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1. The Cancer Genome Anatomy Project: EST Sequencing and the Genetics of Cancer Progression

Author

David B. Krizman, Lukas Wagner, Alex Lash, Robert L. Strausberg, and Michael R. Emmert-Buck

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

As the process of tumor progression proceeds from the normal cellular state to a preneoplastic condition and finally to the fully invasive form, the molecular characteristics of the cell change as well. These characteristics can be considered a molecular fingerprint of the cell at each stage of progression and, analogous to fingerprinting a criminal, can be used as markers of the progression process. Based on this premise, the Cancer Genome Anatomy Project was initiated with the broad goal of determining the comprehensive molecular characterization of normal, premalignant, and malignant tumor cells, thus making a reality the identification of all major cellular mechanisms leading to tumor initiation and progression ([Strausberg, R.L., Dahl, C.A., and Klausner, R.D. (1997). “New opportunities for uncovering the molecular basis of cancer.” Nat. Genet., 16: 415-516.], www.ncbi.nlm.nih.gov/ncicgap/). The expectation of determining the genetic fingerprints of cancer progression will allow for 1) correlation of disease progression with therapeutic outcome; 2) improved evaluation of disease treatment; 3) stimulation of novel approaches to prevention, detection, and therapy; and 4) enhanced diagnostic tools for clinical applications. Whereas acquiring the comprehensive molecular analysis of cancer progression may take years, results from initial, short-term goals are currently being realized and are proving very fruitful.

Published
1999
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2. Supplementary Figures 1-3, Tables 1-9, Methods from Genomic and Biological Characterization of Exon 4 KRAS Mutations in Human Cancer

Author

David B. Solit, Philip B. Paty, Adriana Heguy, Leonard B. Saltz, Marc Ladanyi, Alex Lash, John M. Mariadason, Suresh C. Jhanwar, James A. Fagin, Douglas A. Levine, Yogindra Persaud, Julio Cezar Ricarte Filho, Kety Huberman, Manda Wilson, Ensar Halilovic, Dhananjay Chitale, Barry S. Taylor, Christine A. Pratilas, Zhaoshi Zeng, Efsevia Vakiani, and Manickam Janakiraman

Abstract

Supplementary Figures 1-3, Tables 1-9, Methods from Genomic and Biological Characterization of Exon 4 KRAS Mutations in Human Cancer

Published
2023
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3. Data from Genomic and Biological Characterization of Exon 4 KRAS Mutations in Human Cancer

Author

David B. Solit, Philip B. Paty, Adriana Heguy, Leonard B. Saltz, Marc Ladanyi, Alex Lash, John M. Mariadason, Suresh C. Jhanwar, James A. Fagin, Douglas A. Levine, Yogindra Persaud, Julio Cezar Ricarte Filho, Kety Huberman, Manda Wilson, Ensar Halilovic, Dhananjay Chitale, Barry S. Taylor, Christine A. Pratilas, Zhaoshi Zeng, Efsevia Vakiani, and Manickam Janakiraman

Abstract

Mutations in RAS proteins occur widely in human cancer. Prompted by the confirmation of KRAS mutation as a predictive biomarker of response to epidermal growth factor receptor (EGFR)–targeted therapies, limited clinical testing for RAS pathway mutations has recently been adopted. We performed a multiplatform genomic analysis to characterize, in a nonbiased manner, the biological, biochemical, and prognostic significance of Ras pathway alterations in colorectal tumors and other solid tumor malignancies. Mutations in exon 4 of KRAS were found to occur commonly and to predict for a more favorable clinical outcome in patients with colorectal cancer. Exon 4 KRAS mutations, all of which were identified at amino acid residues K117 and A146, were associated with lower levels of GTP-bound RAS in isogenic models. These same mutations were also often accompanied by conversion to homozygosity and increased gene copy number, in human tumors and tumor cell lines. Models harboring exon 4 KRAS mutations exhibited mitogen-activated protein/extracellular signal-regulated kinase kinase dependence and resistance to EGFR-targeted agents. Our findings suggest that RAS mutation is not a binary variable in tumors, and that the diversity in mutant alleles and variability in gene copy number may also contribute to the heterogeneity of clinical outcomes observed in cancer patients. These results also provide a rationale for broader KRAS testing beyond the most common hotspot alleles in exons 2 and 3. Cancer Res; 70(14); 5901–11. ©2010 AACR.

Published
2023
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4. Simplifying research access to genomics and health data with Library Cards

Author

Anthony J. Brookes, Anne-Marie Tassé, Alex Lash, Giselle Kerry, Knox Carey, Marc Fiume, Dylan Spalding, Francis Jeanson, Susheel Varma, Heidi J. Sofia, Stephanie O.M. Dyke, Ravindra Nath Pandya, and Moran N. Cabili

Subjects
0301 basic medicine, Statistics and Probability, Library card, Computer science, Process (engineering), Comment, Volume (computing), Genomics, 030105 genetics & heredity, Library and Information Sciences, Data science, Computer Science Applications, Education, Health data, Research data, 03 medical and health sciences, Data access, Medical research, Authentication protocol, Statistics, Probability and Uncertainty, Information Systems, Fides
Abstract

The volume of genomics and health data is growing rapidly, driven by sequencing for both research and clinical use. However, under current practices, the data is fragmented into many distinct datasets, and researchers must go through a separate application process for each dataset. This is time-consuming both for the researchers and the data stewards, and it reduces the velocity of research and new discoveries that could improve human health. We propose to simplify this process, by introducing a standard Library Card that identifies and authenticates researchers across all participating datasets. Each researcher would only need to apply once to establish their bona fides as a qualified researcher, and could then use the Library Card to access a wide range of datasets that use a compatible data access policy and authentication protocol.

Published
2018

5. The Somatic Genomic Landscape of Glioblastoma

Author

Cameron W. Brennan, Roel G.W. Verhaak, Aaron McKenna, Benito Campos, Houtan Noushmehr, Sofie R. Salama, Siyuan Zheng, Debyani Chakravarty, J. Zachary Sanborn, Samuel H. Berman, Rameen Beroukhim, Brady Bernard, Chang-Jiun Wu, Giannicola Genovese, Ilya Shmulevich, Jill Barnholtz-Sloan, Lihua Zou, Rahulsimham Vegesna, Sachet A. Shukla, Giovanni Ciriello, W.K. Yung, Wei Zhang, Carrie Sougnez, Tom Mikkelsen, Kenneth Aldape, Darell D. Bigner, Erwin G. Van Meir, Michael Prados, Andrew Sloan, Keith L. Black, Jennifer Eschbacher, Gaetano Finocchiaro, William Friedman, David W. Andrews, Abhijit Guha, Mary Iacocca, Brian P. O’Neill, Greg Foltz, Jerome Myers, Daniel J. Weisenberger, Robert Penny, Raju Kucherlapati, Charles M. Perou, D. Neil Hayes, Richard Gibbs, Marco Marra, Gordon B. Mills, Eric Lander, Paul Spellman, Richard Wilson, Chris Sander, John Weinstein, Matthew Meyerson, Stacey Gabriel, Peter W. Laird, David Haussler, Gad Getz, Lynda Chin, Christopher Benz, Wendi Barrett, Quinn Ostrom, Yingli Wolinsky, Bikash Bose, Paul T. Boulos, Madgy Boulos, Jenn Brown, Christine Czerinski, Matthew Eppley, Thelma Kempista, Teresa Kitko, Yakov Koyfman, Brenda Rabeno, Pawan Rastogi, Michael Sugarman, Patricia Swanson, Kennedy Yalamanchii, Ilana P. Otey, Yingchun Spring Liu, Yonghong Xiao, J.Todd Auman, Peng-Chieh Chen, Angela Hadjipanayis, Eunjung Lee, Semin Lee, Peter J. Park, Jonathan Seidman, Lixing Yang, Steven Kalkanis, Laila M. Poisson, Aditya Raghunathan, Lisa Scarpace, Ryan Bressler, Andrea Eakin, Lisa Iype, Richard B. Kreisberg, Kalle Leinonen, Sheila Reynolds, Hector Rovira, Vesteinn Thorsson, Matti J. Annala, Joseph Paulauskis, Erin Curley, Martha Hatfield, David Mallery, Scott Morris, Troy Shelton, Candace Shelton, Mark Sherman, Peggy Yena, Lucia Cuppini, Francesco DiMeco, Marica Eoli, Emanuela Maderna, Bianca Pollo, Marco Saini, Saianand Balu, Katherine A. Hoadley, Ling Li, C. Ryan Miller, Yan Shi, Michael D. Topal, Junyuan Wu, Gavin Dunn, Caterina Giannini, Brian P. O'Neill, B. Arman Aksoy, Yevgeniy Antipin, Laetitia Borsu, Ethan Cerami, Jianjiong Gao, Benjamin Gross, Anders Jacobsen, Marc Ladanyi, Alex Lash, Yupu Liang, Boris Reva, Nikolaus Schultz, Ronglai Shen, Nicholas D. Socci, Agnes Viale, Martin L. Ferguson, Qing-Rong Chen, John A. Demchok, Laura A.L. Dillon, Kenna R. Mills Shaw, Margi Sheth, Roy Tarnuzzer, Zhining Wang, Liming Yang, Tanja Davidsen, Mark S. Guyer, Bradley A. Ozenberger, Heidi J. Sofia, Julie Bergsten, John Eckman, Jodi Harr, Christine Smith, Kelly Tucker, Cindy Winemiller, Leigh Anne Zach, Julia Y. Ljubimova, Greg Eley, Brenda Ayala, Mark A. Jensen, Ari Kahn, Todd D. Pihl, David A. Pot, Yunhu Wan, Nathan Hansen, Parvi Hothi, Biaoyang Lin, Nameeta Shah, Jae-geun Yoon, Ching Lau, Michael Berens, Kristin Ardlie, Scott L. Carter, Andrew D. Cherniack, Mike Noble, Juok Cho, Kristian Cibulskis, Daniel DiCara, Scott Frazer, Stacey B. Gabriel, Nils Gehlenborg, Jeff Gentry, David Heiman, Jaegil Kim, Rui Jing, Eric S. Lander, Michael Lawrence, Pei Lin, Will Mallard, Robert C. Onofrio, Gordon Saksena, Steve Schumacher, Petar Stojanov, Barbara Tabak, Doug Voet, Hailei Zhang, Nathan N. Dees, Li Ding, Lucinda L. Fulton, Robert S. Fulton, Krishna-Latha Kanchi, Elaine R. Mardis, Richard K. Wilson, Stephen B. Baylin, Larry Harshyne, Mark L. Cohen, Karen Devine, Andrew E. Sloan, Scott R. VandenBerg, Mitchel S. Berger, Daniel Carlin, Brian Craft, Kyle Ellrott, Mary Goldman, Theodore Goldstein, Mia Grifford, Singer Ma, Sam Ng, Joshua Stuart, Teresa Swatloski, Peter Waltman, Jing Zhu, Robin Foss, Barbara Frentzen, Raquel McTiernan, Anthony Yachnis, Yong Mao, Rehan Akbani, Oliver Bogler, Gregory N. Fuller, Wenbin Liu, Yuexin Liu, Yiling Lu, Gordon Mills, Alexei Protopopov, Xiaojia Ren, Youting Sun, W.K. Alfred Yung, Jianhua Zhang, Ken Chen, John N. Weinstein, Moiz S. Bootwalla, Phillip H. Lai, Timothy J. Triche, David J. Van Den Berg, David H. Gutmann, Norman L. Lehman, Erwin G. VanMeir, Daniel Brat, Jeffrey J. Olson, Gena M. Mastrogianakis, Narra S. Devi, Zhaobin Zhang, Darell Bigner, Eric Lipp, and Roger McLendon

Subjects
Male, Telomerase, Proteome, REGULAÇÃO GÊNICA, Somatic cell, Mesenchymal Glioblastoma, PDGFRA, Computational biology, Biology, medicine.disease_cause, Article, General Biochemistry, Genetics and Molecular Biology, medicine, Humans, Gene Regulatory Networks, Gene, Genetics, Glioblastoma cell, Mutation, Brain Neoplasms, Biochemistry, Genetics and Molecular Biology(all), Gene Expression Profiling, Phenotype, Gene expression profiling, DNA methylation, Cancer research, Female, Glioblastoma, Signal Transduction
Abstract

SummaryWe describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

Published
2013
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6. Natural Language Processing Applications in Requirements Engineering

Author

Kevin Raymond Murray, Alex Lash, and Gregory M. Mocko

Subjects
Requirements management, Requirement, Non-functional requirement, Requirements engineering, Requirements traceability, business.industry, Computer science, Requirements elicitation, computer.software_genre, Artificial intelligence, business, computer, Requirements analysis, Natural language processing, Natural language
Abstract

In the design process, the requirements serve as the benchmark for the entire product. Therefore, the quality of requirement statements is essential to the success of a design. Because of their ergonomic-nature, most requirements are written in natural language (NL). However, writing requirements in natural language presents many issues such as ambiguity, specification issues, and incompleteness. Therefore, identifying issues in requirements involves analyzing these NL statements. This paper presents a linguistic approach to requirement analysis, which utilizes grammatical elements of requirements statements to identify requirement statement issues. These issues are organized by the entity—word, sentence, or document—that they affect. The field of natural language processing (NLP) provides a core set of tools that can aid with this linguistic analysis and provide a method to create a requirement analysis support tool. NLP addresses requirements on processing levels: lexical, syntactic, semantic, and pragmatic. While processing on the lexical and syntactic level are well-defined, mining semantic and pragmatic data is performed in a number of different methods. This paper provides an overview of these current requirement analysis methods in light of the presented linguistic approach. This overview will be used to identify areas for further research and development. Finally, a prototype requirement analysis support tool will be presented. This tool seeks to demonstrate how the semantic processing level can begin to be addressed in requirement analysis. The tool will analyze a sample set of requirements from a family of military tactical vehicles (FMTV) requirements document. It implements NLP tools to semantically compare requirements statements based upon their grammatical subject.Copyright © 2012 by ASME

Published
2012
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7. FlyGEM, a full transcriptome array platform for the Drosophila community

Author

Rick, Johnston, Bruce, Wang, Rachel, Nuttall, Michael, Doctolero, Pamela, Edwards, Jining, Lü, Marina, Vainer, Huibin, Yue, Xinhao, Wang, James, Minor, Cathy, Chan, Alex, Lash, Thomas, Goralski, Michael, Parisi, Brian, Oliver, and Scott, Eastman

Subjects
DNA, Complementary, Genome, Gene Expression Profiling, Nucleic Acid Hybridization, Reproducibility of Results, Method, Genes, Insect, DNA, Exons, Blotting, Northern, Drosophila melanogaster, Animals, RNA, DNA Probes, DNA Primers, Fluorescent Dyes, Oligonucleotide Array Sequence Analysis
Abstract

An array, FlyGEM, has been constructed based on amplification of exons from Drosophila genomic DNA. The array gene list has been extensively annotated and linked to other databases., We have constructed a DNA microarray to monitor expression of predicted genes in Drosophila. By using homotypic hybridizations, we show that the array performs reproducibly, that dye effects are minimal, and that array results agree with systematic northern blotting. The array gene list has been extensively annotated and linked-out to other databases. Incyte and the NIH have made the platform available to the community via academic microarray facilities selected by an NIH committee.

Published
2003

8. Molecular profiling of clinical tissues specimens: feasibility and applications

Author

Emmert-Buck, M. R., Strausberg, R. L., Krizman, D. B., Bonaldo, M. F., Bonner, R. F., Bostwick, D. G., Brown, M. R., Buetow, K. H., Chuaqui, R. F., Cole, K. A., Duray, P. H., Englert, C. R., Gillespie, J. W., Greenhut, S., Grouse, L., Hillier, L. W., Katz, K. S., Klausner, R. D., Kuznetzov, V., Alex Lash, Lennon, G., Linehan, W. M., Liotta, L. A., Marra, M. A., Munson, P. J., Ornstein, D. K., Prabhu, V. V., Prang, C., Schuler, G. D., Soares, M. B., Tolstoshev, C. M., Vocke, C. D., and Waterston, R. H.

Subjects
Male, Special Article, Pathology, Clinical, Databases, Factual, Gene Expression Profiling, Gene Expression, Humans, Prostatic Neoplasms, Polymorphism, Single Nucleotide, Gene Library, Oligonucleotide Array Sequence Analysis
Published
2001

15. Molecular profiling of clinical tissue specimens: Feasibility and applications

Author

Emmert-Buck, M. R., Strausberg, R. L., Krizman, D. B., Bonaldo, M. F., Bonner, R. F., Bostwick, D. G., Brown, M. R., Buetow, K. H., Chuaqui, R. F., Cole, K. A., Duray, P. H., Englert, C. R., Gillespie, J. W., Greenhut, S., Grouse, L., Hillier, L. W., Katz, K. S., Klausner, R. D., Kuznetzov, V., Alex Lash, Lennon, G., Linehan, W. M., Liotta, L. A., Marra, M. A., Munson, P. J., Omstein, D. K., Prabhu, V. V., Prange, C., Schuler, G. D., Soares, M. B., Tolstoshev, C. M., Vocke, C. D., and Waterston, R. H.

Subjects
Male, Special Article, DNA, Complementary, Genome, Polymorphism, Genetic, Databases as Topic, Genes, Genetic Techniques, Feasibility Studies, Gene Expression, Humans, Prostatic Neoplasms

17. A public database for gene expression in human cancers

Author

Lal, A., Alex Lash, Altschul, S. F., Velculescu, V., Zhang, L., Mclendon, R. E., Marra, M. A., Prange, C., Morin, P. J., Polyak, K., Papadopoulos, N., Vogelstein, B., Kinzler, K. W., Strausberg, R. L., and Riggins, G. J.

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