16 results on '"O'Neill, Keith"'
Search Results
2. Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain.
- Author
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Lee, Jeffrey C, Vivanco, Igor, Beroukhim, Rameen, Huang, Julie H Y, Feng, Whei L, Debiasi, Ralph M, Yoshimoto, Koji, King, Jennifer C, Nghiemphu, Phioanh, Yuza, Yuki, Xu, Qing, Greulich, Heidi, Thomas, Roman K, Paez, J Guillermo, Peck, Timothy C, Linhart, David J, Glatt, Karen A, Getz, Gad, Onofrio, Robert, Ziaugra, Liuda, Levine, Ross L, Gabriel, Stacey, Kawaguchi, Tomohiro, O'neill, Keith, Khan, Haumith, Liau, Linda M, Nelson, Stanley F, Rao, P Nagesh, Mischel, Paul, Pieper, Russell O, Cloughesy, Tim, Leahy, Daniel J, Sellers, William R, Sawyers, Charles L, Meyerson, Matthew, and Mellinghoff, Ingo K
- Abstract
BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.
- Published
- 2006
3. Strain Characteristics of Streptococcus pneumoniae Carriage and Invasive Disease Isolates during a Cluster-Randomized Clinical Trial of the 7-Valent Pneumococcal Conjugate Vaccine
- Author
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Lipsitch, Marc, O'Neill, Keith, Cordy, Derrick, Bugalter, Boris, Trzcinski, Krzysztof, Thompson, Claudette M., Goldstein, Richard, Pelton, Stephen, Huot, Heather, Bouchet, Valerie, Reid, Raymond, Santosham, Mathuram, and O'Brien, Katherine L.
- Published
- 2007
- Full Text
- View/download PDF
4. Sensitive mutation detection in heterogeneous cancer specimens by massively parallel picoliter reactor sequencing
- Author
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Thomas, Roman K, Nickerson, Elizabeth, Simons, Jan F, Janne, Pasi A, Tengs, Torstein, Yuza, Yuki, Garraway, Levi A, LaFramboise, Thomas, Lee, Jeffrey C, Shah, Kinjal, O'Neill, Keith, Sasaki, Hidefumi, Lindeman, Neal, Wong, Kwok-Kin, Borras, Ana M, Gutmann, Edward J, Dragnev, Konstantin H, DeBiasi, Ralph, Chen, Tzu-Hsiu, Glatt, Karen A, Greulich, Heidi, Desany, Brian, Lubeski, Christine K, Brockman, William, Alvarez, Pablo, Hutchison, Stephen K, Leamon, J H, Ronan, Michael T, Turenchalk, Gregory S, Egholm, Michael, Sellers, William R, Rothberg, Jonathan M, and Meyerson, Matthew
- Abstract
The sensitivity of conventional DNA sequencing in tumor biopsies is limited by stromal contamination and by genetic heterogeneity within the cancer. Here, we show that microreactor-based pyrosequencing can detect rare cancer-associated sequence variations by independent and parallel sampling of multiple representatives of a given DNA fragment. This technology can thereby facilitate accurate molecular diagnosis of heterogeneous cancer specimens and enable patient selection for targeted cancer therapies. NOTE:: In the version of this article initially published, it should have been acknowledged that Jan F. Simons, in addition to Roman K. Thomas and Elizabeth Nickerson, contributed equally to this work. The error has been corrected in the HTML and PDF versions of the article., Author(s): Roman K Thomas [1, 2, 12]; Elizabeth Nickerson [3, 12]; Jan F Simons [3, 11, 12]; Pasi A Janne [1]; Torstein Tengs [1, 2]; Yuki Yuza [1]; Levi A [...]
