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295 results on '"Birol I"'

1. HostSeq: a Canadian whole genome sequencing and clinical data resource

Author

Yoo, S, Garg, E, Elliott, LT, Hung, RJ, Halevy, AR, Brooks, JD, Bull, SB, Gagnon, F, Greenwood, CMT, Lawless, JF, Paterson, AD, Sun, L, Zawati, MH, Lerner-Ellis, J, Abraham, RJS, Birol, I, Bourque, G, Garant, J-M, Gosselin, C, Li, J, Whitney, J, Thiruvahindrapuram, B, Herbrick, J-A, Lorenti, M, Reuter, MS, Adeoye, OO, Liu, S, Allen, U, Bernier, FP, Biggs, CM, Cheung, AM, Cowan, J, Herridge, M, Maslove, DM, Modi, BP, Mooser, V, Morris, SK, Ostrowski, M, Parekh, RS, Pfeffer, G, Suchowersky, O, Taher, J, Upton, J, Warren, RL, Yeung, RSM, Aziz, N, Turvey, SE, Knoppers, BM, Lathrop, M, Jones, SJM, Scherer, SW, and Strug, LJ

Published
2023
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2. Coherent bremsstrahlung, boherent pair production, birefringence and polarimetry in the 20-170 GeV energy range using aligned crystals

Author

NA59 Collaboration, Apyan, A., Avakian, R. O., Badelek, B., Ballestrero, S., Biino, C., Birol, I., Cenci, P., Connell, S. H., Eichblatt, S., Fonseca, T., Freund, A., Gorini, B., Groess, R., Ispirian, K., Ketel, T. J., Kononets, Yu. V., Lopez, A., Mangiarotti, A., van Rens, B., Sellschop, J. P. F., Shieh, M., Sona, P., Strakhovenko, V., Uggerhoj, E., Uggerhoj, U. I., Unel, G., Velasco, M., Vilakazi, Z. Z., and Wessely, O.

Subjects
High Energy Physics - Experiment
Abstract

The processes of coherent bremsstrahlung (CB) and coherent pair production (CPP) based on aligned crystal targets have been studied in the energy range 20-170 GeV. The experimental arrangement allowed for measurements of single photon properties of these phenomena including their polarization dependences. This is significant as the theoretical description of CB and CPP is an area of active theoretical debate and development. With the theoretical approach used in this paper both the measured cross sections and polarization observables are predicted very well. This indicates a proper understanding of CB and CPP up to energies of 170 GeV. Birefringence in CPP on aligned crystals is applied to determine the polarization parameters in our measurements. New technologies for high energy photon beam optics including phase plates and polarimeters for linear and circular polarization are demonstrated in this experiment. Coherent bremsstrahlung for the strings-on-strings (SOS) orientation yields a larger enhancement for hard photons than CB for the channeling orientations of the crystal. Our measurements and our calculations indicate low photon polarizations for the high energy SOS photons., Comment: 23 pages, 27 figures, 2 tables, REVTeX4 two columns

Published
2005
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3. Results on the Coherent Interaction of High Energy Electrons and Photons in Oriented Single Crystals

Author

NA59 Collaboration, Apyan, A., Avakian, R. O., Badelek, B., Ballestrero, S., Biino, C., Birol, I., Cenci, P., Connell, S. H., Eichblatt, S., Fonseca, T., Freund, A., Gorini, B., Groess, R., Ispirian, K., Ketel, T. J., Kononets, Yu. V., Lopez, A., Mangiarotti, A., van Rens, B., Sellschop, J. P. F., Shieh, M., Sona, P., Strakhovenko, V., Uggerhoj, E., Uggerhoj, U. I., Unel, G., Velasco, M., Vilakazi, Z. Z., and Wessely, O.

Subjects
High Energy Physics - Experiment
Abstract

The CERN-NA-59 experiment examined a wide range of electromagnetic processes for multi-GeV electrons and photons interacting with oriented single crystals. The various types of crystals and their orientations were used for producing photon beams and for converting and measuring their polarisation. The radiation emitted by 178 GeV unpolarised electrons incident on a 1.5 cm thick Si crystal oriented in the Coherent Bremsstrahlung (CB) and the String-of-Strings (SOS) modes was used to obtain multi-GeV linearly polarised photon beams. A new crystal polarimetry technique was established for measuring the linear polarisation of the photon beam. The polarimeter is based on the dependence of the Coherent Pair Production (CPP) cross section in oriented single crystals on the direction of the photon polarisation with respect to the crystal plane. Both a 1 mm thick single crystal of Germanium and a 4 mm thick multi-tile set of synthetic Diamond crystals were used as analyzers of the linear polarisation. A birefringence phenomenon, the conversion of the linear polarisation of the photon beam into circular polarisation, was observed. This was achieved by letting the linearly polarised photon beam pass through a 10 cm thick Silicon single crystal that acted as a "quarter wave plate" (QWP) as suggested by N. Cabibbo et al., Comment: Presented at International workshop "Relativistic Channeling and Related Coherent Phenomena", Frascati (Rome) 23-26 March 2004

Published
2005
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4. Measurement of Coherent Emission and Linear Polarization of Photons by Electrons in the Strong Fields of Aligned Crystals

Author

NA59 Collaboration, Apyan, A., Avakian, R. O., Badelek, B., Ballestrero, S., Biino, C., Birol, I., Cenci, P., Connell, S. H., Eichblatt, S., Fonseca, T., Freund, A., Gorini, B., Groess, R., Ispirian, K., Ketel, T. J., Kononets, Yu. V., Lopez, A., Mangiarotti, A., van Rens, B., Sellschop, J. P. F., Shieh, M., Sona, P., Strakhovenko, V., Uggerhoj, E., Uggerhoj, U. I., Unel, G., Velasco, M., Vilakazi, Z. Z., and Wessely, O.

Subjects
High Energy Physics - Experiment
Abstract

We present new results regarding the features of high energy photon emission by an electron beam of 178 GeV penetrating a 1.5 cm thick single Si crystal aligned at the Strings-Of-Strings (SOS) orientation. This concerns a special case of coherent bremsstrahlung where the electron interacts with the strong fields of successive atomic strings in a plane and for which the largest enhancement of the highest energy photons is expected. The polarization of the resulting photon beam was measured by the asymmetry of electron-positron pair production in an aligned diamond crystal analyzer. By the selection of a single pair the energy and the polarization of individual photons could be measured in an the environment of multiple photons produced in the radiator crystal. Photons in the high energy region show less than 20% linear polarization at the 90% confidence level., Comment: 8 pages, 7 figures, REVTeX4 two column, Version for publication

Published
2004

5. Linear to Circular Polarisation Conversion using Birefringent Properties of Aligned Crystals for Multi-GeV Photons

Author

NA59 Collaboration, Apyan, A., Avakian, R. O., Badelek, B., Ballestrero, S., Biino, C., Birol, I., Cenci, P., Connell, S. H., Eichblatt, S., Fonseca, T., Freund, A., Gorini, B., Groess, R., Ispirian, K., Ketel, T. J., Kononets, Yu. V., Lopez, A., Mangiarotti, A., van Rens, B., Sellschop, J. P. F., Shieh, M., Sona, P., Strakhovenko, V., Uggerhoj, E., Uggerhoj, U. I., Unel, G., Velasco, M., Vilakazi, Z. Z., and Wessely, O.

Subjects
High Energy Physics - Experiment
Abstract

We present the first experimental results on the use of a thick aligned Si crystal acting as a quarter wave plate to induce a degree of circular polarisation in a high energy linearly polarised photon beam. The linearly polarised photon beam is produced from coherent bremsstrahlung radiation by 178 GeV unpolarised electrons incident on an aligned Si crystal, acting as a radiator. The linear polarisation of the photon beam is characterised by measuring the asymmetry in electron-positron pair production in a Ge crystal, for different crystal orientations. The Ge crystal therefore acts as an analyser. The birefringence phenomenon, which converts the linear polarisation to circular polarisation, is observed by letting the linearly polarised photons beam pass through a thick Si quarter wave plate crystal, and then measuring the asymmetry in electron-positron pair production again for a selection of relative angles between the crystallographic planes of the radiator, analyser and quarter wave plate. The systematics of the difference between the measured asymmetries with and without the quarter wave plate are predicted by theory to reveal an evolution in the Stokes parameters from which the appearance of a circularly polarised component in the photon beam can be demonstrated. The measured magnitude of the circularly polarised component was consistent with the theoretical predictions, and therefore is in indication of the existence of the birefringence effect., Comment: 12 pages, 12 figures, 1 table, REVTeX4 two column, Version for publication

Published
2003

6. Coherent Pair Production by Photons in the 20-170 GeV Energy Range Incident on Crystals and Birefringence

Author

NA59 Collaboration, Apyan, A., Avakian, R. O., Badelek, B., Ballestrero, S., Biino, C., Birol, I., Cenci, P., Connell, S. H., Eichblatt, S., Fonseca, T., Freund, A., Gorini, B., Groess, R., Ispirian, K., Ketel, T. J., Kononets, Yu. V., Lopez, A., Mangiarotti, A., van Rens, B., Sellschop, J. P. F., Shieh, M., Sona, P., Strakhovenko, V., Uggerhoj, E., Uggerhoj, U. I., Unel, G., Velasco, M., Vilakazi, Z. Z., and Wessely, O.

Subjects
High Energy Physics - Experiment
Abstract

The cross section for coherent pair production by linearly polarised photons in the 20-170 GeV energy range was measured for photon aligned incidence on ultra-high quality diamond and germanium crystals. The theoretical description of coherent bremsstrahlung and coherent pair production phenomena is an area of active theoretical debate and development. However, under our experimental conditions, the theory predicted the combined cross section and polarisation experimental observables very well indeed. In macroscopic terms, our experiment measured a birefringence effect in pair production in a crystal. This study of this effect also constituted a measurement of the energy dependent linear polarisation of photons produced by coherent bremsstrahlung in aligned crystals. New technologies for manipulating high energy photon beams can be realised based on an improved understanding of QED phenomena at these energies. In particular, this experiment demonstrates an efficient new polarimetry technique. The pair production measurements were done using two independent methods simultaneously. The more complex method using a magnet spectrometer showed that the simpler method using a multiplicity detector was also viable., Comment: 10 pages, 13 figures, 1 table, REVTeX4 two column, Version for publication

Published
2003

7. Coherent bremsstrahlung, coherent pair production, birefringence, and polarimetry in the 20-170 GeV energy range using aligned crystals

Author

Apyan, A., Avakian, R., Badelek, B., Ballestrero, S., Biino, C., Birol, I., Cenci, P., Connell, S., Eichblatt, S., Fonseca, T., Freund, A., Gorini, B., Groess, R., Ispirian, K., Ketel, T., Kononets, Yu., Lopez, A., Mangiarotti, A., van Rens, B., Sellschop, J., Shieh, M., Sona, P., Strakhovenko, V., Uggerhøj, E., Uggerhøj, U., Unel, G., Velasco, M., Vilakazi, Z., Wessely, O., and NA59 Collaboration, .

Subjects
hard photon-emission, multi-gev electrons, single-crystals, linear-polarization, na59 experiment, synthetic diamonds, radiation emission, oriented graphite, fields, positrons
Abstract

The processes of coherent bremsstrahlung (CB) and coherent pair production (CPP) based on aligned crystal targets have been studied in the energy range 20-170 GeV. The experimental arrangement allowed for measurements of single photon properties of these phenomena including their polarization dependences. This is significant as the theoretical description of CB and CPP is an area of active debate and development. With the approach used in this paper, both the measured cross sections and polarization observables are predicted very well. This indicates a proper understanding of CB and CPP up to energies of 170 GeV. Birefringence in CPP on aligned crystals is applied to determine the polarization parameters in our measurements. New technologies for high-energy photon beam optics including phase plates and polarimeters for linear and circular polarization are demonstrated in this experiment. Coherent bremsstrahlung for the strings-on-strings (SOS) orientation yields a larger enhancement for hard photons than CB for the channeling orientations of the crystal. Our measurements and our calculations indicate low photon polarizations for the high-energy SOS photons.

Published
2008

8. Additional file 1 of HostSeq: a Canadian whole genome sequencing and clinical data resource

Author

Yoo, S, Garg, E, Elliott, LT, Hung, RJ, Halevy, AR, Brooks, JD, Bull, SB, Gagnon, F, Greenwood, CMT, Lawless, JF, Paterson, AD, Sun, L, Zawati, MH, Lerner-Ellis, J, Abraham, RJS, Birol, I, Bourque, G, Garant, J-M, Gosselin, C, Li, J, Whitney, J, Thiruvahindrapuram, B, Herbrick, J-A, Lorenti, M, Reuter, MS, Adeoye, OO, Liu, S, Allen, U, Bernier, FP, Biggs, CM, Cheung, AM, Cowan, J, Herridge, M, Maslove, DM, Modi, BP, Mooser, V, Morris, SK, Ostrowski, M, Parekh, RS, Pfeffer, G, Suchowersky, O, Taher, J, Upton, J, Warren, RL, Yeung, RSM, Aziz, N, Turvey, SE, Knoppers, BM, Lathrop, M, Jones, SJM, Scherer, SW, and Strug, LJ

Abstract

Additional file 1: Table S1. HostSeq Core Consent Elements. In order to deposit datasets in HostSeq COVID-19 controlled-access Databank, all the elements in this table must be obtained in the research consent. Table S2. HostSeq Case Report Form. Table S3. Software used for processing WGS data. Table S4. List of HostSeq participating studies as described in respective protocols. Table S5. Distribution of sex and age across HostSeq studies (n = 9,427). SD: Standard deviation; IQR: interquartile range. Figure S1. Quality of HostSeq genomes. (A) Missing rate < 5%, (B) Contamination rate < 3%, (C) Mean coverage >10. Figure S2. Predicted population admixture and ancestry classification in HostSeq genomes. Each bar represents a genome. Proportion of African, East Asian and European ancestries is determined, and genomes classified into 8 ancestry groups using GRAF-pop. They are further categorized into 5 superpopulations: AFR - African and African-American, AMR - Latin American Asian and Latin American African, EAS - Asian-Pacific Islander and East Asian, SAS - South Asian, and EUR - European. 3% of genomes remain uncategorized. Figure S3. Genetic distances score of HostSeq genomes. The four genetic distances (GD1-4) scores from GRAF-pop represent the distance of each genome from several reference populations and are used to predict ancestry. Barycentric coordinates of GD1 and GD2 are used to predict admixture proportion of African, East Asian and European ancestries.

