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739 results on '"Shah, Sohrab P"'

205. Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer

Author

McPherson, Andrew, primary, Roth, Andrew, additional, Laks, Emma, additional, Masud, Tehmina, additional, Bashashati, Ali, additional, Zhang, Allen W, additional, Ha, Gavin, additional, Biele, Justina, additional, Yap, Damian, additional, Wan, Adrian, additional, Prentice, Leah M, additional, Khattra, Jaswinder, additional, Smith, Maia A, additional, Nielsen, Cydney B, additional, Mullaly, Sarah C, additional, Kalloger, Steve, additional, Karnezis, Anthony, additional, Shumansky, Karey, additional, Siu, Celia, additional, Rosner, Jamie, additional, Chan, Hector Li, additional, Ho, Julie, additional, Melnyk, Nataliya, additional, Senz, Janine, additional, Yang, Winnie, additional, Moore, Richard, additional, Mungall, Andrew J, additional, Marra, Marco A, additional, Bouchard-Côté, Alexandre, additional, Gilks, C Blake, additional, Huntsman, David G, additional, McAlpine, Jessica N, additional, Aparicio, Samuel, additional, and Shah, Sohrab P, additional

Published
2016
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208. Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer

Author

Clermont, Pier-Luc, primary, Crea, Francesco, additional, Chiang, Yan Ting, additional, Lin, Dong, additional, Zhang, Amy, additional, Wang, James Z. L., additional, Parolia, Abhijit, additional, Wu, Rebecca, additional, Xue, Hui, additional, Wang, Yuwei, additional, Ding, Jiarui, additional, Thu, Kelsie L., additional, Lam, Wan L., additional, Shah, Sohrab P., additional, Collins, Colin C., additional, Wang, Yuzhuo, additional, and Helgason, Cheryl D., additional

Published
2016
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209. Spatial genomic heterogeneity within localized, multifocal prostate cancer

Author

Boutros, Paul C., Boutros, Paul C., Fraser, Michael, Harding, Nicholas J., de Borja, Richard, Trudel, Dominique, Lalonde, Emilie, Meng, Alice, Hennings-Yeomans, Pablo H., McPherson, Andrew, Sabelnykova, Veronica Y., Zia, Amin, Fox, Natalie S., Livingstone, Julie, Shiah, Yu-Jia, Wang, Jianxin, Beck, Timothy A., Have, Cherry L., Chong, Taryne, Sam, Michelle, Johns, Jeremy, Timms, Lee, Buchner, Nicholas, Wong, Ada, Watson, John D., Simmons, Trent T., P'ng, Christine, Zafarana, Gaetano, Nguyen, Francis, Luo, Xuemei, Chu, Kenneth C., Prokopec, Stephenie D., Sykes, Jenna, Dal Pra, Alan, Berlin, Alejandro, Brown, Andrew, Chan-Seng-Yue, Michelle A., Yousif, Fouad, Denroche, Robert E., Chong, Lauren C., Chen, Gregory M., Jung, Esther, Fung, Clement, Starmans, Maud H. W., Chen, Hanbo, Govind, Shaylan K., Hawley, James, D'Costa, Alister, Pintilie, Melania, Waggott, Daryl, Hach, Faraz, Lambin, Philippe, Muthuswamy, Lakshmi B., Cooper, Colin, Eeles, Rosalind, Neal, David, Tetu, Bernard, Sahinalp, Cenk, Stein, Lincoln D., Fleshner, Neil, Shah, Sohrab P., Collins, Colin C., Hudson, Thomas J., McPherson, John D., van der Kwast, Theodorus, Bristow, Robert G., Boutros, Paul C., Boutros, Paul C., Fraser, Michael, Harding, Nicholas J., de Borja, Richard, Trudel, Dominique, Lalonde, Emilie, Meng, Alice, Hennings-Yeomans, Pablo H., McPherson, Andrew, Sabelnykova, Veronica Y., Zia, Amin, Fox, Natalie S., Livingstone, Julie, Shiah, Yu-Jia, Wang, Jianxin, Beck, Timothy A., Have, Cherry L., Chong, Taryne, Sam, Michelle, Johns, Jeremy, Timms, Lee, Buchner, Nicholas, Wong, Ada, Watson, John D., Simmons, Trent T., P'ng, Christine, Zafarana, Gaetano, Nguyen, Francis, Luo, Xuemei, Chu, Kenneth C., Prokopec, Stephenie D., Sykes, Jenna, Dal Pra, Alan, Berlin, Alejandro, Brown, Andrew, Chan-Seng-Yue, Michelle A., Yousif, Fouad, Denroche, Robert E., Chong, Lauren C., Chen, Gregory M., Jung, Esther, Fung, Clement, Starmans, Maud H. W., Chen, Hanbo, Govind, Shaylan K., Hawley, James, D'Costa, Alister, Pintilie, Melania, Waggott, Daryl, Hach, Faraz, Lambin, Philippe, Muthuswamy, Lakshmi B., Cooper, Colin, Eeles, Rosalind, Neal, David, Tetu, Bernard, Sahinalp, Cenk, Stein, Lincoln D., Fleshner, Neil, Shah, Sohrab P., Collins, Colin C., Hudson, Thomas J., McPherson, John D., van der Kwast, Theodorus, and Bristow, Robert G.

Abstract

Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

Published
2015

210. Interpretable dimensionality reduction of single cell transcriptome data with deep generative models.

Author

Jiarui Ding, Condon, Anne, and Shah, Sohrab P.

Subjects
DATA structures, GENE expression, STATISTICAL models, CELLS
Abstract

Single-cell RNA-sequencing has great potential to discover cell types, identify cell states, trace development lineages, and reconstruct the spatial organization of cells. However, dimension reduction to interpret structure in single-cell sequencing data remains a challenge. Existing algorithms are either not able to uncover the clustering structures in the data or lose global information such as groups of clusters that are close to each other. We present a robust statistical model, scvis, to capture and visualize the low-dimensional structures in single-cell gene expression data. Simulation results demonstrate that low-dimensional representations learned by scvis preserve both the local and global neighbor structures in the data. In addition, scvis is robust to the number of data points and learns a probabilistic parametric mapping function to add new data points to an existing embedding. We then use scvis to analyze four single-cell RNA-sequencing datasets, exemplifying interpretable twodimensional representations of the high-dimensional single-cell RNA-sequencing data. [ABSTRACT FROM AUTHOR]

Published
2018
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211. Large-scale clinicogenomic models of solid tumor CNS metastasis.

Author

Jee, Justin, Luthra, Anisha, Fong, Christopher, Pichotta, Karl, Tran, Thinh, Altoe, Mirella, Miller, Alex, Shen, Ronglai, Berger, Michael F., Sanchez-Vega, Francisco, Maron, Steven Brad, Safonov, Anton, Kehl, Kenneth L., Reis-Filho, Jorge S., Schrag, Deborah, Shah, Sohrab P, Razavi, Pedram, Li, Bob T., Riely, Gregory J., and Schultz, Nikolaus

Published
2023
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212. Identification of Recurrent Non-Coding Driver Mutations in Non-Hodgkin Lymphomas through Integrative Genomic Analysis of 777 Patients

Author

Jiang, