, IDH, RNA sequencing, TCGA, cholangiocarcinoma, integrative genomics, lncRNAs, multi-omics, whole exome, Biochemistry and Cell Biology, Medical Physiology
Abstract

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.

Published
2017

49. 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

50. Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition

Author

Cohen-Sharir, Yael, McFarland, James M., Abdusamad, Mai, Marquis, Carolyn, Bernhard, Sara V., Kazachkova, Mariya, Tang, Helen, Ippolito, Marica R., Laue, Kathrin, Zerbib, Johanna, Malaby, Heidi L. H., Jones, Andrew, Stautmeister, Lisa-Marie, Bockaj, Irena, Wardenaar, René, Lyons, Nicholas, Nagaraja, Ankur, Bass, Adam J., Spierings, Diana C. J., Foijer, Floris, Beroukhim, Rameen, Santaguida, Stefano, Golub, Todd R., Stumpff, Jason, Storchová, Zuzana, and Ben-David, Uri

Published
2021
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