Published
2023
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9. HostSeq : A Canadian Whole Genome Sequencing and Clinical Data Resource

Author

Yoo, S, primary, Garg, E, additional, Elliott, LT, additional, Hung, RJ, additional, Halevy, AR, additional, Brooks, JD, additional, Bull, SB, additional, Gagnon, F, additional, Greenwood, CMT, additional, Lawless, JF, additional, Paterson, AD, additional, Sun, L, additional, Zawati, MH, additional, Lerner-Ellis, J, additional, Abraham, RJS, additional, Birol, I, additional, Bourque, G, additional, Garant, J-M, additional, Gosselin, C, additional, Li, J, additional, Whitney, J, additional, Thiruvahindrapuram, B, additional, Herbrick, J-A, additional, Lorenti, M, additional, Reuter, MS, additional, Adeoye, NO, additional, Liu, S, additional, Allen, U, additional, Bernier, FP, additional, Biggs, CM, additional, Cheung, AM, additional, Cowan, J, additional, Herridge, M, additional, Maslove, DM, additional, Modi, BP, additional, Mooser, V, additional, Morris, SK, additional, Ostrowski, M, additional, Parekh, RS, additional, Pfeffer, G, additional, Suchowersky, O, additional, Taher, J, additional, Upton, J, additional, Warren, RL, additional, Yeung, RSM, additional, Aziz, N, additional, Turvey, SE, additional, Knoppers, BM, additional, Lathrop, M, additional, Jones, SJM, additional, Scherer, SW, additional, and Strug, LJ, additional

Published
2022
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13. Results on the coherent interaction of high energy electrons and photons in oriented single crystals

Author

Apyan, A., Avakian, R.O., Badelek, B., Ballestrero, S., Biino, C., Birol, I., Cenci, P., Connell, S.H., Eichblatt, S., Fonseca, T., Freund, A., Gorini, B., Groess, R., Ispirian, K., Ketel, T.J., Kononets, Yu.V., Lopez, A., Mangiarotti, A., van Rens, B., Sellschop, J.P.F., Shieh, M., Sona, P., Strakhovenko, V., Uggerhøj, E., Uggerhøj, U.I., Unel, G., Velasco, M., Vilakazi, Z.Z., and Wessely, O.

Published
2005
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14. Genome-Enhanced Detection and Identification (GEDI) of plant pathogens

Author

Feau, N. (Nicolas), Beauseigle, S. (Stéphanie), Bergeron, M.-J. (Marie-Josée), Bilodeau, G. J. (Guillaume J.), Birol, I. (Inanc), Cervantes-Arango, S. (Sandra), Dhillon, B. (Braham), Dale, A. L. (Angela L.), Herath, P. (Padmini), Jones, S. J. (Steven J.M.), Lamarche, J. (Josyanne), Ojeda, D. I. (Dario I.), Sakalidis, M. L. (Monique L.), Taylor, G. (Greg), Tsui, C. K. (Clement K.M.), Uzunovic, A. (Adnan), Yueh, H. (Hesther), Tanguay, P. (Philippe), Hamelin, R. C. (Richard C.), Feau, N. (Nicolas), Beauseigle, S. (Stéphanie), Bergeron, M.-J. (Marie-Josée), Bilodeau, G. J. (Guillaume J.), Birol, I. (Inanc), Cervantes-Arango, S. (Sandra), Dhillon, B. (Braham), Dale, A. L. (Angela L.), Herath, P. (Padmini), Jones, S. J. (Steven J.M.), Lamarche, J. (Josyanne), Ojeda, D. I. (Dario I.), Sakalidis, M. L. (Monique L.), Taylor, G. (Greg), Tsui, C. K. (Clement K.M.), Uzunovic, A. (Adnan), Yueh, H. (Hesther), Tanguay, P. (Philippe), and Hamelin, R. C. (Richard C.)

Abstract

Plant diseases caused by fungi and Oomycetes represent worldwide threats to crops and forest ecosystems. Effective prevention and appropriate management of emerging diseases rely on rapid detection and identification of the causal pathogens. The increase in genomic resources makes it possible to generate novel genome-enhanced DNA detection assays that can exploit whole genomes to discover candidate genes for pathogen detection. A pipeline was developed to identify genome regions that discriminate taxa or groups of taxa and can be converted into PCR assays. The modular pipeline is comprised of four components: (1) selection and genome sequencing of phylogenetically related taxa, (2) identification of clusters of orthologous genes, (3) elimination of false positives by filtering, and (4) assay design. This pipeline was applied to some of the most important plant pathogens across three broad taxonomic groups: Phytophthoras (Stramenopiles, Oomycota), Dothideomycetes (Fungi, Ascomycota) and Pucciniales (Fungi, Basidiomycota). Comparison of 73 fungal and Oomycete genomes led the discovery of 5,939 gene clusters that were unique to the targeted taxa and an additional 535 that were common at higher taxonomic levels. Approximately 28% of the 299 tested were converted into qPCR assays that met our set of specificity criteria. This work demonstrates that a genome-wide approach can efficiently identify multiple taxon-specific genome regions that can be converted into highly specific PCR assays. The possibility to easily obtain multiple alternative regions to design highly specific qPCR assays should be of great help in tackling challenging cases for which higher taxon-resolution is needed.

Published
2018

15. Combining multiple tools outperforms individual methods in gene set enrichment analyses

Author

Birol, I, Alhamdoosh, M, Ng, M, Wilson, NJ, Sheridan, JM, Huynh, H, Wilson, MJ, Ritchie, ME, Birol, I, Alhamdoosh, M, Ng, M, Wilson, NJ, Sheridan, JM, Huynh, H, Wilson, MJ, and Ritchie, ME

Abstract

MOTIVATION: Gene set enrichment (GSE) analysis allows researchers to efficiently extract biological insight from long lists of differentially expressed genes by interrogating them at a systems level. In recent years, there has been a proliferation of GSE analysis methods and hence it has become increasingly difficult for researchers to select an optimal GSE tool based on their particular dataset. Moreover, the majority of GSE analysis methods do not allow researchers to simultaneously compare gene set level results between multiple experimental conditions. RESULTS: The ensemble of genes set enrichment analyses (EGSEA) is a method developed for RNA-sequencing data that combines results from twelve algorithms and calculates collective gene set scores to improve the biological relevance of the highest ranked gene sets. EGSEA's gene set database contains around 25 000 gene sets from sixteen collections. It has multiple visualization capabilities that allow researchers to view gene sets at various levels of granularity. EGSEA has been tested on simulated data and on a number of human and mouse datasets and, based on biologists' feedback, consistently outperforms the individual tools that have been combined. Our evaluation demonstrates the superiority of the ensemble approach for GSE analysis, and its utility to effectively and efficiently extrapolate biological functions and potential involvement in disease processes from lists of differentially regulated genes. AVAILABILITY AND IMPLEMENTATION: EGSEA is available as an R package at http://www.bioconductor.org/packages/EGSEA/ . The gene sets collections are available in the R package EGSEAdata from http://www.bioconductor.org/packages/EGSEAdata/ . CONTACTS: monther.alhamdoosh@csl.com.au mritchie@wehi.edu.au. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Published
2017

16. A road map for emerging low-exergy HVAC systems

Author

Kilkis, Birol I.

Subjects
HVAC equipment -- Energy use, Engineering and manufacturing industries
Abstract

Byline: Birol I. Kilkis An exergy-conscious life cycle costing algorithm was developed. This algorithm establishes a reference tool to compare conventional air conditioning systems with alternative HVAC systems, which can directly operate with low-exergy alternative energy resources. The cost of exergy waste in conventional heating, ventilating, and air-conditioning systems (HVAC) is included in terms of the difference between energy supply and HVAC operation temperatures. In order to establish a robust road map for a solution, this paper introduces a composite radiant wall panel system, which optimally integrates HVAC functions at moderate temperatures without any modification or add-on equipment.

Published
2005

17. A simplistic thermal model for solving the exergy flow of the universe with continuous functions of cosmological parameters

Author

Kilkis, Birol I.

Subjects
Universe -- Models, Extraterrestrial radiation -- Analysis, Engineering and manufacturing industries
Abstract

Byline: Birol I. Kilkis A new thermo-mathematical model of the universe presented in this paper solves the large-scale cosmological parameters as continuous functions of the cosmic age and establishes a composite correlation among them. The universe is assumed to be thermally radiating to an infinitely large thermal bath at 0 K. This model permits and enables to calculate the exergy flow from the universe, which may explain the currently accelerating rate of expansion of the universe and the preceding decelerating phase. Calculations predicted the present time Hubble constant to be 65.7km s-1 Mpc-1 and the cosmic age to be 14.9 Gyr. The same calculations showed that the expansion of the universe has been accelerating since the cosmic age of 4.4 Gyr due to a positive, time dependent cosmological number whose present magnitude is 8.8x10-36 s-2, and it is decreasing. This Model predicts that there is an exergy flow from the universe, which diminishes in the infinite size of the thermal bath.

Published
2004

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

Author

Lawrence, MS, Sougnez, C, Lichtenstein, L, Cibulskis, K, Lander, E, Gabriel, SB, Getz, G, Ally, A, Balasundaram, M, Birol, I, Bowlby, R, Brooks, D, Butterfield, YSN, Carlsen, R, Cheng, D, Chu, A, Dhalla, N, Guin, R, Holt, RA, Jones, SJM, Lee, D, Li, HI, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Robertson, AG, Schein, JE, Sipahimalani, P, Tam, A, Thiessen, N, Wong, T, Protopopov, A, Santoso, N, Lee, S, Parfenov, M, Zhang, J, Mahadeshwar, HS, Tang, J, Ren, X, Seth, S, Haseley, P, Zeng, D, Yang, L, Xu, AW, Song, X, Pantazi, A, Bristow, CA, Hadjipanayis, A, Seidman, J, Chin, L, Park, PJ, Kucherlapati, R, Akbani, R, Casasent, T, Liu, W, Lu, Y, Mills, G, Motter, T, Weinstein, J, Diao, L, Wang, J, Hong Fan, Y, Liu, J, Wang, K, Auman, JT, Balu, S, Bodenheimer, T, Buda, E, Hayes, DN, Hoadley, KA, Hoyle, AP, Jefferys, SR, Jones, CD, Kimes, PK, Liu, Y, Marron, JS, Meng, S, Mieczkowski, PA, Mose, LE, Parker, JS, Perou, CM, Prins, JF, Roach, J, Shi, Y, Simons, JV, Singh, D, Soloway, MG, Tan, D, Veluvolu, U, Walter, V, Waring, S, Wilkerson, MD, and Wu, J

Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.

Published
2015

21. Integrated genomic characterization of endometrial carcinoma

Author

Getz, G, Gabriel, SB, Cibulskis, K, Lander, E, Sivachenko, A, Sougnez, C, Lawrence, M, Kandoth, C, Dooling, D, Fulton, R, Fulton, L, Kalicki-Veizer, J, McLellan, MD, O'Laughlin, M, Schmidt, H, Wilson, RK, Ye, K, Li, D, Ally, A, Balasundaram, M, Birol, I, Butterfield, YSN, Carlsen, R, Carter, C, Chu, A, Chuah, E, Chun, HJE, Dhalla, N, Guin, R, Hirst, C, Holt, RA, Jones, SJM, Lee, D, Li, HI, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Plettner, P, Schein, JE, Sipahimalani, P, Tam, A, Varhol, RJ, Gordon Robertson, A, Cherniack, AD, Pashtan, I, Saksena, G, Onofrio, RC, Schumacher, SE, Tabak, B, Carter, SL, Hernandez, B, Gentry, J, Salvesen, HB, Ardlie, K, Winckler, W, Beroukhim, R, Meyerson, M, Hadjipanayis, A, Lee, S, Mahadeshwar, HS, Park, P, Protopopov, A, Ren, X, Seth, S, Song, X, Tang, J, Xi, R, Yang, L, Dong, Z, Kucherlapati, R, Chin, L, Zhang, J, Todd Auman, J, Balu, S, Bodenheimer, T, Buda, E, Neil Hayes, D, Hoyle, AP, Jefferys, SR, Jones, CD, Meng, S, Mieczkowski, PA, Mose, LE, Parker, JS, and Perou, CM

Subjects
endocrine system diseases
Abstract

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array-and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours. © 2013 Macmillan Publishers Limited. All rights reserved.

Published
2013

22. Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Author

Northcott, PA, Shih, DJH, Peacock, J, Garzia, L, Sorana Morrissy, A, Zichner, T, Stútz, AM, Korshunov, A, Reimand, J, Schumacher, SE, Beroukhim, R, Ellison, DW, Marshall, CR, Lionel, AC, MacK, S, Dubuc, A, Yao, Y, Ramaswamy, V, Luu, B, Rolider, A, Cavalli, FMG, Wang, X, Remke, M, Wu, X, Chiu, RYB, Chu, A, Chuah, E, Corbett, RD, Hoad, GR, Jackman, SD, Li, Y, Lo, A, Mungall, KL, Ming Nip, K, Qian, JQ, Raymond, AGJ, Thiessen, N, Varhol, RJ, Birol, I, Moore, RA, Mungall, AJ, Holt, R, Kawauchi, D, Roussel, MF, Kool, M, Jones, DTW, Witt, H, Fernandez-L, A, Kenney, AM, Wechsler-Reya, RJ, Dirks, P, Aviv, T, Grajkowska, WA, Perek-Polnik, M, Haberler, CC, Delattre, O, Reynaud, SS, Doz, FF, Pernet-Fattet, SS, Cho, BK, Kim, SK, Wang, KC, Scheurlen, W, Eberhart, CG, Fèvre-Montange, M, Jouvet, A, Pollack, IF, Fan, X, Muraszko, KM, Yancey Gillespie, G, Di Rocco, C, Massimi, L, Michiels, EMC, Kloosterhof, NK, French, PJ, Kros, JM, Olson, JM, Ellenbogen, RG, Zitterbart, K, Kren, L, Thompson, RC, and Cooper, MK

Subjects
Oncogene Proteins, Fusion, DNA Copy Number Variations, Genome, Human, General Science & Technology, NF-kappa B, Genes, myc, Proteins, Nerve Tissue Proteins, Genomics, Translocation, Genetic, Transforming Growth Factor beta, Gene Duplication, Genomic Structural Variation, MD Multidisciplinary, Humans, Hedgehog Proteins, RNA, Long Noncoding, Cerebellar Neoplasms, Carrier Proteins, Child, Medulloblastoma, Signal Transduction
Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy. © 2012 Macmillan Publishers Limited. All rights reserved.