- Published
- 2006
- Full Text
- View/download PDF
5. Analysis of the DNA sequence and duplication history of human chromosome 15
- Author
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Zody, Michael C., Garber, Manuel, Sharpe, Ted, Young, Sarah K., Rowen, Lee, O'Neill, Keith, Whittaker, Charles A., Kamal, Michael, Chang, Jean L., Cuomo, Christina A., Dewar, Ken, FitzGerald, Michael G., Kodira, Chinnappa D., Madan, Anup, Qin, Shizhen, Yang, Xiaoping, Abbasi, Nissa, Abouelleil, Amr, Arachchi, Harindra M., Baradarani, Lida, Birditt, Brian, Bloom, Scott, Bloom, Toby, Borowsky, Mark L., Burke, Jeremy, Butler, Jonathan, Cook, April, DeArellano, Kurt, DeCaprio, David, Dorris, III, Lester, Dors, Monica, Eichler, Evan E., Engels, Reinhard, Fahey, Jessica, Fleetwood, Peter, Friedman, Cynthia, Gearin, Gary, Hall, Jennifer L., Hensley, Grace, Johnson, Ericka, Jones, Charlien, Kamat, Asha, Kaur, Amardeep, Locke, Devin P., Madan, Anuradha, Munson, Glen, Jaffe, David B., Lui, Annie, Macdonald, Pendexter, Mauceli, Evan, Naylor, Jerome W., Nesbitt, Ryan, Nicol, Robert, O'Leary, Sinead B., Ratcliffe, Amber, Rounsley, Steven, She, Xinwei, Sneddon, Katherine M. B., Stewart, Sandra, Sougnez, Carrie, Stone, Sabrina M., Topham, Kerri, Vincent, Dascena, Wang, Shunguang, Zimmer, Andrew R., Birren, Bruce W., Hood, Leroy, Lander, Eric S., and Nusbaum, Chad
- Subjects
Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Michael C. Zody (corresponding author) [1]; Manuel Garber [1]; Ted Sharpe [1]; Sarah K. Young [1]; Lee Rowen [2]; Keith O'Neill [1]; Charles A. Whittaker [1, 6]; Michael Kamal [...]
- Published
- 2006
- Full Text
- View/download PDF
6. DNA sequence and analysis of human chromosome 8
- Author
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Nusbaum, Chad, Mikkelsen, Tarjei S., Zody, Michael C., Asakawa, Shuichi, Taudien, Stefan, Garber, Manuel, Kodira, Chinnappa D., Schueler, Mary G., Shimizu, Atsushi, Whittaker, Charles A., Chang, Jean L., Cuomo, Christina A., Dewar, Ken, FitzGerald, Michael G., Yang, Xiaoping, Allen, Nicole R., Anderson, Scott, Asakawa, Teruyo, Blechschmidt, Karin, Bloom, Toby, Borowsky, Mark L., Butler, Jonathan, Cook, April, Corum, Benjamin, DeArellano, Kurt, DeCaprio, David, Dooley, Kathleen T., Dorris, III, Lester, Engels, Reinhard, Glockner, Gernot, Hafez, Nabil, Hagopian, Daniel S., Hall, Jennifer L., Ishikawa, Sabine K., Jaffe, David B., Kamat, Asha, Kudoh, Jun, Lehmann, Rudiger, Lokitsang, Tashi, Macdonald, Pendexter, Major, John E., Matthews, Charles D., Mauceli, Evan, Menzel, Uwe, Mihalev, Atanas H., Minoshima, Shinsei, Murayama, Yuji, Naylor, Jerome W., Nicol, Robert, Nguyen, Cindy, O'Leary, Sinead B., O'Neill, Keith, Parker, Stephen C. J., Polley, Andreas, Raymond, Christina K., Reichwald, Kathrin, Rodriguez, Joseph, Sasaki, Takashi, Schilhabel, Markus, Siddiqui, Roman, Smith, Cherylyn L., Sneddon, Tam P., Talamas, Jessica A., Tenzin, Pema, Topham, Kerri, Venkataraman, Vijay, Wen, Gaiping, Yamazaki, Satoru, Young, Sarah K., Zeng, Qiandong, Zimmer, Andrew R., Rosenthal, Andre, Birren, Bruce W., Platzer, Matthias, Shimizu, Nobuyoshi, and Lander, Eric S.
- Subjects
Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Chad Nusbaum (corresponding author) [1]; Tarjei S. Mikkelsen [1]; Michael C. Zody [1]; Shuichi Asakawa [2]; Stefan Taudien [3]; Manuel Garber [1]; Chinnappa D. Kodira [1]; Mary G. Schueler [...]
- Published
- 2006
- Full Text
- View/download PDF
7. Genome sequence, comparative analysis and haplotype structure of the domestic dog
- Author
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Lindblad-Toh, Kerstin, Wade, Claire M., Mikkelsen, Tarjei S., Karlsson, Elinor K., Jaffe, David B., Kamal, Michael, Clamp, Michele, Chang, Jean L., Kulbokas, III, Edward J., Zody, Michael C., Mauceli, Evan, Xie, Xiaohui, Breen, Matthew, Wayne, Robert K., Ostrander, Elaine A., Ponting, Chris P., Galibert, Francis, Smith, Douglas R., deJong, Pieter J., Kirkness, Ewen, Alvarez, Pablo, Biagi, Tara, Brockman, William, Butler, Jonathan, Chin, Chee-Wye, Cook, April, Cuff, James, Daly, Mark J., DeCaprio, David, Gnerre, Sante, Grabherr, Manfred, Kellis, Manolis, Kleber, Michael, Bardeleben, Carolyne, Goodstadt, Leo, Heger, Andreas, Hitte, Christophe, Kim, Lisa, Koepfli, Klaus-Peter, Parker, Heidi G., Pollinger, John P., Searle, Stephen M. J., Sutter, Nathan B., Thomas, Rachael, Webber, Caleb, Baldwin, Jennifer, Abebe, Adal, Abouelleil, Amr, Aftuck, Lynne, Ait-zahra, Mostafa, Aldredge, Tyler, Allen, Nicole, An, Peter, Anderson, Scott, Antoine, Claudel, Arachchi, Harindra, Aslam, Ali, Ayotte, Laura, Bachantsang, Pasang, Barry, Andrew, Bayul, Tashi, Benamara, Mostafa, Berlin, Aaron, Bessette, Daniel, Blitshteyn, Berta, Bloom, Toby, Blye, Jason, Boguslavskiy, Leonid, Bonnet, Claude, Boukhgalter, Boris, Brown, Adam, Cahill, Patrick, Calixte, Nadia, Camarata, Jody, Cheshatsang, Yama, Chu, Jeffrey, Citroen, Mieke, Collymore, Alville, Cooke, Patrick, Dawoe, Tenzin, Daza, Riza, Decktor, Karin, DeGray, Stuart, Dhargay, Norbu, Dooley, Kimberly, Dooley, Kathleen, Dorje, Passang, Dorjee, Kunsang, Dorris, Lester, Duffey, Noah, Dupes, Alan, Egbiremolen, Osebhajajeme, Elong, Richard, Falk, Jill, Farina, Abderrahim, Faro, Susan, Ferguson, Diallo, Ferreira, Patricia, Fisher, Sheila, FitzGerald, Mike, Foley, Karen, Foley, Chelsea, Franke, Alicia, Friedrich, Dennis, Gage, Diane, Garber, Manuel, Gearin, Gary, Giannoukos, Georgia, Goode, Tina, Goyette, Audra, Graham, Joseph, Grandbois, Edward, Gyaltsen, Kunsang, Hafez, Nabil, Hagopian, Daniel, Hagos, Birhane, Hall, Jennifer, Healy, Claire, Hegarty, Ryan, Honan, Tracey, Horn, Andrea, Houde, Nathan, Hughes, Leanne, Hunnicutt, Leigh, Husby, M., Jester, Benjamin, Jones, Charlien, Kamat, Asha, Kanga, Ben, Kells, Cristyn, Khazanovich, Dmitry, Kieu, Alix Chinh, Kisner, Peter, Kumar, Mayank, Lance, Krista, Landers, Thomas, Lara, Marcia, Lee, William, Leger, Jean-Pierre, Lennon, Niall, Leuper, Lisa, LeVine, Sarah, Liu, Jinlei, Liu, Xiaohong, Lokyitsang, Yeshi, Lokyitsang, Tashi, Lui, Annie, Macdonald, Jan, Major, John, Marabella, Richard, Maru, Kebede, Matthews, Charles, McDonough, Susan, Mehta, Teena, Meldrim, James, Melnikov, Alexandre, Meneus, Louis, Mihalev, Atanas, Mihova, Tanya, Miller, Karen, Mittelman, Rachel, Mlenga, Valentine, Mulrain, Leonidas, Munson, Glen, Navidi, Adam, Naylor, Jerome, Nguyen, Tuyen, Nguyen, Nga, Nguyen, Cindy, Nguyen, Thu, Nicol, Robert, Norbu, Nyima, Norbu, Choe, Novod, Nathaniel, Nyima, Tenchoe, Olandt, Peter, O'Neill, Barry, O'Neill, Keith, Osman, Sahal, Oyono, Lucien, Patti, Christopher, Perrin, Danielle, Phunkhang, Pema, Pierre, Fritz, Priest, Margaret, Rachupka, Anthony, Raghuraman, Sujaa, Rameau, Rayale, Ray, Verneda, Raymond, Christina, Rege, Filip, Rise, Cecil, Rogers, Julie, Rogov, Peter, Sahalie, Julie, Settipalli, Sampath, Sharpe, Theodore, Shea, Terrance, Sheehan, Mechele, Sherpa, Ngawang, Shi, Jianying, Shih, Diana, Sloan, Jessie, Smith, Cherylyn, Sparrow, Todd, Stalker, John, Stange-Thomann, Nicole, Stavropoulos, Sharon, Stone, Catherine, Stone, Sabrina, Sykes, Sean, Tchuinga, Pierre, Tenzing, Pema, Tesfaye, Senait, Thoulutsang, Dawa, Thoulutsang, Yama, Topham, Kerri, Topping, Ira, Tsamla, Tsamla, Vassiliev, Helen, Venkataraman, Vijay, Vo, Andy, Wangchuk, Tsering, Wangdi, Tsering, Weiand, Michael, Wilkinson, Jane, Wilson, Adam, Yadav, Shailendra, Yang, Shuli, Yang, Xiaoping, Young, Geneva, Yu, Qing, Zainoun, Joanne, Zembek, Lisa, Zimmer, Andrew, and Lander, Eric S.
- Subjects
Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Kerstin Lindblad-Toh (corresponding author) [1]; Claire M Wade [1, 2]; Tarjei S. Mikkelsen [1, 3]; Elinor K. Karlsson [1, 4]; David B. Jaffe [1]; Michael Kamal [1]; Michele Clamp [...]
- Published
- 2005
- Full Text
- View/download PDF
8. The ner gene of Photorhabdus: effects on primary-form-specific phenotypes and outer membrane protein composition
- Author
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O'Neill, Keith H., Roche, Declan M., Clarke, David J., and Dowds, Barbara C.A.
- Subjects
Symbiosis -- Genetic aspects ,Nematoda -- Genetic aspects ,Cell cycle -- Physiological aspects ,Phenotype -- Analysis ,Biological sciences - Abstract
Results reveal that the endogenous ner gene is not involved in the secondary phenotype switching but inactivation of the primary form ner affects outer membrane protein profile in Photorhabdus. Data show accumulation of outer membrane proteins in the stationary phase.
- Published
- 2002
9. Genome sequence and analysis of the Irish potato famine pathogen Phytophthora infestans
- Author
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Haas, Brian J., Kamoun, Sophien, Zody, Michael C., Jiang, Rays H. Y., Handsaker, Robert E., Cano, Liliana M., Grabherr, Manfred, Kodira, Chinnappa D., Raffaele, Sylvain, Torto-Alalibo, Trudy, Bozkurt, Tolga O., Ah-Fong, Audrey M. V., Alvarado, Lucia, Anderson, Vicky L., Armstrong, Miles R., Avrova, Anna, Baxter, Laura, Beynon, Jim, Boevink, Petra C., Bollmann, Stephanie R., Bos, Jorunn I. B., Bulone, Vincent, Cai, Guohong, Cakir, Cahid, Carrington, James C., Chawner, Megan, Conti, Lucio, Costanzo, Stefano, Ewan, Richard, Fahlgren, Noah, Fischbach, Michael A., Fugelstad, Johanna, Gilroy, Eleanor M., Gnerre, Sante, Green, Pamela J., Grenville-Briggs, Laura J., Griffith, John, Grünwald, Niklaus J., Horn, Karolyn, Horner, Neil R., Hu, Chia-Hui, Huitema, Edgar, Jeong, Dong-Hoon, Jones, Alexandra M. E., Jones, Jonathan D. G., Jones, Richard W., Karlsson, Elinor K., Kunjeti, Sridhara G., Lamour, Kurt, Liu, Zhenyu, Ma, LiJun, MacLean, Daniel, Chibucos, Marcus C., McDonald, Hayes, McWalters, Jessica, Meijer, Harold J. G., Morgan, William, Morris, Paul F., Munro, Carol A., O’Neill, Keith, Ospina-Giraldo, Manuel, Pinzón, Andrés, Pritchard, Leighton, Ramsahoye, Bernard, Ren, Qinghu, Restrepo, Silvia, Roy, Sourav, Sadanandom, Ari, Savidor, Alon, Schornack, Sebastian, Schwartz, David C., Schumann, Ulrike D., Schwessinger, Ben, Seyer, Lauren, Sharpe, Ted, Silvar, Cristina, Song, Jing, Studholme, David J., Sykes, Sean, Thines, Marco, van de Vondervoort, Peter J. I., Phuntumart, Vipaporn, Wawra, Stephan, Weide, Rob, Win, Joe, Young, Carolyn, Zhou, Shiguo, Fry, William, Meyers, Blake C., van West, Pieter, Ristaino, Jean, Govers, Francine, Birch, Paul R. J., Whisson, Stephen C., Judelson, Howard S., and Nusbaum, Chad
- Published
- 2009
- Full Text
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10. Genomic representations using concatenates of Type IIB restriction endonuclease digestion fragments
- Author
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Tengs, Torstein, LaFramboise, Thomas, Den, Robert B., Hayes, David N., Zhang, Jianhua, DebRoy, Saikat, Gentleman, Robert C., O'Neill, Keith, Birren, Bruce, and Meyerson, Matthew
- Published
- 2004
11. Corrigendum: DNA sequence and analysis of human chromosome 18
- Author
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Nusbaum, Chad, Zody, Michael C., Borowsky, Mark L., Kamal, Michael, Kodira, Chinnappa D., Taylor, Todd D., Whittaker, Charles A., Chang, Jean L., Cuomo, Christina A., Dewar, Ken, FitzGerald, Michael G., Yang, Xiaoping, Abouelleil, Amr, Allen, Nicole R., Anderson, Scott, Bloom, Toby, Bugalter, Boris, Butler, Jonathan, Cook, April, DeCaprio, David, Engels, Reinhard, Garber, Manuel, Gnirke, Andreas, Hafez, Nabil, Hall, Jennifer L., Norman, Catherine Hosage, Itoh, Takehiko, Jaffe, David B., Kuroki, Yoko, Lehoczky, Jessica, Lui, Annie, Macdonald, Pendexter, Mauceli, Evan, Mikkelsen, Tarjei S., Naylor, Jerome W., Nicol, Robert, Nguyen, Cindy, Noguchi, Hideki, O'Leary, Sinead B., O'Neill, Keith, Piqani, Bruno, Smith, Cherylyn L., Talamas, Jessica A., Topham, Kerri, Totoki, Yasushi, Toyoda, Atsushi, Wain, Hester M., Young, Sarah K., Zeng, Qiandong, Zimmer, Andrew R., Fujiyama, Asao, Hattori, Masahira, Birren, Bruce W., Sakaki, Yoshiyuki, and Lander, Eric S.
- Subjects
Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Chad Nusbaum; Michael C. Zody; Mark L. Borowsky; Michael Kamal; Chinnappa D. Kodira; Todd D. Taylor; Charles A. Whittaker; Jean L. Chang; Christina A. Cuomo; Ken Dewar; Michael G. [...]
- Published
- 2005
- Full Text
- View/download PDF
12. TOPO TA is A-OK: a test of phylogenetic bias in fungal environmental clone library construction.
- Author
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Taylor, D. Lee, Herriott, Ian C., Long, James, and O'Neill, Keith
- Subjects
CLONING ,DNA ,DEOXYRIBOSE ,PHYLOGENY ,BIOLOGY - Abstract
TA cloning methods are widely used in analyses of environmental microbial diversity, yet the potential of TA methods to yield phylogenetically biased results has received little attention. To test for a TA bias, we constructed clone libraries of fungal amplicons spanning the ribosomal internally transcribed spacer (ITS) and partial large subunit (LSU) from 92 boreal forest soil DNA extracts using two contrasting methods: the Invitrogen TOPO-TA system and the Lucigen PCR-SMART system. The Lucigen system utilizes blunt-ended rather than TA cloning and transcription terminators to reduce biases due to toxicity of expressed inserts. We analysed 588 clone sequences from the two libraries. Species diversity estimators applied to operational taxonomical units (OTUs) were slightly higher for Invitrogen than Lucigen, but confidence intervals for accumulation curves overlapped. Abundances of OTUs were correlated between the libraries ( r
2 = 0.5, P < 0.0001), but certain OTUs had contrasting abundances in the two libraries and a likelihood ratio test rejected homogeneity of the OTU counts. We constructed parsimony and Bayesian trees from aligned LSU regions, and the ‘phylogenetic test’ revealed that lineage representation was not significantly different between the two libraries. We conclude that characterization of this fungal community was fairly robust to cloning method and no biases due to TA cloning were found. [ABSTRACT FROM AUTHOR]- Published
- 2007
- Full Text
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13. A “Perfect Standard?” Exploring Perceptions of Student Life and Culture at Wheaton College.
- Author
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Cumings, Kevin D., Haworth, Jennifer Grant, and O'Neill, Keith
- Published
- 2001
- Full Text
- View/download PDF
14. Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain
- Author
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Vivanco, Igor, Feng, Whei L, Yoshimoto, Koji, King, Jennifer C, Nghiemphu, Phioanh, Yuza, Yuki, Xu, Qing, Thomas, Roman K, Peck, Timothy C, Linhart, David J, Glatt, Karen A, Getz, Gad, Onofrio, Robert, Ziaugra, Liuda, Levine, Ross L, Gabriel, Stacey, Kawaguchi, Tomohiro, O'Neill, Keith, Khan, Haumith, Liau, Linda M, Nelson, Stanley F, Rao, P. Nagesh, Mischel, Paul, Pieper, Russell O, Cloughesy, Tim, Leahy, Daniel J, Sellers, William R, Sawyers, Charles L, Mellinghoff, Ingo K, Lee, Jeffrey C., Beroukhim, Rameen, Huang, Julie, DeBiasi, Ralph Michael, Greulich, Heidi E., Paez, J. Guillermo, and Meyerson, Matthew Langer
- Subjects
genetics and genomics ,oncology - Abstract
Background: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. Methods and Findings: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/ 8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. Conclusions: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.
- Published
- 2006
- Full Text
- View/download PDF
15. Assembly of polymorphic genomes: Algorithms and application to Ciona savignyi.
- Author
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Vinson, Jade P., Jaffe, David B., O'Neill, Keith, Karlsson, Elinor K., Stange-Thomann, Nicole, Anderson, Scott, Mesirov, Jill P., Satoh, Nori, Satou, Yutaka, Nusbaum, Chad, Birren, Bruce, Galagan, James E., and Lander, Eric S.
- Subjects
- *
CIONA savignyi , *GENOMES , *GENETIC polymorphisms , *POPULATION genetics , *GENOMICS , *ALGORITHMS - Abstract
Whole-genome assembly is now used routinely to obtain high-quality draft sequence for the genomes of species with low levels of polymorphism. However, genome assembly remains extremely challenging for highly polymorphic species. The difficulty arises because two divergent haplotypes are sequenced together, making it difficult to distinguish alleles at the same locus from paralogs at different loci. We present here a method for assembling highly polymorphic diploid genomes that involves assembling the two haplotypes separately and then merging them to obtain a reference sequence. Our method was developed to assemble the genome of the sea squirt Ciona savignyi, which was sequenced to a depth of 12.7× from a single wild individual. By comparing finished clones of the two haplotypes we determined that the sequenced individual had an extremely high heterozygosity rate, averaging 4.6% with significant regional variation and rearrangements at all physical scales. Applied to these data, our method produced a reference assembly covering 157 Mb, with N50 contig and scaffold sizes of 47 kb and 989 kb, respectively. Alignment of ESTs indicates that 88% of loci are present at least once and 81% exactly once in the reference assembly. Our method represented loci in a single copy more reliably and achieved greater contiguity than a conventional whole-genome assembly method. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
16. DNA sequence and analysis of human chromosome 18.
- Author
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Nusbaum C, Zody MC, Borowsky ML, Kamal M, Kodira CD, Taylor TD, Whittaker CA, Chang JL, Cuomo CA, Dewar K, FitzGerald MG, Yang X, Abouelleil A, Allen NR, Anderson S, Bloom T, Bugalter B, Butler J, Cook A, DeCaprio D, Engels R, Garber M, Gnirke A, Hafez N, Hall JL, Norman CH, Itoh T, Jaffe DB, Kuroki Y, Lehoczky J, Lui A, Macdonald P, Mauceli E, Mikkelsen TS, Naylor JW, Nicol R, Nguyen C, Noguchi H, O'Leary SB, O'Neill K, Piqani B, Smith CL, Talamas JA, Topham K, Totoki Y, Toyoda A, Wain HM, Young SK, Zeng Q, Zimmer AR, Fujiyama A, Hattori M, Birren BW, Sakaki Y, and Lander ES
- Subjects
- Aneuploidy, Animals, Conserved Sequence genetics, CpG Islands genetics, Exons genetics, Expressed Sequence Tags, Genes genetics, Genome, Human, Humans, Introns genetics, Molecular Sequence Data, Sequence Analysis, DNA, Synteny, Chromosomes, Human, Pair 18 genetics, DNA genetics
- Abstract
Chromosome 18 appears to have the lowest gene density of any human chromosome and is one of only three chromosomes for which trisomic individuals survive to term. There are also a number of genetic disorders stemming from chromosome 18 trisomy and aneuploidy. Here we report the finished sequence and gene annotation of human chromosome 18, which will allow a better understanding of the normal and disease biology of this chromosome. Despite the low density of protein-coding genes on chromosome 18, we find that the proportion of non-protein-coding sequences evolutionarily conserved among mammals is close to the genome-wide average. Extending this analysis to the entire human genome, we find that the density of conserved non-protein-coding sequences is largely uncorrelated with gene density. This has important implications for the nature and roles of non-protein-coding sequence elements.
- Published
- 2005
- Full Text
- View/download PDF
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