Published
2012

23. Comprehensive molecular characterization of gastric adenocarcinoma

Author

Bass, AJ, Thorsson, V, Shmulevich, I, Reynolds, SM, Miller, M, Bernard, B, Hinoue, T, Laird, PW, Curtis, C, Shen, H, Weisenberger, DJ, Schultz, N, Shen, R, Weinhold, N, Keiser, DP, Bowlby, R, Sipahimalani, P, Cherniack, AD, Getz, G, Liu, Y, Noble, MS, Pedamallu, C, Sougnez, C, Taylor-Weiner, A, Akbani, R, Lee, J-S, Liu, W, Mills, GB, Yang, D, Zhang, W, Pantazi, A, Parfenov, M, Gulley, M, Piazuelo, MB, Schneider, BG, Kim, J, Boussioutas, A, Sheth, M, Demchok, JA, Rabkin, CS, Willis, JE, Ng, S, Garman, K, Beer, DG, Pennathur, A, Raphael, BJ, Wu, H-T, Odze, R, Kim, HK, Bowen, J, Leraas, KM, Lichtenberg, TM, Weaver, L, McLellan, M, Wiznerowicz, M, Sakai, R, Lawrence, MS, Cibulskis, K, Lichtenstein, L, Fisher, S, Gabriel, SB, Lander, ES, Ding, L, Niu, B, Ally, A, Balasundaram, M, Birol, I, Brooks, D, Butterfield, YSN, Carlsen, R, Chu, A, Chu, J, Chuah, E, Chun, H-JE, Clarke, A, Dhalla, N, Guin, R, Holt, RA, Jones, SJM, Kasaian, K, Lee, D, Li, HA, Lim, E, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Mungall, KL, Nip, KM, Robertson, AG, Schein, JE, Tam, A, Thiessen, N, Beroukhim, R, Carter, SL, Cho, J, DiCara, D, Frazer, S, Gehlenborg, N, Heiman, DI, Jung, J, Lin, P, Meyerson, M, Ojesina, AI, Pedamallu, CS, Saksena, G, Schumacher, SE, Stojanov, P, Tabak, B, Voet, D, Rosenberg, M, Zack, TI, Zhang, H, Zou, L, Protopopov, A, Santoso, N, Lee, S, Zhang, J, Mahadeshwar, HS, Tang, J, Ren, X, Seth, S, Yang, L, Xu, AW, Song, X, Xi, R, Bristow, CA, Hadjipanayis, A, Seidman, J, Chin, L, Park, PJ, Kucherlapati, R, Ling, S, Rao, A, Weinstein, JN, Kim, S-B, Lu, Y, Mills, G, Bootwalla, MS, Lai, PH, Triche, T, Van Den Berg, DJ, Baylin, SB, Herman, JG, Murray, BA, Askoy, BA, Ciriello, G, Dresdner, G, Gao, J, Gross, B, Jacobsen, A, Lee, W, Ramirez, R, Sander, C, Senbabaoglu, Y, Sinha, R, Sumer, SO, Sun, Y, Iype, L, Kramer, RW, Kreisberg, R, Rovira, H, Tasman, N, Haussler, D, Stuart, JM, Verhaak, RGW, Leiserson, MDM, Taylor, BS, Black, AD, Carney, JA, Gastier-Foster, JM, Helsel, C, McAllister, C, Ramirez, NC, Tabler, TR, Wise, L, Zmuda, E, Penny, R, Crain, D, Gardner, J, Lau, K, Curely, E, Mallery, D, Morris, S, Paulauskis, J, Shelton, T, Shelton, C, Sherman, M, Benz, C, Lee, J-H, Fedosenko, K, Manikhas, G, Voronina, O, Belyaev, D, Dolzhansky, O, Rathmell, WK, Brzezinski, J, Ibbs, M, Korski, K, Kycler, W, Lazniak, R, Leporowska, E, Mackiewicz, A, Murawa, D, Murawa, P, Spychala, A, Suchorska, WM, Tatka, H, Teresiak, M, Abdel-Misih, R, Bennett, J, Brown, J, Iacocca, M, Rabeno, B, Kwon, S-Y, Kemkes, A, Curley, E, Alexopoulou, I, Engel, J, Bartlett, J, Albert, M, Park, D-Y, Dhir, R, Luketich, J, Landreneau, R, Janjigian, YY, Kelsen, DP, Cho, E, Ladanyi, M, Tang, L, McCall, SJ, Park, YS, Cheong, J-H, Ajani, J, Camargo, MC, Alonso, S, Ayala, B, Jensen, MA, Pihl, T, Raman, R, Walton, J, Wan, Y, Eley, G, Shaw, KRM, Tarnuzzer, R, Wang, Z, Zenklusen, JC, Davidsen, T, Hutter, CM, Sofia, HJ, Burton, R, Chudamani, S, Liu, J, Bass, AJ, Thorsson, V, Shmulevich, I, Reynolds, SM, Miller, M, Bernard, B, Hinoue, T, Laird, PW, Curtis, C, Shen, H, Weisenberger, DJ, Schultz, N, Shen, R, Weinhold, N, Keiser, DP, Bowlby, R, Sipahimalani, P, Cherniack, AD, Getz, G, Liu, Y, Noble, MS, Pedamallu, C, Sougnez, C, Taylor-Weiner, A, Akbani, R, Lee, J-S, Liu, W, Mills, GB, Yang, D, Zhang, W, Pantazi, A, Parfenov, M, Gulley, M, Piazuelo, MB, Schneider, BG, Kim, J, Boussioutas, A, Sheth, M, Demchok, JA, Rabkin, CS, Willis, JE, Ng, S, Garman, K, Beer, DG, Pennathur, A, Raphael, BJ, Wu, H-T, Odze, R, Kim, HK, Bowen, J, Leraas, KM, Lichtenberg, TM, Weaver, L, McLellan, M, Wiznerowicz, M, Sakai, R, Lawrence, MS, Cibulskis, K, Lichtenstein, L, Fisher, S, Gabriel, SB, Lander, ES, Ding, L, Niu, B, Ally, A, Balasundaram, M, Birol, I, Brooks, D, Butterfield, YSN, Carlsen, R, Chu, A, Chu, J, Chuah, E, Chun, H-JE, Clarke, A, Dhalla, N, Guin, R, Holt, RA, Jones, SJM, Kasaian, K, Lee, D, Li, HA, Lim, E, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Mungall, KL, Nip, KM, Robertson, AG, Schein, JE, Tam, A, Thiessen, N, Beroukhim, R, Carter, SL, Cho, J, DiCara, D, Frazer, S, Gehlenborg, N, Heiman, DI, Jung, J, Lin, P, Meyerson, M, Ojesina, AI, Pedamallu, CS, Saksena, G, Schumacher, SE, Stojanov, P, Tabak, B, Voet, D, Rosenberg, M, Zack, TI, Zhang, H, Zou, L, Protopopov, A, Santoso, N, Lee, S, Zhang, J, Mahadeshwar, HS, Tang, J, Ren, X, Seth, S, Yang, L, Xu, AW, Song, X, Xi, R, Bristow, CA, Hadjipanayis, A, Seidman, J, Chin, L, Park, PJ, Kucherlapati, R, Ling, S, Rao, A, Weinstein, JN, Kim, S-B, Lu, Y, Mills, G, Bootwalla, MS, Lai, PH, Triche, T, Van Den Berg, DJ, Baylin, SB, Herman, JG, Murray, BA, Askoy, BA, Ciriello, G, Dresdner, G, Gao, J, Gross, B, Jacobsen, A, Lee, W, Ramirez, R, Sander, C, Senbabaoglu, Y, Sinha, R, Sumer, SO, Sun, Y, Iype, L, Kramer, RW, Kreisberg, R, Rovira, H, Tasman, N, Haussler, D, Stuart, JM, Verhaak, RGW, Leiserson, MDM, Taylor, BS, Black, AD, Carney, JA, Gastier-Foster, JM, Helsel, C, McAllister, C, Ramirez, NC, Tabler, TR, Wise, L, Zmuda, E, Penny, R, Crain, D, Gardner, J, Lau, K, Curely, E, Mallery, D, Morris, S, Paulauskis, J, Shelton, T, Shelton, C, Sherman, M, Benz, C, Lee, J-H, Fedosenko, K, Manikhas, G, Voronina, O, Belyaev, D, Dolzhansky, O, Rathmell, WK, Brzezinski, J, Ibbs, M, Korski, K, Kycler, W, Lazniak, R, Leporowska, E, Mackiewicz, A, Murawa, D, Murawa, P, Spychala, A, Suchorska, WM, Tatka, H, Teresiak, M, Abdel-Misih, R, Bennett, J, Brown, J, Iacocca, M, Rabeno, B, Kwon, S-Y, Kemkes, A, Curley, E, Alexopoulou, I, Engel, J, Bartlett, J, Albert, M, Park, D-Y, Dhir, R, Luketich, J, Landreneau, R, Janjigian, YY, Kelsen, DP, Cho, E, Ladanyi, M, Tang, L, McCall, SJ, Park, YS, Cheong, J-H, Ajani, J, Camargo, MC, Alonso, S, Ayala, B, Jensen, MA, Pihl, T, Raman, R, Walton, J, Wan, Y, Eley, G, Shaw, KRM, Tarnuzzer, R, Wang, Z, Zenklusen, JC, Davidsen, T, Hutter, CM, Sofia, HJ, Burton, R, Chudamani, S, and Liu, J

Abstract

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

Published
2014

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

Author

Hoadley, K., Yau, C., Wolf, D., Cherniack, A., Tamborero, D., Ng, S., Leiserson, M., Niu, B., McLellan, M., Uzunangelov, V., Zhang, J., Kandoth, C., Akbani, R., Shen, H., Omberg, L., Chu, A., Margolin, A., van't Veer, L., Lopez-Bigas, N., Laird, P., Raphael, B., Ding, L., Robertson, A., Byers, L., Mills, G., Weinstein, J., Van Waes, C., Chen, Z., Collisson, E., Benz, C., Perou, C., Stuart, J., Abbott, R., Abbott, S., Aksoy, B., Aldape, K., Ally, A., Amin, S., Anastassiou, D., Auman, J., Baggerly, K., Balasundaram, M., Balu, S., Baylin, S., Benz, S., Berman, B., Bernard, B., Bhatt, A., Birol, I., Black, A., Bodenheimer, T., Bootwalla, M., Bowen, J., Bressler, R., Bristow, C., Brooks, A., Broom, B., Buda, E., Burton, R., Butterfield, Y., Carlin, D., Carter, S., Casasent, T., Chang, K., Chanock, S., Chin, L., Cho, D., Cho, J., Chuah, E., Chun, H., Cibulskis, K., Ciriello, G., Cleland, J., Cline, M., Craft, B., Creighton, C., Danilova, L., Davidsen, T., Davis, C., Dees, N., Delehaunty, K., Demchok, J., Dhalla, N., DiCara, D., Dinh, H., Dobson, J., Dodda, D., Doddapaneni, H., Donehower, L., Dooling, D., Dresdner, G., Drummond, J., Eakin, A., Edgerton, M., Eldred, J., Eley, G., Ellrott, K., Fan, C., Fei, S., Felau, I., Frazer, S., Freeman, S., Frick, J., Fronick, C., Fulton, L., Fulton, R., Gabriel, S., Gao, J., Gastier-Foster, J., Gehlenborg, N., George, M., Getz, G., Gibbs, R., Goldman, M., Gonzalez-Perez, A., Gross, B., Guin, R., Gunaratne, P., Hadjipanayis, A., Hamilton, M., Hamilton, S., Han, L., Han, Y., Harper, H., Haseley, P., Haussler, D., Hayes, D., Heiman, D., Helman, E., Helsel, C., Herbrich, S., Herman, J., Hinoue, T., Hirst, C., Hirst, M., Holt, R., Hoyle, A., Iype, L., Jacobsen, A., Jeffreys, S., Jensen, M., Jones, C., Jones, S., Ju, Z., Jung, J., Kahles, A., Kahn, A., Kalicki-Veizer, J., Kalra, D., Kanchi, K., Kane, D., Kim, H., Kim, J., Knijnenburg, T., Koboldt, D., Kovar, C., Kramer, R., Kreisberg, R., Kucherlapati, R., Ladanyi, M., Lander, E., Larson, D., Lawrence, M., Lee, D., Lee, E., Lee, S., Lee, W., Lehmann, K., Leinonen, K., Leraas, K., Lerner, S., Levine, D., Lewis, L., Ley, T., Li, H., Li, J., Li, W., Liang, H., Lichtenberg, T., Lin, J., Lin, L., Lin, P., Liu, W., Liu, Y., Lorenzi, P., Lu, C., Lu, Y., Luquette, L., Ma, S., Magrini, V., Mahadeshwar, H., Mardis, E., Marra, M., Mayo, M., McAllister, C., McGuire, S., McMichael, J., Melott, J., Meng, S., Meyerson, M., Mieczkowski, P., Miller, C., Miller, M., Moore, R., Morgan, M., Morton, D., Mose, L., Mungall, A., Muzny, D., Nguyen, L., Noble, M., Noushmehr, H., O'Laughlin, M., Ojesina, A., Yang, T., Ozenberger, B., Pantazi, A., Parfenov, M., Park, P., Parker, J., Paull, E., Pedamallu, C., Pihl, T., Pohl, C., Pot, D., Protopopov, A., Przytycka, T., Radenbaugh, A., Ramirez, N., Ramirez, R., Ratsch, G., Reid, J., Ren, X., Reva, B., Reynolds, S., Rhie, S., Roach, J., Rovira, H., Ryan, M., Saksena, G., Salama, S., Sander, C., Santoso, N., Schein, J., Schmidt, H., Schultz, N., Schumacher, S., Seidman, J., Senbabaoglu, Y., Seth, S., Sharpe, S., Shen, R., Sheth, M., Shi, Y., Shmulevich, I., Silva, G., Simons, J., Sinha, R., Sipahimalani, P., Smith, S., Sofia, H., Sokolov, A., Soloway, M., Song, X., Sougnez, C., Spellman, P., Staudt, L., Stewart, C., Stojanov, P., Su, X., Sumer, S., Sun, Y., Swatloski, T., Tabak, B., Tam, A., Tan, D., Tang, J., Tarnuzzer, R., Taylor, B., Thiessen, N., Thorsson, V., Triche, T., Van Den Berg, D., Vandin, F., Varhol, Richard, Vaske, C., Veluvolu, U., Verhaak, R., Voet, D., Walker, J., Wallis, J., Waltman, P., Wan, Y., Wang, M., Wang, W., Wang, Z., Waring, S., Weinhold, N., Weisenberger, D., Wendl, M., Wheeler, D., Wilkerson, M., Wilson, R., Wise, L., Wong, A., Wu, C., Wu, H., Wu, J., Wylie, T., Xi, L., Xi, R., Xia, Z., Xu, A., Yang, D., Yang, L., Yang, Y., Yao, J., Yao, R., Ye, K., Yoshihara, K., Yuan, Y., Yung, A., Zack, T., Zeng, D., Zenklusen, J., Zhang, H., Zhang, N., Zhang, Q., Zhang, W., Zhao, W., Zheng, S., Zhu, J., Zmuda, E., Zou, L., Hoadley, K., Yau, C., Wolf, D., Cherniack, A., Tamborero, D., Ng, S., Leiserson, M., Niu, B., McLellan, M., Uzunangelov, V., Zhang, J., Kandoth, C., Akbani, R., Shen, H., Omberg, L., Chu, A., Margolin, A., van't Veer, L., Lopez-Bigas, N., Laird, P., Raphael, B., Ding, L., Robertson, A., Byers, L., Mills, G., Weinstein, J., Van Waes, C., Chen, Z., Collisson, E., Benz, C., Perou, C., Stuart, J., Abbott, R., Abbott, S., Aksoy, B., Aldape, K., Ally, A., Amin, S., Anastassiou, D., Auman, J., Baggerly, K., Balasundaram, M., Balu, S., Baylin, S., Benz, S., Berman, B., Bernard, B., Bhatt, A., Birol, I., Black, A., Bodenheimer, T., Bootwalla, M., Bowen, J., Bressler, R., Bristow, C., Brooks, A., Broom, B., Buda, E., Burton, R., Butterfield, Y., Carlin, D., Carter, S., Casasent, T., Chang, K., Chanock, S., Chin, L., Cho, D., Cho, J., Chuah, E., Chun, H., Cibulskis, K., Ciriello, G., Cleland, J., Cline, M., Craft, B., Creighton, C., Danilova, L., Davidsen, T., Davis, C., Dees, N., Delehaunty, K., Demchok, J., Dhalla, N., DiCara, D., Dinh, H., Dobson, J., Dodda, D., Doddapaneni, H., Donehower, L., Dooling, D., Dresdner, G., Drummond, J., Eakin, A., Edgerton, M., Eldred, J., Eley, G., Ellrott, K., Fan, C., Fei, S., Felau, I., Frazer, S., Freeman, S., Frick, J., Fronick, C., Fulton, L., Fulton, R., Gabriel, S., Gao, J., Gastier-Foster, J., Gehlenborg, N., George, M., Getz, G., Gibbs, R., Goldman, M., Gonzalez-Perez, A., Gross, B., Guin, R., Gunaratne, P., Hadjipanayis, A., Hamilton, M., Hamilton, S., Han, L., Han, Y., Harper, H., Haseley, P., Haussler, D., Hayes, D., Heiman, D., Helman, E., Helsel, C., Herbrich, S., Herman, J., Hinoue, T., Hirst, C., Hirst, M., Holt, R., Hoyle, A., Iype, L., Jacobsen, A., Jeffreys, S., Jensen, M., Jones, C., Jones, S., Ju, Z., Jung, J., Kahles, A., Kahn, A., Kalicki-Veizer, J., Kalra, D., Kanchi, K., Kane, D., Kim, H., Kim, J., Knijnenburg, T., Koboldt, D., Kovar, C., Kramer, R., Kreisberg, R., Kucherlapati, R., Ladanyi, M., Lander, E., Larson, D., Lawrence, M., Lee, D., Lee, E., Lee, S., Lee, W., Lehmann, K., Leinonen, K., Leraas, K., Lerner, S., Levine, D., Lewis, L., Ley, T., Li, H., Li, J., Li, W., Liang, H., Lichtenberg, T., Lin, J., Lin, L., Lin, P., Liu, W., Liu, Y., Lorenzi, P., Lu, C., Lu, Y., Luquette, L., Ma, S., Magrini, V., Mahadeshwar, H., Mardis, E., Marra, M., Mayo, M., McAllister, C., McGuire, S., McMichael, J., Melott, J., Meng, S., Meyerson, M., Mieczkowski, P., Miller, C., Miller, M., Moore, R., Morgan, M., Morton, D., Mose, L., Mungall, A., Muzny, D., Nguyen, L., Noble, M., Noushmehr, H., O'Laughlin, M., Ojesina, A., Yang, T., Ozenberger, B., Pantazi, A., Parfenov, M., Park, P., Parker, J., Paull, E., Pedamallu, C., Pihl, T., Pohl, C., Pot, D., Protopopov, A., Przytycka, T., Radenbaugh, A., Ramirez, N., Ramirez, R., Ratsch, G., Reid, J., Ren, X., Reva, B., Reynolds, S., Rhie, S., Roach, J., Rovira, H., Ryan, M., Saksena, G., Salama, S., Sander, C., Santoso, N., Schein, J., Schmidt, H., Schultz, N., Schumacher, S., Seidman, J., Senbabaoglu, Y., Seth, S., Sharpe, S., Shen, R., Sheth, M., Shi, Y., Shmulevich, I., Silva, G., Simons, J., Sinha, R., Sipahimalani, P., Smith, S., Sofia, H., Sokolov, A., Soloway, M., Song, X., Sougnez, C., Spellman, P., Staudt, L., Stewart, C., Stojanov, P., Su, X., Sumer, S., Sun, Y., Swatloski, T., Tabak, B., Tam, A., Tan, D., Tang, J., Tarnuzzer, R., Taylor, B., Thiessen, N., Thorsson, V., Triche, T., Van Den Berg, D., Vandin, F., Varhol, Richard, Vaske, C., Veluvolu, U., Verhaak, R., Voet, D., Walker, J., Wallis, J., Waltman, P., Wan, Y., Wang, M., Wang, W., Wang, Z., Waring, S., Weinhold, N., Weisenberger, D., Wendl, M., Wheeler, D., Wilkerson, M., Wilson, R., Wise, L., Wong, A., Wu, C., Wu, H., Wu, J., Wylie, T., Xi, L., Xi, R., Xia, Z., Xu, A., Yang, D., Yang, L., Yang, Y., Yao, J., Yao, R., Ye, K., Yoshihara, K., Yuan, Y., Yung, A., Zack, T., Zeng, D., Zenklusen, J., Zhang, H., Zhang, N., Zhang, Q., Zhang, W., Zhao, W., Zheng, S., Zhu, J., Zmuda, E., and Zou, L.

Abstract

© 2014 Elsevier Inc. Recent genomic analyses of pathologically defined tumor types identify 'within-a-tissue' disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-oforigin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pancancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.

Published
2014

25. Measurement of Coherent Emission and Linear Polarization of Photons by Electrons in the Strong Fields of Aligned Crystals

Author

Apyan, A., Avakian, R.O., Badelek, B., Ballestrero, S., Biino, C., Birol, I., Cenci, P., Connell, S.H., Eichblatt, S., Fonseca, T., Freund, A., Gorini, B., Groess, R., Ispirian, K., Ketel, T.J., Kononets, Yu.V., Lopez, A., Mangiarotti, A., van Rens, B., Sellschop, J.P.F., Shieh, M., Sona, P., Strakhovenko, V., Uggerhoj, E., Uggerhj, Ulrik Ingerslev, Unel, G., Velasco, M., Vilakazi, Z.Z., and Wessely, O.

Subjects
Physics::Optics, Particle Physics - Experiment
Abstract

We present new results regarding the features of high energy photon emission by an electron beam of 178 GeV penetrating a 1.5 cm thick single Si crystal aligned at the Strings-Of-Strings (SOS) orientation. This concerns a special case of coherent bremsstrahlung where the electron interacts with the strong fields of successive atomic strings in a plane and for which the largest enhancement of the highest energy photons is expected. The polarization of the resulting photon beam was measured by the asymmetry of electron-positron pair production in an aligned diamond crystal analyzer. By the selection of a single pair the energy and the polarization of individual photons could be measured in an the environment of multiple photons produced in the radiator crystal. Photons in the high energy region show less than 20% linear polarization at the 90% confidence level. We present new results regarding the features of high energy photon emission by an electron beam of 178 GeV penetrating a 1.5 cm thick single Si crystal aligned at the Strings-Of-Strings (SOS) orientation. This concerns a special case of coherent bremsstrahlung where the electron interacts with the strong fields of successive atomic strings in a plane and for which the largest enhancement of the highest energy photons is expected. The polarization of the resulting photon beam was measured by the asymmetry of electron-positron pair production in an aligned diamond crystal analyzer. By the selection of a single pair the energy and the polarization of individual photons could be measured in an the environment of multiple photons produced in the radiator crystal. Photons in the high energy region show less than 20% linear polarization at the 90% confidence level.

Published
2004

27. Linear to Circular Polarisation Conversion using Birefringent Properties of Aligned Crystals for Multi-GeV Photons

Author

Apyan, A., Avakian, R.O., Badelek, B., Ballestrero, S., Biino, C., Birol, I., Cenci, P., Connell, S.H., Eichblatt, S., Fonseca, T., Freund, A., Gorini, B., Groess, R., Ispirian, K., Ketel, T.J., Kononets, Yu.V., Lopez, A., Mangiarotti, A., van Rens, B., Sellschop, J.P.F., Shieh, M., Sona, P., Strakhovenko, V., Uggerhoj, E., Uggerhj, Ulrik Ingerslev, Unel, G., Velasco, M., Vilakazi, Z.Z., and Wessely, O.

Subjects
Physics::Optics, Particle Physics - Experiment
Abstract

We present the first experimental results on the use of a thick aligned Si crystal acting as a quarter wave plate to induce a degree of circular polarisation in a high energy linearly polarised photon beam. The linearly polarised photon beam is produced from coherent bremsstrahlung radiation by 178 GeV unpolarised electrons incident on an aligned Si crystal, acting as a radiator. The linear polarisation of the photon beam is characterised by measuring the asymmetry in electron-positron pair production in a Ge crystal, for different crystal orientations. The Ge crystal therefore acts as an analyser. The birefringence phenomenon, which converts the linear polarisation to circular polarisation, is observed by letting the linearly polarised photons beam pass through a thick Si quarter wave plate crystal, and then measuring the asymmetry in electron-positron pair production again for a selection of relative angles between the crystallographic planes of the radiator, analyser and quarter wave plate. The systematics of the difference between the measured asymmetries with and without the quarter wave plate are predicted by theory to reveal an evolution in the Stokes parameters from which the appearance of a circularly polarised component in the photon beam can be demonstrated. The measured magnitude of the circularly polarised component was consistent with the theoretical predictions, and therefore is in indication of the existence of the birefringence effect. We present the first experimental results on the use of a thick aligned Si crystal acting as a quarter wave plate to induce a degree of circular polarisation in a high energy linearly polarised photon beam. The linearly polarised photon beam is produced from coherent bremsstrahlung radiation by 178 GeV unpolarised electrons incident on an aligned Si crystal, acting as a radiator. The linear polarisation of the photon beam is characterised by measuring the asymmetry in electron-positron pair production in a Ge crystal, for different crystal orientations. The Ge crystal therefore acts as an analyser. The birefringence phenomenon, which converts the linear polarisation to circular polarisation, is observed by letting the linearly polarised photons beam pass through a thick Si quarter wave plate crystal, and then measuring the asymmetry in electron-positron pair production again for a selection of relative angles between the crystallographic planes of the radiator, analyser and quarter wave plate. The systematics of the difference between the measured asymmetries with and without the quarter wave plate are predicted by theory to reveal an evolution in the Stokes parameters from which the appearance of a circularly polarised component in the photon beam can be demonstrated. The measured magnitude of the circularly polarised component was consistent with the theoretical predictions, and therefore is in indication of the existence of the birefringence effect.

Published
2003

28. Coherent Pair Production by Photons in the 20-170 GeV Energy Range Incident on Crystals and Birefringence

Author

Apyan, A., Avakian, R.O., Badelek, B., Ballestrero, S., Biino, C., Birol, I., Cenci, P., Connell, S.H., Eichblatt, S., Fonseca, T., Freund, A., Gorini, B., Groess, R., Ispirian, K., Ketel, T.J., Kononets, Yu.V., Lopez, A., Mangiarotti, A., van Rens, B., Sellschop, J.P.F., Shieh, M., Sona, P., Strakhovenko, V., Uggerhoj, E., Uggerhj, Ulrik Ingerslev, Unel, G., Velasco, M., Vilakazi, Z.Z., and Wessely, O.

Subjects
Particle Physics - Experiment
Abstract

The cross section for coherent pair production by linearly polarised photons in the 20-170 GeV energy range was measured for photon aligned incidence on ultra-high quality diamond and germanium crystals. The theoretical description of coherent bremsstrahlung and coherent pair production phenomena is an area of active theoretical debate and development. However, under our experimental conditions, the theory predicted the combined cross section and polarisation experimental observables very well indeed. In macroscopic terms, our experiment measured a birefringence effect in pair production in a crystal. This study of this effect also constituted a measurement of the energy dependent linear polarisation of photons produced by coherent bremsstrahlung in aligned crystals. New technologies for manipulating high energy photon beams can be realised based on an improved understanding of QED phenomena at these energies. In particular, this experiment demonstrates an efficient new polarimetry technique. The pair production measurements were done using two independent methods simultaneously. The more complex method using a magnet spectrometer showed that the simpler method using a multiplicity detector was also viable. The cross section for coherent pair production by linearly polarised photons in the 20-170 GeV energy range was measured for photon aligned incidence on ultra-high quality diamond and germanium crystals. The theoretical description of coherent bremsstrahlung and coherent pair production phenomena is an area of active theoretical debate and development. However, under our experimental conditions, the theory predicted the combined cross section and polarisation experimental observables very well indeed. In macroscopic terms, our experiment measured a birefringence effect in pair production in a crystal. This study of this effect also constituted a measurement of the energy dependent linear polarisation of photons produced by coherent bremsstrahlung in aligned crystals. New technologies for manipulating high energy photon beams can be realised based on an improved understanding of QED phenomena at these energies. In particular, this experiment demonstrates an efficient new polarimetry technique. The pair production measurements were done using two independent methods simultaneously. The more complex method using a magnet spectrometer showed that the simpler method using a multiplicity detector was also viable.

Published
2003

29. Assemblathon 2 : Evaluating de novo methods of genome assembly in three vertebrate species

Author

Bradnam, K. R., Fass, J. N., Alexandrov, A., Baranay, P., Bechner, M., Birol, I., Boisvert, S., Chapman, J. A., Chapuis, G., Chikhi, R., Chitsaz, H., Chou, W. -C, Corbeil, J., Fabbro, C. D., Docking, T. R., Durbin, R., Earl, D., Emrich, S., Fedotov, P., Fonseca, N. A., Ganapathy, G., Gibbs, R. A., Gnerre, S., Godzaridis, E., Goldstein, S., Haimel, M., Hall, G., Haussler, D., Hiatt, J. B., Ho, I. Y., Howard, J., Hunt, M., Jackman, S. D., Jaffe, D. B., Jarvis, E. D., Jiang, H., Kazakov, S., Kersey, P. J., Kitzman, J. O., Knight, J. R., Koren, S., Lam, T. -W, Lavenier, D., Laviolette, F., Li, Y., Li, Z., Liu, B., Liu, Y., Luo, R., MacCallum, I., MacManes, M. D., Maillet, N., Melnikov, S., Naquin, D., Ning, Z., Otto, T. D., Paten, B., Paulo, O. S., Phillippy, A. M., Pina-Martins, F., Place, M., Przybylski, D., Qin, X., Qu, C., Ribeiro, F. J., Richards, S., Rokhsar, D. S., Ruby, J. G., Scalabrin, S., Schatz, M. C., Schwartz, D. C., Sergushichev, A., Sharpe, T., Shaw, T. I., Shendure, J., Shi, Y., Simpson, J. T., Song, H., Tsarev, F., Vezzi, F., Vicedomini, R., Vieira, B. M., Wang, J., Worley, K. C., Yin, S., Yiu, S. -M, Yuan, J., Zhang, G., Zhang, H., Zhou, S., Korf, I. F., Bradnam, K. R., Fass, J. N., Alexandrov, A., Baranay, P., Bechner, M., Birol, I., Boisvert, S., Chapman, J. A., Chapuis, G., Chikhi, R., Chitsaz, H., Chou, W. -C, Corbeil, J., Fabbro, C. D., Docking, T. R., Durbin, R., Earl, D., Emrich, S., Fedotov, P., Fonseca, N. A., Ganapathy, G., Gibbs, R. A., Gnerre, S., Godzaridis, E., Goldstein, S., Haimel, M., Hall, G., Haussler, D., Hiatt, J. B., Ho, I. Y., Howard, J., Hunt, M., Jackman, S. D., Jaffe, D. B., Jarvis, E. D., Jiang, H., Kazakov, S., Kersey, P. J., Kitzman, J. O., Knight, J. R., Koren, S., Lam, T. -W, Lavenier, D., Laviolette, F., Li, Y., Li, Z., Liu, B., Liu, Y., Luo, R., MacCallum, I., MacManes, M. D., Maillet, N., Melnikov, S., Naquin, D., Ning, Z., Otto, T. D., Paten, B., Paulo, O. S., Phillippy, A. M., Pina-Martins, F., Place, M., Przybylski, D., Qin, X., Qu, C., Ribeiro, F. J., Richards, S., Rokhsar, D. S., Ruby, J. G., Scalabrin, S., Schatz, M. C., Schwartz, D. C., Sergushichev, A., Sharpe, T., Shaw, T. I., Shendure, J., Shi, Y., Simpson, J. T., Song, H., Tsarev, F., Vezzi, F., Vicedomini, R., Vieira, B. M., Wang, J., Worley, K. C., Yin, S., Yiu, S. -M, Yuan, J., Zhang, G., Zhang, H., Zhou, S., and Korf, I. F.

Abstract

Background: The process of generating raw genome sequence data continues to become cheaper, faster, and more accurate. However, assembly of such data into high-quality, finished genome sequences remains challenging. Many genome assembly tools are available, but they differ greatly in terms of their performance (speed, scalability, hardware requirements, acceptance of newer read technologies) and in their final output (composition of assembled sequence). More importantly, it remains largely unclear how to best assess the quality of assembled genome sequences. The Assemblathon competitions are intended to assess current state-of-the-art methods in genome assembly. Results: In Assemblathon 2, we provided a variety of sequence data to be assembled for three vertebrate species (a bird, a fish, and snake). This resulted in a total of 43 submitted assemblies from 21 participating teams. We evaluated these assemblies using a combination of optical map data, Fosmid sequences, and several statistical methods. From over 100 different metrics, we chose ten key measures by which to assess the overall quality of the assemblies. Conclusions: Many current genome assemblers produced useful assemblies, containing a significant representation of their genes and overall genome structure. However, the high degree of variability between the entries suggests that there is still much room for improvement in the field of genome assembly and that approaches which work well in assembling the genome of one species may not necessarily work well for another., QC 20170307

Published
2013
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30. Complete genomic landscape of a recurring sporadic parathyroid carcinoma

Author

Kasaian, K., Wiseman, S., Thiessen, N., Mungall, K., Corbett, R., Qian, J., Nip, K., He, A., Tse, K., Chuah, E., Varhol, Richard, Pandoh, P., McDonald, H., Zeng, T., Tam, A., Schein, J., Birol, I., Mungall, A., Moore, R., Zhao, Y., Hirst, M., Marra, M., Walker, B., Jones, S., Kasaian, K., Wiseman, S., Thiessen, N., Mungall, K., Corbett, R., Qian, J., Nip, K., He, A., Tse, K., Chuah, E., Varhol, Richard, Pandoh, P., McDonald, H., Zeng, T., Tam, A., Schein, J., Birol, I., Mungall, A., Moore, R., Zhao, Y., Hirst, M., Marra, M., Walker, B., and Jones, S.

Abstract

Parathyroid carcinoma is a rare endocrine malignancy with an estimated incidence of less than 1 per million population. Excessive secretion of parathyroid hormone, extremely high serum calcium level, and the deleterious effects of hypercalcaemia are the clinical manifestations of the disease. Up to 60% of patients develop multiple disease recurrences and although long-term survival is possible with palliative surgery, permanent remission is rarely achieved. Molecular drivers of sporadic parathyroid carcinoma have remained largely unknown. Previous studies, mostly based on familial cases of the disease, suggested potential roles for the tumour suppressor MEN1 and proto-oncogene RET in benign parathyroid tumourigenesis, while the tumour suppressor HRPT2 and proto-oncogene CCND1 may also act as drivers in parathyroid cancer. Here, we report the complete genomic analysis of a sporadic and recurring parathyroid carcinoma. Mutational landscapes of the primary and recurrent tumour specimens were analysed using high-throughput sequencing technologies. Such molecular profiling allowed for identification of somatic mutations never previously identified in this malignancy. These included single nucleotide point mutations in well-characterized cancer genes such as mTOR, MLL2, CDKN2C, and PIK3CA. Comparison of acquired mutations in patient-matched primary and recurrent tumours revealed loss of PIK3CA activating mutation during the evolution of the tumour from the primary to the recurrence. Structural variations leading to gene fusions and regions of copy loss and gain were identified at a single-base resolution. Loss of the short arm of chromosome 1, along with somatic missense and truncating mutations in CDKN2C and THRAP3, respectively, provides new evidence for the potential role of these genes as tumour suppressors in parathyroid cancer. The key somatic mutations identified in this study can serve as novel diagnostic markers as well as therapeutic targets. Copyright © 2013 Pa

Published
2013

31. The cancer genome atlas pan-cancer analysis project

Author

Weinstein, J., Collisson, E., Mills, G., Shaw, K., Ozenberger, B., Ellrott, K., Sander, C., Stuart, J., Chang, K., Creighton, C., Davis, C., Donehower, L., Drummond, J., Wheeler, D., Ally, A., Balasundaram, M., Birol, I., Butterfield, Y., Chu, A., Chuah, E., Chun, H., Dhalla, N., Guin, R., Hirst, M., Hirst, C., Holt, R., Jones, S., Lee, D., Li, H., Marra, M., Mayo, M., Moore, R., Mungall, A., Robertson, A., Schein, J., Sipahimalani, P., Tam, A., Thiessen, N., Varhol, Richard, Beroukhim, R., Bhatt, A., Brooks, A., Cherniack, A., Freeman, S., Gabriel, S., Helman, E., Jung, J., Meyerson, M., Ojesina, A., Pedamallu, C., Saksena, G., Schumacher, S., Tabak, B., Zack, T., Lander, E., Bristow, C., Hadjipanayis, A., Haseley, P., Kucherlapati, R., Lee, S., Lee, E., Luquette, L., Mahadeshwar, H., Pantazi, A., Parfenov, M., Park, P., Protopopov, A., Ren, X., Santoso, N., Seidman, J., Seth, S., Song, X., Tang, J., Xi, R., Xu, A., Yang, L., Zeng, D., Auman, J., Balu, S., Buda, E., Weinstein, J., Collisson, E., Mills, G., Shaw, K., Ozenberger, B., Ellrott, K., Sander, C., Stuart, J., Chang, K., Creighton, C., Davis, C., Donehower, L., Drummond, J., Wheeler, D., Ally, A., Balasundaram, M., Birol, I., Butterfield, Y., Chu, A., Chuah, E., Chun, H., Dhalla, N., Guin, R., Hirst, M., Hirst, C., Holt, R., Jones, S., Lee, D., Li, H., Marra, M., Mayo, M., Moore, R., Mungall, A., Robertson, A., Schein, J., Sipahimalani, P., Tam, A., Thiessen, N., Varhol, Richard, Beroukhim, R., Bhatt, A., Brooks, A., Cherniack, A., Freeman, S., Gabriel, S., Helman, E., Jung, J., Meyerson, M., Ojesina, A., Pedamallu, C., Saksena, G., Schumacher, S., Tabak, B., Zack, T., Lander, E., Bristow, C., Hadjipanayis, A., Haseley, P., Kucherlapati, R., Lee, S., Lee, E., Luquette, L., Mahadeshwar, H., Pantazi, A., Parfenov, M., Park, P., Protopopov, A., Ren, X., Santoso, N., Seidman, J., Seth, S., Song, X., Tang, J., Xi, R., Xu, A., Yang, L., Zeng, D., Auman, J., Balu, S., and Buda, E.

Abstract

The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.

Published
2013

32. Comprehensivemolecular characterization of clear cell renal cell carcinoma

Author

Creighton, C., Morgan, M., Gunaratne, P., Wheeler, D., Gibbs, R., Robertson, A., Chu, A., Beroukhim, R., Cibulskis, K., Signoretti, S., Vandin, F., Wu, H., Raphael, B., Verhaak, R., Tamboli, P., Torres-Garcia, W., Akbani, R., Weinstein, J., Reuter, V., Hsieh, J., Brannon, A., Hakimi, A., Jacobsen, A., Ciriello, G., Reva, B., Ricketts, C., Linehan, W., Stuart, J., Rathmell, W., Shen, H., Laird, P., Muzny, D., Davis, C., Xi, L., Chang, K., Kakkar, N., Trevino, L., Benton, S., Reid, J., Morton, D., Doddapaneni, H., Han, Y., Lewis, L., Dinh, H., Kovar, C., Zhu, Y., Santibanez, J., Wang, M., Hale, W., Kalra, D., Getz, G., Lawrence, M., Sougnez, C., Carter, S., Sivachenko, A., Lichtenstein, L., Stewart, C., Voet, D., Fisher, S., Gabriel, S., Lander, E., Schumacher, S., Tabak, B., Saksena, G., Onofrio, R., Cherniack, A., Gentry, J., Ardlie, K., Meyerson, M., Chun, H., Mungall, A., Sipahimalani, P., Stoll, D., Ally, A., Balasundaram, M., Butterfield, Y., Carlsen, R., Carter, C., Chuah, E., Coope, R., Dhalla, N., Gorski, S., Guin, R., Hirst, C., Hirst, M., Holt, R., Lebovitz, C., Lee, D., Li, H., Mayo, M., Moore, R., Pleasance, E., Plettner, P., Schein, J., Shafiei, A., Slobodan, J., Tam, A., Thiessen, N., Varhol, Richard, Wye, N., Zhao, Y., Birol, I., Jones, S., Marra, M., Auman, J., Tan, D., Jones, C., Hoadley, K., Mieczkowski, P., Mose, L., Jefferys, S., Topal, M., Liquori, C., Turman, Y., Shi, Y., Waring, S., Buda, E., Walsh, J., Wu, J., Bodenheimer, T., Hoyle, A., Simons, J., Soloway, M., Balu, S., Parker, J., Hayes, D., Perou, C., Kucherlapati, R., Park, P., Triche, T., Weisenberger, D., Lai, P., Bootwalla, M., Maglinte, D., Mahurkar, S., Berman, B., Van den Berg, D., Cope, L., Baylin, S., Noble, M., DiCara, D., Zhang, H., Cho, J., Heiman, D., Gehlenborg, N., Mallard, W., Lin, P., Frazer, S., Stojanov, P., Liu, Y., Zhou, L., Kim, J., Chin, L., Benz, C., Yau, C., Reynolds, S., Shmulevich, I., Vegesna, R., Kim, H., Zhang, W., Cogdell, D., Jonasch, E., Ding, Z., Lu, Y., Zhang, N., Unruh, A., Casasent, T., Wakefield, C., Tsavachidou, D., Mills, G., Schultz, N., Antipin, Y., Gao, J., Cerami, E., Gross, B., Aksoy, B., Sinha, R., Weinhold, N., Sumer, S., Taylor, B., Shen, R., Ostrovnaya, I., Berger, M., Ladanyi, M., Sander, C., Fei, S., Stout, A., Spellman, P., Rubin, D., Liu, T., Sam, N., Paull, E., Carlin, D., Goldstein, T., Waltman, P., Ellrott, K., Zhu, J., Haussler, D., Xiao, W., Shelton, C., Gardner, J., Penny, R., Sherman, M., Mallery, D., Morris, S., Paulauskis, J., Burnett, K., Shelton, T., Kaelin, W., Choueiri, T., Atkins, M., Curley, E., Tickoo, S., Thorne, L., Boice, L., Huang, M., Fisher, J., Vocke, C., Peterson, J., Worrell, R., Merino, M., Schmidt, L., Czerniak, B., Aldape, K., Wood, C., Boyd, J., Weaver, J., Iacocca, M., Petrelli, N., Witkin, G., Brown, J., Czerwinski, C., Huelsenbeck-Dill, L., Rabeno, B., Myers, J., Morrison, C., Bergsten, J., Eckman, J., Harr, J., Smith, C., Tucker, K., Zach, L., Bshara, W., Gaudioso, C., Dhir, R., Maranchie, J., Nelson, J., Parwani, A., Potapova, O., Fedosenko, K., Cheville, J., Thompson, R., Mosquera, J., Rubin, M., Blute, M., Pihl, T., Jensen, M., Sfeir, R., Kahn, A., Kothiyal, P., Snyder, E., Pontius, J., Ayala, B., Backus, M., Walton, J., Baboud, J., Berton, D., Nicholls, M., Srinivasan, D., Raman, R., Girshik, S., Kigonya, P., Alonso, S., Sanbhadti, R., Barletta, S., Pot, D., Sheth, M., Demchok, J., Davidsen, T., Wang, Z., Yang, L., Tarnuzzer, R., Zhang, J., Eley, G., Ferguson, M., Shaw, K., Guyer, M., Ozenberger, B., Sofia, H., Creighton, C., Morgan, M., Gunaratne, P., Wheeler, D., Gibbs, R., Robertson, A., Chu, A., Beroukhim, R., Cibulskis, K., Signoretti, S., Vandin, F., Wu, H., Raphael, B., Verhaak, R., Tamboli, P., Torres-Garcia, W., Akbani, R., Weinstein, J., Reuter, V., Hsieh, J., Brannon, A., Hakimi, A., Jacobsen, A., Ciriello, G., Reva, B., Ricketts, C., Linehan, W., Stuart, J., Rathmell, W., Shen, H., Laird, P., Muzny, D., Davis, C., Xi, L., Chang, K., Kakkar, N., Trevino, L., Benton, S., Reid, J., Morton, D., Doddapaneni, H., Han, Y., Lewis, L., Dinh, H., Kovar, C., Zhu, Y., Santibanez, J., Wang, M., Hale, W., Kalra, D., Getz, G., Lawrence, M., Sougnez, C., Carter, S., Sivachenko, A., Lichtenstein, L., Stewart, C., Voet, D., Fisher, S., Gabriel, S., Lander, E., Schumacher, S., Tabak, B., Saksena, G., Onofrio, R., Cherniack, A., Gentry, J., Ardlie, K., Meyerson, M., Chun, H., Mungall, A., Sipahimalani, P., Stoll, D., Ally, A., Balasundaram, M., Butterfield, Y., Carlsen, R., Carter, C., Chuah, E., Coope, R., Dhalla, N., Gorski, S., Guin, R., Hirst, C., Hirst, M., Holt, R., Lebovitz, C., Lee, D., Li, H., Mayo, M., Moore, R., Pleasance, E., Plettner, P., Schein, J., Shafiei, A., Slobodan, J., Tam, A., Thiessen, N., Varhol, Richard, Wye, N., Zhao, Y., Birol, I., Jones, S., Marra, M., Auman, J., Tan, D., Jones, C., Hoadley, K., Mieczkowski, P., Mose, L., Jefferys, S., Topal, M., Liquori, C., Turman, Y., Shi, Y., Waring, S., Buda, E., Walsh, J., Wu, J., Bodenheimer, T., Hoyle, A., Simons, J., Soloway, M., Balu, S., Parker, J., Hayes, D., Perou, C., Kucherlapati, R., Park, P., Triche, T., Weisenberger, D., Lai, P., Bootwalla, M., Maglinte, D., Mahurkar, S., Berman, B., Van den Berg, D., Cope, L., Baylin, S., Noble, M., DiCara, D., Zhang, H., Cho, J., Heiman, D., Gehlenborg, N., Mallard, W., Lin, P., Frazer, S., Stojanov, P., Liu, Y., Zhou, L., Kim, J., Chin, L., Benz, C., Yau, C., Reynolds, S., Shmulevich, I., Vegesna, R., Kim, H., Zhang, W., Cogdell, D., Jonasch, E., Ding, Z., Lu, Y., Zhang, N., Unruh, A., Casasent, T., Wakefield, C., Tsavachidou, D., Mills, G., Schultz, N., Antipin, Y., Gao, J., Cerami, E., Gross, B., Aksoy, B., Sinha, R., Weinhold, N., Sumer, S., Taylor, B., Shen, R., Ostrovnaya, I., Berger, M., Ladanyi, M., Sander, C., Fei, S., Stout, A., Spellman, P., Rubin, D., Liu, T., Sam, N., Paull, E., Carlin, D., Goldstein, T., Waltman, P., Ellrott, K., Zhu, J., Haussler, D., Xiao, W., Shelton, C., Gardner, J., Penny, R., Sherman, M., Mallery, D., Morris, S., Paulauskis, J., Burnett, K., Shelton, T., Kaelin, W., Choueiri, T., Atkins, M., Curley, E., Tickoo, S., Thorne, L., Boice, L., Huang, M., Fisher, J., Vocke, C., Peterson, J., Worrell, R., Merino, M., Schmidt, L., Czerniak, B., Aldape, K., Wood, C., Boyd, J., Weaver, J., Iacocca, M., Petrelli, N., Witkin, G., Brown, J., Czerwinski, C., Huelsenbeck-Dill, L., Rabeno, B., Myers, J., Morrison, C., Bergsten, J., Eckman, J., Harr, J., Smith, C., Tucker, K., Zach, L., Bshara, W., Gaudioso, C., Dhir, R., Maranchie, J., Nelson, J., Parwani, A., Potapova, O., Fedosenko, K., Cheville, J., Thompson, R., Mosquera, J., Rubin, M., Blute, M., Pihl, T., Jensen, M., Sfeir, R., Kahn, A., Kothiyal, P., Snyder, E., Pontius, J., Ayala, B., Backus, M., Walton, J., Baboud, J., Berton, D., Nicholls, M., Srinivasan, D., Raman, R., Girshik, S., Kigonya, P., Alonso, S., Sanbhadti, R., Barletta, S., Pot, D., Sheth, M., Demchok, J., Davidsen, T., Wang, Z., Yang, L., Tarnuzzer, R., Zhang, J., Eley, G., Ferguson, M., Shaw, K., Guyer, M., Ozenberger, B., and Sofia, H.

Abstract

Genetic changes underlying clear cell renal cell carcinoma(ccRCC) include alterations in genes controlling cellularoxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreasedAMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment. © 2013 Macmillan Publishers Limited. All rights reserved.

Published
2013

33. Barnacle: Detecting and characterizing tandem duplications and fusions in transcriptome assemblies

Author

Swanson, L., Robertson, G., Mungall, K., Butterfield, Y., Chiu, R., Corbett, R., Docking, T., Hogge, D., Jackman, S., Moore, R., Mungall, A., Nip, K., Parker, J., Qian, J., Raymond, A., Sung, S., Tam, A., Thiessen, N., Varhol, Richard, Wang, S., Yorukoglu, D., Zhao, Y., Hoodless, P., Sahinalp, S., Karsan, A., Birol, I., Swanson, L., Robertson, G., Mungall, K., Butterfield, Y., Chiu, R., Corbett, R., Docking, T., Hogge, D., Jackman, S., Moore, R., Mungall, A., Nip, K., Parker, J., Qian, J., Raymond, A., Sung, S., Tam, A., Thiessen, N., Varhol, Richard, Wang, S., Yorukoglu, D., Zhao, Y., Hoodless, P., Sahinalp, S., Karsan, A., and Birol, I.

Abstract

Background: Chimeric transcripts, including partial and internal tandem duplications (PTDs, ITDs) and gene fusions, are important in the detection, prognosis, and treatment of human cancers.Results: We describe Barnacle, a production-grade analysis tool that detects such chimeras in de novo assemblies of RNA-seq data, and supports prioritizing them for review and validation by reporting the relative coverage of co-occurring chimeric and wild-type transcripts. We demonstrate applications in large-scale disease studies, by identifying PTDs in MLL, ITDs in FLT3, and reciprocal fusions between PML and RARA, in two deeply sequenced acute myeloid leukemia (AML) RNA-seq datasets.Conclusions: Our analyses of real and simulated data sets show that, with appropriate filter settings, Barnacle makes highly specific predictions for three types of chimeric transcripts that are important in a range of cancers: PTDs, ITDs, and fusions. High specificity makes manual review and validation efficient, which is necessary in large-scale disease studies. Characterizing an extended range of chimera types will help generate insights into progression, treatment, and outcomes for complex diseases. © 2013 Swanson et al.; licensee BioMed Central Ltd.

Published
2013

34. Integrated genomic characterization of endometrial carcinoma

Author

Getz, G., Gabriel, S., Cibulskis, K., Lander, E., Sivachenko, A., Sougnez, C., Lawrence, M., Kandoth, C., Dooling, D., Fulton, R., Fulton, L., Kalicki-Veizer, J., McLellan, M., O'Laughlin, M., Schmidt, H., Wilson, R., Ye, K., Li, D., Ally, A., Balasundaram, M., Birol, I., Butterfield, Y., Carlsen, R., Carter, C., Chu, A., Chuah, E., Chun, H., Dhalla, N., Guin, R., Hirst, C., Holt, R., Jones, S., Lee, D., Li, H., Marra, M., Mayo, M., Moore, R., Mungall, A., Plettner, P., Schein, J., Sipahimalani, P., Tam, A., Varhol, Richard, Gordon Robertson, A., Cherniack, A., Pashtan, I., Saksena, G., Onofrio, R., Schumacher, S., Tabak, B., Carter, S., Hernandez, B., Gentry, J., Salvesen, H., Ardlie, K., Winckler, W., Beroukhim, R., Meyerson, M., Hadjipanayis, A., Lee, S., Mahadeshwar, H., Park, P., Protopopov, A., Ren, X., Seth, S., Song, X., Tang, J., Xi, R., Yang, L., Dong, Z., Kucherlapati, R., Chin, L., Zhang, J., Todd Auman, J., Balu, S., Bodenheimer, T., Buda, E., Neil Hayes, D., Hoyle, A., Jefferys, S., Jones, C., Meng, S., Mieczkowski, P., Mose, L., Parker, J., Perou, C., Getz, G., Gabriel, S., Cibulskis, K., Lander, E., Sivachenko, A., Sougnez, C., Lawrence, M., Kandoth, C., Dooling, D., Fulton, R., Fulton, L., Kalicki-Veizer, J., McLellan, M., O'Laughlin, M., Schmidt, H., Wilson, R., Ye, K., Li, D., Ally, A., Balasundaram, M., Birol, I., Butterfield, Y., Carlsen, R., Carter, C., Chu, A., Chuah, E., Chun, H., Dhalla, N., Guin, R., Hirst, C., Holt, R., Jones, S., Lee, D., Li, H., Marra, M., Mayo, M., Moore, R., Mungall, A., Plettner, P., Schein, J., Sipahimalani, P., Tam, A., Varhol, Richard, Gordon Robertson, A., Cherniack, A., Pashtan, I., Saksena, G., Onofrio, R., Schumacher, S., Tabak, B., Carter, S., Hernandez, B., Gentry, J., Salvesen, H., Ardlie, K., Winckler, W., Beroukhim, R., Meyerson, M., Hadjipanayis, A., Lee, S., Mahadeshwar, H., Park, P., Protopopov, A., Ren, X., Seth, S., Song, X., Tang, J., Xi, R., Yang, L., Dong, Z., Kucherlapati, R., Chin, L., Zhang, J., Todd Auman, J., Balu, S., Bodenheimer, T., Buda, E., Neil Hayes, D., Hoyle, A., Jefferys, S., Jones, C., Meng, S., Mieczkowski, P., Mose, L., Parker, J., and Perou, C.

Abstract

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array-and sequencing-based technologies. Uterine serous tumours and ~25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours. © 2013 Macmillan Publishers Limited. All rights reserved.

Published
2013

35. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia

Author

Ley, T., Miller, C., Ding, L., Raphael, B., Mungall, A., Robertson, G., Hoadley, K., Triche, T., Laird, P., Baty, J., Fulton, L., Fulton, R., Heath, S., Kalicki-Veizer, J., Kandoth, C., Klco, J., Koboldt, D., Kanchi, K., Kulkarni, S., Lamprecht, T., Larson, D., Lin, G., Lu, C., McLellan, M., McMichael, J., Payton, J., Schmidt, H., Spencer, D., Tomasson, M., Wallis, J., Wartman, L., Watson, M., Welch, J., Wendl, M., Ally, A., Balasundaram, M., Birol, I., Butterfield, Y., Chiu, R., Chu, A., Chuah, E., Chun, H., Corbett, R., Dhalla, N., Guin, R., He, A., Hirst, C., Hirst, M., Holt, R., Jones, S., Karsan, A., Lee, D., Li, H., Marra, M., Mayo, M., Moore, R., Mungall, K., Parker, J., Pleasance, E., Plettner, P., Schein, J., Stoll, D., Swanson, L., Tam, A., Thiessen, N., Varhol, Richard, Wye, N., Zhao, Y., Gabriel, S., Getz, G., Sougnez, C., Zou, L., Leiserson, M., Vandin, F., Wu, H., Applebaum, F., Baylin, S., Akbani, R., Broom, B., Chen, K., Motter, T., Nguyen, K., Weinstein, J., Zhang, N., Ferguson, M., Adams, C., Black, A., Bowen, J., Gastier-Foster, J., Grossman, T., Lichtenberg, T., Wise, L., Davidsen, T., Demchok, J., Mills Shaw, K., Sheth, M., Sofia, H., Yang, L., Downing, J., Eley, G., Ley, T., Miller, C., Ding, L., Raphael, B., Mungall, A., Robertson, G., Hoadley, K., Triche, T., Laird, P., Baty, J., Fulton, L., Fulton, R., Heath, S., Kalicki-Veizer, J., Kandoth, C., Klco, J., Koboldt, D., Kanchi, K., Kulkarni, S., Lamprecht, T., Larson, D., Lin, G., Lu, C., McLellan, M., McMichael, J., Payton, J., Schmidt, H., Spencer, D., Tomasson, M., Wallis, J., Wartman, L., Watson, M., Welch, J., Wendl, M., Ally, A., Balasundaram, M., Birol, I., Butterfield, Y., Chiu, R., Chu, A., Chuah, E., Chun, H., Corbett, R., Dhalla, N., Guin, R., He, A., Hirst, C., Hirst, M., Holt, R., Jones, S., Karsan, A., Lee, D., Li, H., Marra, M., Mayo, M., Moore, R., Mungall, K., Parker, J., Pleasance, E., Plettner, P., Schein, J., Stoll, D., Swanson, L., Tam, A., Thiessen, N., Varhol, Richard, Wye, N., Zhao, Y., Gabriel, S., Getz, G., Sougnez, C., Zou, L., Leiserson, M., Vandin, F., Wu, H., Applebaum, F., Baylin, S., Akbani, R., Broom, B., Chen, K., Motter, T., Nguyen, K., Weinstein, J., Zhang, N., Ferguson, M., Adams, C., Black, A., Bowen, J., Gastier-Foster, J., Grossman, T., Lichtenberg, T., Wise, L., Davidsen, T., Demchok, J., Mills Shaw, K., Sheth, M., Sofia, H., Yang, L., Downing, J., and Eley, G.

Abstract

BACKGROUND: Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. METHODS: We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. RESULTS: AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. CONCLUSIONS: We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.) Copyright © 2013 Massachusetts Medical Society.

Published
2013

36. Profiling thyroid cancers on the molecular level

Author

Kasaian, K., He, A., Thiessen, N., Mungall, K., Qian, J., Varhol, Richard, Zhao, Y., Birol, I., Moore, R., Mungall, A., Hirst, M., Marra, M., Walker, B., Wiseman, S., Jones, S., Kasaian, K., He, A., Thiessen, N., Mungall, K., Qian, J., Varhol, Richard, Zhao, Y., Birol, I., Moore, R., Mungall, A., Hirst, M., Marra, M., Walker, B., Wiseman, S., and Jones, S.

Published
2012

37. Comprehensive molecular portraits of human breast tumours

Author

Koboldt, D., Fulton, R., McLellan, M., Schmidt, H., Kalicki-Veizer, J., McMichael, J., Fulton, L., Dooling, D., Ding, L., Mardis, E., Wilson, R., Ally, A., Balasundaram, M., Butterfield, Y., Carlsen, R., Carter, C., Chu, A., Chuah, E., Chun, H., Coope, R., Dhalla, N., Guin, R., Hirst, C., Hirst, M., Holt, R., Lee, D., Li, H., Mayo, M., Moore, R., Mungall, A., Pleasance, E., Robertson, A., Schein, J., Shafiei, A., Sipahimalani, P., Slobodan, J., Stoll, D., Tam, A., Thiessen, N., Varhol, Richard, Wye, N., Zeng, T., Zhao, Y., Birol, I., Jones, S., Marra, M., Cherniack, A., Saksena, G., Onofrio, R., Pho, N., Carter, S., Schumacher, S., Tabak, B., Hernandez, B., Gentry, J., Nguyen, H., Crenshaw, A., Ardlie, K., Beroukhim, R., Winckler, W., Getz, G., Gabriel, S., Meyerson, M., Chin, L., Kucherlapati, R., Hoadley, K., Auman, J., Fan, C., Turman, Y., Shi, Y., Li, L., Topal, M., He, X., Chao, H., Prat, A., Silva, G., Iglesia, M., Koboldt, D., Fulton, R., McLellan, M., Schmidt, H., Kalicki-Veizer, J., McMichael, J., Fulton, L., Dooling, D., Ding, L., Mardis, E., Wilson, R., Ally, A., Balasundaram, M., Butterfield, Y., Carlsen, R., Carter, C., Chu, A., Chuah, E., Chun, H., Coope, R., Dhalla, N., Guin, R., Hirst, C., Hirst, M., Holt, R., Lee, D., Li, H., Mayo, M., Moore, R., Mungall, A., Pleasance, E., Robertson, A., Schein, J., Shafiei, A., Sipahimalani, P., Slobodan, J., Stoll, D., Tam, A., Thiessen, N., Varhol, Richard, Wye, N., Zeng, T., Zhao, Y., Birol, I., Jones, S., Marra, M., Cherniack, A., Saksena, G., Onofrio, R., Pho, N., Carter, S., Schumacher, S., Tabak, B., Hernandez, B., Gentry, J., Nguyen, H., Crenshaw, A., Ardlie, K., Beroukhim, R., Winckler, W., Getz, G., Gabriel, S., Meyerson, M., Chin, L., Kucherlapati, R., Hoadley, K., Auman, J., Fan, C., Turman, Y., Shi, Y., Li, L., Topal, M., He, X., Chao, H., Prat, A., Silva, G., and Iglesia, M.

Abstract

We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at.10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer. © 2012 Macmillan Publishers Limited. All rights reserved.

Published
2012

38. Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers

Author

Yip, S., Butterfield, Y., Morozova, O., Chittaranjan, S., Blough, M., An, J., Birol, I., Chesnelong, C., Chiu, R., Chuah, E., Corbett, R., Docking, R., Firme, M., Hirst, M., Jackman, S., Karsan, A., Li, H., Louis, D., Maslova, A., Moore, R., Moradian, A., Mungall, K., Perizzolo, M., Qian, J., Roldan, G., Smith, E., Tamura-Wells, J., Thiessen, N., Varhol, Richard, Weiss, S., Wu, W., Young, S., Zhao, Y., Mungall, A., Jones, S., Morin, G., Chan, J., Cairncross, J., Marra, M., Yip, S., Butterfield, Y., Morozova, O., Chittaranjan, S., Blough, M., An, J., Birol, I., Chesnelong, C., Chiu, R., Chuah, E., Corbett, R., Docking, R., Firme, M., Hirst, M., Jackman, S., Karsan, A., Li, H., Louis, D., Maslova, A., Moore, R., Moradian, A., Mungall, K., Perizzolo, M., Qian, J., Roldan, G., Smith, E., Tamura-Wells, J., Thiessen, N., Varhol, Richard, Weiss, S., Wu, W., Young, S., Zhao, Y., Mungall, A., Jones, S., Morin, G., Chan, J., Cairncross, J., and Marra, M.

Abstract

Oligodendroglioma is characterized by unique clinical, pathological, and genetic features. Recurrent losses of chromosomes 1p and 19q are strongly associated with this brain cancer but knowledge of the identity and function of the genes affected by these alterations is limited. We performed exome sequencing on a discovery set of 16 oligodendrogliomas with 1p/19q co-deletion to identify new molecular features at base-pair resolution. As anticipated, there was a high rate of IDH mutations: all cases had mutations in either IDH1 (14/16) or IDH2 (2/16). In addition, we discovered somatic mutations and insertions/deletions in the CIC gene on chromosome 19q13.2 in 13/16 tumours. These discovery set mutations were validated by deep sequencing of 13 additional tumours, which revealed seven others with CIC mutations, thus bringing the overall mutation rate in oligodendrogliomas in this study to 20/29 (69%). In contrast, deep sequencing of astrocytomas and oligoastrocytomas without 1p/19q loss revealed that CIC alterations were otherwise rare (1/60; 2%). Of the 21 non-synonymous somatic mutations in 20 CIC-mutant oligodendrogliomas, nine were in exon 5 within an annotated DNA-interacting domain and three were in exon 20 within an annotated protein-interacting domain. The remaining nine were found in other exons and frequently included truncations. CIC mutations were highly associated with oligodendroglioma histology, 1p/19q co-deletion, and IDH1/2 mutation (p < 0.001). Although we observed no differences in the clinical outcomes of CIC mutant versus wild-type tumours, in a background of 1p/19q co-deletion, hemizygous CIC mutations are likely important. We hypothesize that the mutant CIC on the single retained 19q allele is linked to the pathogenesis of oligodendrogliomas with IDH mutation. Our detailed study of genetic aberrations in oligodendroglioma suggests a functional interaction between CIC mutation, IDH1/2 mutation, and 1p/19q co-deletion. Copyright © 2011 Pathologi

Published
2012

39. Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Author

Northcott, P., Shih, D., Peacock, J., Garzia, L., Sorana Morrissy, A., Zichner, T., Stútz, A., Korshunov, A., Reimand, J., Schumacher, S., Beroukhim, R., Ellison, D., Marshall, C., Lionel, A., MacK, S., Dubuc, A., Yao, Y., Ramaswamy, V., Luu, B., Rolider, A., Cavalli, F., Wang, X., Remke, M., Wu, X., Chiu, R., Chu, A., Chuah, E., Corbett, R., Hoad, G., Jackman, S., Li, Y., Lo, A., Mungall, K., Ming Nip, K., Qian, J., Raymond, A., Thiessen, N., Varhol, Richard, Birol, I., Moore, R., Mungall, A., Holt, R., Kawauchi, D., Roussel, M., Kool, M., Jones, D., Witt, H., Fernandez-L, A., Kenney, A., Wechsler-Reya, R., Dirks, P., Aviv, T., Grajkowska, W., Perek-Polnik, M., Haberler, C., Delattre, O., Reynaud, S., Doz, F., Pernet-Fattet, S., Cho, B., Kim, S., Wang, K., Scheurlen, W., Eberhart, C., Fèvre-Montange, M., Jouvet, A., Pollack, I., Fan, X., Muraszko, K., Yancey Gillespie, G., Di Rocco, C., Massimi, L., Michiels, E., Kloosterhof, N., French, P., Kros, J., Olson, J., Ellenbogen, R., Zitterbart, K., Kren, L., Thompson, R., Cooper, M., Northcott, P., Shih, D., Peacock, J., Garzia, L., Sorana Morrissy, A., Zichner, T., Stútz, A., Korshunov, A., Reimand, J., Schumacher, S., Beroukhim, R., Ellison, D., Marshall, C., Lionel, A., MacK, S., Dubuc, A., Yao, Y., Ramaswamy, V., Luu, B., Rolider, A., Cavalli, F., Wang, X., Remke, M., Wu, X., Chiu, R., Chu, A., Chuah, E., Corbett, R., Hoad, G., Jackman, S., Li, Y., Lo, A., Mungall, K., Ming Nip, K., Qian, J., Raymond, A., Thiessen, N., Varhol, Richard, Birol, I., Moore, R., Mungall, A., Holt, R., Kawauchi, D., Roussel, M., Kool, M., Jones, D., Witt, H., Fernandez-L, A., Kenney, A., Wechsler-Reya, R., Dirks, P., Aviv, T., Grajkowska, W., Perek-Polnik, M., Haberler, C., Delattre, O., Reynaud, S., Doz, F., Pernet-Fattet, S., Cho, B., Kim, S., Wang, K., Scheurlen, W., Eberhart, C., Fèvre-Montange, M., Jouvet, A., Pollack, I., Fan, X., Muraszko, K., Yancey Gillespie, G., Di Rocco, C., Massimi, L., Michiels, E., Kloosterhof, N., French, P., Kros, J., Olson, J., Ellenbogen, R., Zitterbart, K., Kren, L., Thompson, R., and Cooper, M.

Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4a. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-ß signalling in Group 3, and NF-?B signalling in Group 4, suggest future avenues for rational, targeted therapy. © 2012 Macmillan Publishers Limited. All rights reserved.

Published
2012

40. The clonal and mutational evolution spectrum of primary triple-negative breast cancers

Author

Shah, S., Roth, A., Goya, R., Oloumi, A., Ha, G., Zhao, Y., Turashvili, G., Ding, J., Tse, K., Haffari, G., Bashashati, A., Prentice, L., Khattra, J., Burleigh, A., Yap, D., Bernard, V., McPherson, A., Shumansky, K., Crisan, A., Giuliany, R., Heravi-Moussavi, A., Rosner, J., Lai, D., Birol, I., Varhol, Richard, Tam, A., Dhalla, N., Zeng, T., Ma, K., Chan, S., Griffith, M., Moradian, A., Cheng, S., Morin, G., Watson, P., Gelmon, K., Chia, S., Chin, S., Curtis, C., Rueda, O., Pharoah, P., Damaraju, S., MacKey, J., Hoon, K., Harkins, T., Tadigotla, V., Sigaroudinia, M., Gascard, P., Tlsty, T., Costello, J., Meyer, I., Eaves, C., Wasserman, W., Jones, S., Huntsman, D., Hirst, M., Caldas, C., Marra, M., Aparicio, S., Shah, S., Roth, A., Goya, R., Oloumi, A., Ha, G., Zhao, Y., Turashvili, G., Ding, J., Tse, K., Haffari, G., Bashashati, A., Prentice, L., Khattra, J., Burleigh, A., Yap, D., Bernard, V., McPherson, A., Shumansky, K., Crisan, A., Giuliany, R., Heravi-Moussavi, A., Rosner, J., Lai, D., Birol, I., Varhol, Richard, Tam, A., Dhalla, N., Zeng, T., Ma, K., Chan, S., Griffith, M., Moradian, A., Cheng, S., Morin, G., Watson, P., Gelmon, K., Chia, S., Chin, S., Curtis, C., Rueda, O., Pharoah, P., Damaraju, S., MacKey, J., Hoon, K., Harkins, T., Tadigotla, V., Sigaroudinia, M., Gascard, P., Tlsty, T., Costello, J., Meyer, I., Eaves, C., Wasserman, W., Jones, S., Huntsman, D., Hirst, M., Caldas, C., Marra, M., and Aparicio, S.

Abstract

Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time-to our knowledge-in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes. © 2012 Macmillan Publishers Limited. All rights reserved.

Published
2012

41. Comprehensive molecular characterization of human colon and rectal cancer

Author

Muzny, D., Bainbridge, M., Chang, K., Dinh, H., Drummond, J., Fowler, G., Kovar, C., Lewis, L., Morgan, M., Newsham, I., Reid, J., Santibanez, J., Shinbrot, E., Trevino, L., Wu, Y., Wang, M., Gunaratne, P., Donehower, L., Creighton, C., Wheeler, D., Gibbs, R., Lawrence, M., Voet, D., Jing, R., Cibulskis, K., Sivachenko, A., Stojanov, P., McKenna, A., Lander, E., Gabriel, S., Ding, L., Fulton, R., Koboldt, D., Wylie, T., Walker, J., Dooling, D., Fulton, L., Delehaunty, K., Fronick, C., Demeter, R., Mardis, E., Wilson, R., Chu, A., Chun, H., Mungall, A., Pleasance, E., Gordon Robertson, A., Stoll, D., Balasundaram, M., Birol, I., Butterfield, Y., Chuah, E., Coope, R., Dhalla, N., Guin, R., Hirst, C., Hirst, M., Holt, R., Lee, D., Li, H., Mayo, M., Moore, R., Schein, J., Slobodan, J., Tam, A., Thiessen, N., Varhol, Richard, Zeng, T., Zhao, Y., Jones, S., Marra, M., Bass, A., Ramos, A., Saksena, G., Cherniack, A., Schumacher, S., Tabak, B., Carter, S., Pho, N., Nguyen, H., Onofrio, R., Crenshaw, A., Ardlie, K., Muzny, D., Bainbridge, M., Chang, K., Dinh, H., Drummond, J., Fowler, G., Kovar, C., Lewis, L., Morgan, M., Newsham, I., Reid, J., Santibanez, J., Shinbrot, E., Trevino, L., Wu, Y., Wang, M., Gunaratne, P., Donehower, L., Creighton, C., Wheeler, D., Gibbs, R., Lawrence, M., Voet, D., Jing, R., Cibulskis, K., Sivachenko, A., Stojanov, P., McKenna, A., Lander, E., Gabriel, S., Ding, L., Fulton, R., Koboldt, D., Wylie, T., Walker, J., Dooling, D., Fulton, L., Delehaunty, K., Fronick, C., Demeter, R., Mardis, E., Wilson, R., Chu, A., Chun, H., Mungall, A., Pleasance, E., Gordon Robertson, A., Stoll, D., Balasundaram, M., Birol, I., Butterfield, Y., Chuah, E., Coope, R., Dhalla, N., Guin, R., Hirst, C., Hirst, M., Holt, R., Lee, D., Li, H., Mayo, M., Moore, R., Schein, J., Slobodan, J., Tam, A., Thiessen, N., Varhol, Richard, Zeng, T., Zhao, Y., Jones, S., Marra, M., Bass, A., Ramos, A., Saksena, G., Cherniack, A., Schumacher, S., Tabak, B., Carter, S., Pho, N., Nguyen, H., Onofrio, R., Crenshaw, A., and Ardlie, K.

Abstract

To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase µ (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression. © 2012 Macmillan Publishers Limited. All rights reserved.

Published
2012

42. Comprehensive genomic characterization of squamous cell lung cancers

Author

Hammerman, P., Voet, D., Lawrence, M., Jing, R., Cibulskis, K., Sivachenko, A., Stojanov, P., McKenna, A., Lander, E., Gabriel, S., Getz, G., Imielinski, M., Helman, E., Hernandez, B., Pho, N., Meyerson, M., Chu, A., Hye-Chun, J., Mungall, A., Pleasance, E., Robertson, A., Sipahimalani, P., Stoll, D., Balasundaram, M., Birol, I., Butterfield, Y., Chuah, E., Coope, R., Corbett, R., Dhalla, N., Guin, R., He, A., Hirst, C., Hirst, M., Holt, R., Lee, D., Li, H., Mayo, M., Moore, R., Mungall, K., Nip, K., Olshen, A., Schein, J., Slobodan, J., Tam, A., Thiessen, N., Varhol, Richard, Zeng, T., Zhao, Y., Jones, S., Marra, M., Saksena, G., Cherniack, A., Schumacher, S., Tabak, B., Carter, S., Nguyen, H., Onofrio, R., Crenshaw, A., Ardlie, K., Beroukhim, R., Winckler, W., Protopopov, A., Zhang, J., Hadjipanayis, A., Lee, S., Xi, R., Yang, L., Ren, X., Zhang, H., Shukla, S., Chen, P., Haseley, P., Lee, E., Chin, L., Hammerman, P., Voet, D., Lawrence, M., Jing, R., Cibulskis, K., Sivachenko, A., Stojanov, P., McKenna, A., Lander, E., Gabriel, S., Getz, G., Imielinski, M., Helman, E., Hernandez, B., Pho, N., Meyerson, M., Chu, A., Hye-Chun, J., Mungall, A., Pleasance, E., Robertson, A., Sipahimalani, P., Stoll, D., Balasundaram, M., Birol, I., Butterfield, Y., Chuah, E., Coope, R., Corbett, R., Dhalla, N., Guin, R., He, A., Hirst, C., Hirst, M., Holt, R., Lee, D., Li, H., Mayo, M., Moore, R., Mungall, K., Nip, K., Olshen, A., Schein, J., Slobodan, J., Tam, A., Thiessen, N., Varhol, Richard, Zeng, T., Zhao, Y., Jones, S., Marra, M., Saksena, G., Cherniack, A., Schumacher, S., Tabak, B., Carter, S., Nguyen, H., Onofrio, R., Crenshaw, A., Ardlie, K., Beroukhim, R., Winckler, W., Protopopov, A., Zhang, J., Hadjipanayis, A., Lee, S., Xi, R., Yang, L., Ren, X., Zhang, H., Shukla, S., Chen, P., Haseley, P., Lee, E., and Chin, L.

Abstract

Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers. © 2012 Macmillan Publishers Limited. All rights reserved.

Published
2012

43. Assemblathon 1: A competitive assessment of de novo short read assembly methods

Author

Earl, D, Bradnam, K, St. John, J, Darling, A, Lin, D, Fass, J, Yu, HOK, Buffalo, V, Zerbino, DR, Diekhans, M, Nguyen, N, Ariyaratne, PN, Sung, WK, Ning, Z, Haimel, M, Simpson, JT, Fonseca, NA, Birol, I, Docking, TR, Ho, IY, Rokhsar, DS, Chikhi, R, Lavenier, D, Chapuis, G, Naquin, D, Maillet, N, Schatz, MC, Kelley, DR, Phillippy, AM, Koren, S, Yang, SP, Wu, W, Chou, WC, Srivastava, A, Shaw, TI, Ruby, JG, Skewes-Cox, P, Betegon, M, Dimon, MT, Solovyev, V, Seledtsov, I, Kosarev, P, Vorobyev, D, Ramirez-Gonzalez, R, Leggett, R, MacLean, D, Xia, F, Luo, R, Li, Z, Xie, Y, Liu, B, Gnerre, S, MacCallum, I, Przybylski, D, Ribeiro, FJ, Sharpe, T, Hall, G, Kersey, PJ, Durbin, R, Jackman, SD, Chapman, JA, Huang, X, DeRisi, JL, Caccamo, M, Li, Y, Jaffe, DB, Green, RE, Haussler, D, Korf, I, Paten, B, Earl, D, Bradnam, K, St. John, J, Darling, A, Lin, D, Fass, J, Yu, HOK, Buffalo, V, Zerbino, DR, Diekhans, M, Nguyen, N, Ariyaratne, PN, Sung, WK, Ning, Z, Haimel, M, Simpson, JT, Fonseca, NA, Birol, I, Docking, TR, Ho, IY, Rokhsar, DS, Chikhi, R, Lavenier, D, Chapuis, G, Naquin, D, Maillet, N, Schatz, MC, Kelley, DR, Phillippy, AM, Koren, S, Yang, SP, Wu, W, Chou, WC, Srivastava, A, Shaw, TI, Ruby, JG, Skewes-Cox, P, Betegon, M, Dimon, MT, Solovyev, V, Seledtsov, I, Kosarev, P, Vorobyev, D, Ramirez-Gonzalez, R, Leggett, R, MacLean, D, Xia, F, Luo, R, Li, Z, Xie, Y, Liu, B, Gnerre, S, MacCallum, I, Przybylski, D, Ribeiro, FJ, Sharpe, T, Hall, G, Kersey, PJ, Durbin, R, Jackman, SD, Chapman, JA, Huang, X, DeRisi, JL, Caccamo, M, Li, Y, Jaffe, DB, Green, RE, Haussler, D, Korf, I, and Paten, B

Abstract

Low-cost short read sequencing technology has revolutionized genomics, though it is only just becoming practical for the high-quality de novo assembly of a novel large genome. We describe the Assemblathon 1 competition, which aimed to comprehensively assess the state of the art in de novo assembly methods when applied to current sequencing technologies. In a collaborative effort, teams were asked to assemble a simulated Illumina HiSeq data set of an unknown, simulated diploid genome. A total of 41 assemblies from 17 different groups were received. Novel haplotype aware assessments of coverage, contiguity, structure, base calling, and copy number were made. We establish that within this benchmark: (1) It is possible to assemble the genome to a high level of coverage and accuracy, and that (2) large differences exist between the assemblies, suggesting room for further improvements in current methods. The simulated benchmark, including the correct answer, the assemblies, and the code that was used to evaluate the assemblies is now public and freely available from http://www.assemblathon.org/. © 2011 by Cold Spring Harbor Laboratory Press.

Published
2011

44. The Lung Microbiome In COPD

Author

Sze, M., Gosselink, J., McDonough, J., Elliott, M., Adam, S., Friedman, J., Zhao, Y., Varhol, Richard, Miller, D., He, A., Moore, R., Birol, I., Dimitriu, P., Mohn, W., Sin, D., Hayashi, S., Hogg, J., Sze, M., Gosselink, J., McDonough, J., Elliott, M., Adam, S., Friedman, J., Zhao, Y., Varhol, Richard, Miller, D., He, A., Moore, R., Birol, I., Dimitriu, P., Mohn, W., Sin, D., Hayashi, S., and Hogg, J.

Published
2011

45. Whole-genome sequencing and social-network analysis of a tuberculosis outbreak

Author

Gardy, J., Johnston, J., Ho Sui, S., Cook, V., Shah, L., Brodkin, E., Rempel, S., Moore, R., Zhao, Y., Holt, R., Varhol, Richard, Birol, I., Lem, M., Sharma, M., Elwood, K., Jones, S., Brinkman, F., Brunham, R., Tang, P., Gardy, J., Johnston, J., Ho Sui, S., Cook, V., Shah, L., Brodkin, E., Rempel, S., Moore, R., Zhao, Y., Holt, R., Varhol, Richard, Birol, I., Lem, M., Sharma, M., Elwood, K., Jones, S., Brinkman, F., Brunham, R., and Tang, P.

Abstract

Background: An outbreak of tuberculosis occurred over a 3-year period in a medium-size community in British Columbia, Canada. The results of mycobacterial interspersed repetitive unit-variable-number tandem-repeat (MIRU-VNTR) genotyping suggested the outbreak was clonal. Traditional contact tracing did not identify a source. We used whole-genome sequencing and social-network analysis in an effort to describe the outbreak dynamics at a higher resolution. Methods: We sequenced the complete genomes of 32 Mycobacterium tuberculosis outbreak isolates and 4 historical isolates (from the same region but sampled before the outbreak) with matching genotypes, using short-read sequencing. Epidemiologic and genomic data were overlaid on a social network constructed by means of interviews with patients to determine the origins and transmission dynamics of the outbreak. Results: Whole-genome data revealed two genetically distinct lineages of M. tuberculosis with identical MIRU-VNTR genotypes, suggesting two concomitant outbreaks. Integration of social-network and phylogenetic analyses revealed several transmission events, including those involving "superspreaders." Both lineages descended from a common ancestor and had been detected in the community before the outbreak, suggesting a social, rather than genetic, trigger. Further epidemiologic investigation revealed that the onset of the outbreak coincided with a recorded increase in crack cocaine use in the community. Conclusions: Through integration of large-scale bacterial whole-genome sequencing and social-network analysis, we show that a socioenvironmental factor - most likely increased crack cocaine use - triggered the simultaneous expansion of two extant lineages of M. tuberculosis that was sustained by key members of a high-risk social network. Genotyping and contact tracing alone did not capture the true dynamics of the outbreak. (Funded by Genome British Columbia and others.) Copyright © 2011 Massachusetts Medical Society

Published
2011

46. The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance

Author

Atanur, S.S., Birol, I., Guryev, V., Hirst, M., Hummel, O., Morrissey, C., Behmoaras, J., Fernandez-Suarez, X.M., Johnson, M.D., McLaren, W.M., Patone, G., Petretto, E., Plessy, C., Rockland, K.S., Rockland, C., Saar, K., Zhao, Y., Carninci, P., Flicek, P., Kurtz, T., Cuppen, E., Pravenec, M., Hubner, N., Jones, S., Birney, E., Aitman, T., Atanur, S.S., Birol, I., Guryev, V., Hirst, M., Hummel, O., Morrissey, C., Behmoaras, J., Fernandez-Suarez, X.M., Johnson, M.D., McLaren, W.M., Patone, G., Petretto, E., Plessy, C., Rockland, K.S., Rockland, C., Saar, K., Zhao, Y., Carninci, P., Flicek, P., Kurtz, T., Cuppen, E., Pravenec, M., Hubner, N., Jones, S., Birney, E., and Aitman, T.

Abstract

The spontaneously hypertensive rat (SHR) is the most widely studied animal model of hypertension. Scores of SHR quantitative loci (QTLs) have been mapped for hypertension and other phenotypes. We have sequenced the SHR/OlaIpcv genome at 10.7-fold coverage by paired-end sequencing on the Illumina platform. We identified 3.6 million high-quality single nucleotide polymorphisms (SNPs) between the SHR/OlaIpcv and Brown Norway (BN) reference genome, with a high rate of validation (sensitivity 96.3%-98.0% and specificity 99%-100%). We also identified 343,243 short indels between the SHR/OlaIpcv and reference genomes. These SNPs and indels resulted in 161 gain or loss of stop codons and 629 frameshifts compared with the BN reference sequence. We also identified 13,438 larger deletions that result in complete or partial absence of 107 genes in the SHR/OlaIpcv genome compared with the BN reference and 588 copy number variants (CNVs) that overlap with the gene regions of 688 genes. Genomic regions containing genes whose expression had been previously mapped as cis-regulated expression quantitative trait loci (eQTLs) were significantly enriched with SNPs, short indels, and larger deletions, suggesting that some of these variants have functional effects on gene expression. Genes that were affected by major alterations in their coding sequence were highly enriched for genes related to ion transport, transport, and plasma membrane localization, providing insights into the likely molecular and cellular basis of hypertension and other phenotypes specific to the SHR strain. This near complete catalog of genomic differences between two extensively studied rat strains provides the starting point for complete elucidation, at the molecular level, of the physiological and pathophysiological phenotypic differences between individuals from these strains., The spontaneously hypertensive rat (SHR) is the most widely studied animal model of hypertension. Scores of SHR quantitative loci (QTLs) have been mapped for hypertension and other phenotypes. We have sequenced the SHR/OlaIpcv genome at 10.7-fold coverage by paired-end sequencing on the Illumina platform. We identified 3.6 million high-quality single nucleotide polymorphisms (SNPs) between the SHR/OlaIpcv and Brown Norway (BN) reference genome, with a high rate of validation (sensitivity 96.3%-98.0% and specificity 99%-100%). We also identified 343,243 short indels between the SHR/OlaIpcv and reference genomes. These SNPs and indels resulted in 161 gain or loss of stop codons and 629 frameshifts compared with the BN reference sequence. We also identified 13,438 larger deletions that result in complete or partial absence of 107 genes in the SHR/OlaIpcv genome compared with the BN reference and 588 copy number variants (CNVs) that overlap with the gene regions of 688 genes. Genomic regions containing genes whose expression had been previously mapped as cis-regulated expression quantitative trait loci (eQTLs) were significantly enriched with SNPs, short indels, and larger deletions, suggesting that some of these variants have functional effects on gene expression. Genes that were affected by major alterations in their coding sequence were highly enriched for genes related to ion transport, transport, and plasma membrane localization, providing insights into the likely molecular and cellular basis of hypertension and other phenotypes specific to the SHR strain. This near complete catalog of genomic differences between two extensively studied rat strains provides the starting point for complete elucidation, at the molecular level, of the physiological and pathophysiological phenotypic differences between individuals from these strains.

Published
2010

47. De novo assembly and analysis of RNA-seq data

Author

Robertson, G., Schein, J., Chiu, R., Corbett, R., Field, M., Jackman, S., Mungall, K., Lee, S., Okada, H., Qian, J., Griffith, M., Raymond, A., Thiessen, N., Cezard, T., Butterfield, Y., Newsome, R., Chan, S., She, R., Varhol, Richard, Kamoh, B., Prabhu, A., Tam, A., Zhao, Y., Moore, R., Hirst, M., Marra, M., Jones, S., Hoodless, P., Birol, I., Robertson, G., Schein, J., Chiu, R., Corbett, R., Field, M., Jackman, S., Mungall, K., Lee, S., Okada, H., Qian, J., Griffith, M., Raymond, A., Thiessen, N., Cezard, T., Butterfield, Y., Newsome, R., Chan, S., She, R., Varhol, Richard, Kamoh, B., Prabhu, A., Tam, A., Zhao, Y., Moore, R., Hirst, M., Marra, M., Jones, S., Hoodless, P., and Birol, I.

Abstract

We describe Trans-ABySS, a de novo short-read transcriptome assembly and analysis pipeline that addresses variation in local read densities by assembling read substrings with varying stringencies and then merging the resulting contigs before analysis. Analyzing 7.4 gigabases of 50-base-pair paired-end Illumina reads from an adult mouse liver poly(A) RNA library, we identified known, new and alternative structures in expressed transcripts, and achieved high sensitivity and specificity relative to reference-based assembly methods. © 2010 Nature America, Inc. All rights reserved.

Published
2010

48. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin

Author

Morin, R., Johnson, N., Severson, T., Mungall, A., An, J., Goya, R., Paul, J., Boyle, M., Woolcock, B., Kuchenbauer, F., Yap, D., Humphries, R., Griffith, O., Shah, S., Zhu, H., Kimbara, M., Shashkin, P., Charlot, J., Tcherpakov, M., Corbett, R., Tam, A., Varhol, Richard, Smailus, D., Moksa, M., Zhao, Y., Delaney, A., Qian, H., Birol, I., Schein, J., Moore, R., Holt, R., Horsman, D., Connors, J., Jones, S., Aparicio, S., Hirst, M., Gascoyne, R., Marra, M., Morin, R., Johnson, N., Severson, T., Mungall, A., An, J., Goya, R., Paul, J., Boyle, M., Woolcock, B., Kuchenbauer, F., Yap, D., Humphries, R., Griffith, O., Shah, S., Zhu, H., Kimbara, M., Shashkin, P., Charlot, J., Tcherpakov, M., Corbett, R., Tam, A., Varhol, Richard, Smailus, D., Moksa, M., Zhao, Y., Delaney, A., Qian, H., Birol, I., Schein, J., Moore, R., Holt, R., Horsman, D., Connors, J., Jones, S., Aparicio, S., Hirst, M., Gascoyne, R., and Marra, M.

Abstract

Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B cells. Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-B pathway that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-specific mutations have been identified. Here we report recurrent somatic mutations affecting the polycomb-group oncogene EZH2, which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27). After the recent discovery of mutations in KDM6A (UTX), which encodes the histone H3K27me3 demethylase UTX, in several cancer types, EZH2 is the second histone methyltransferase gene found to be mutated in cancer. These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs. Our data are consistent with the notion that EZH2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro.

Published
2010

49. De novo transcriptome assembly with ABySS

Author

Birol, I., Jackman, S., Nielsen, C., Qian, J., Varhol, Richard, Stazyk, G., Morin, R., Zhao, Y., Hirst, M., Schein, J., Horsman, D., Connors, J., Gascoyne, R., Marra, M., Jones, S., Birol, I., Jackman, S., Nielsen, C., Qian, J., Varhol, Richard, Stazyk, G., Morin, R., Zhao, Y., Hirst, M., Schein, J., Horsman, D., Connors, J., Gascoyne, R., Marra, M., and Jones, S.

Abstract

Motivation: Whole transcriptome shotgun sequencing data from non-normalized samples offer unique opportunities to study the metabolic states of organisms. One can deduce gene expression levels using sequence coverage as a surrogate, identify coding changes or discover novel isoforms or transcripts. Especially for discovery of novel events, de novo assembly of transcriptomes is desirable. Results: Transcriptome from tumor tissue of a patient with follicular lymphoma was sequenced with 36 base pair (bp) single- and paired-end reads on the Illumina Genome Analyzer II platform. We assembled ~194 million reads using ABySS into 66 921 contigs 100 bp or longer, with a maximum contig length of 10 951 bp, representing over 30 million base pairs of unique transcriptome sequence, or roughly 1% of the genome. © The Author 2009. Published by Oxford University Press. All rights reserved.

Published
2009

50. A search for neutrino_muon -> neutrino_tau oscillation

Author

Eskut, E., Kayis, A., Onengüt, G., van Dantzig, R., de Jong, M., Konijn, J., Melzer, O., Oldeman, R. G. C., van der Poel, C. A. F. J., Uiterwijk, J. W. E., Visschers, J. L., Ayan, A. S., Pesen, E., Serin Zeyrek, M., Sever, R., Tolun, P., Zeyrek, M. T., Armenise, N., Cassol, F., Catanesi, M. G., Muciaccia, M. T., Radicioni, E., Simone, S., Vivolo, L., Bülte, A., Lendermann, P., Meyer Sievers, A., Patzak, T., Winter, K., Annis, P., Gruwé, M., Mommaert, C., Vander Donckt, M., van de Vyver, B., Vilain, P., Wilquet, G., Righini, P., Saitta, B., di Capua, E., Luppi, C., Zucchelli, P., Ishii, Y., Kawamura, T., Kazuno, M., Ogawa, S., Shibuya, H., Beyer, R., Brunner, J., Cussans, D., Fabre, J. P., Ferreira, R., Flegel, W., Gurin, R., Litmaath, M., Ludovici, L., Macina, D., Meijer Drees, R., Meinhard, H., Migliozzi, P., Niu, E., Øverasolars, H., Panman, J., Papadopoulos, I. M., Riccardi, F., Ricciardi, S., Rozanov, A., Saltzberg, D., Santacesaria, R., Stefanini, G., Tsenov, R., Weinheimer, C. h., Wong, H., Goldberg, J., Hoepfner, K., Chikawa, M., Arik, E., Birol, I., Mailov, A. A., Hahn, C. H., Jang, H. I., Park, I. G., Park, M. S., Song, J. S., Yoon, C. S., Kodama, K., Ushida, N., Aoki, S., Hara, T., Brooijmans, G., Favart, D., Grégoire, G., Hérin, J., Lemaître, V., Artamonov, A., Gorbunov, P., Khovansky, V., Shamanov, V., Smirnitsky, V., Bonekämper, D., Frekers, D., Rondeshagen, D., Wolff, T., Hoshino, K., Kobayashi, M., Kotaka, Y., Kozaki, T., Miyanishi, M., Nakamura, M., Nakazawa, K., Nakano, T., Niu, K., Niwa, K., Obayashi, Y., Sato, O., Toshito, T., Buontempo, S., Cocco, A., D'Ambrosio, N., de Lellis, G., Ereditato, A., Fiorillo, G., Garufi, F., Marchetti Stasi, F., Messina, M., Palladino, V., Sorrentino, S., Strolin, P., Nakamura, K., Okusawa, T., Yoshida, T., Capone, Antonio, de Pedis, D., di Liberto, S., Dore, Ubaldo, Loverre, Pier Ferruccio, Maslennikov, A., Mazzoni, M. A., Meddi, Franco, Piredda, G., di Bartolomeo, A., Bozza, C., Grella, G., Iovane, G., Romano, G., Rosa, Giovanni, Sato, Y., and Tezuka, I.

Published
1998

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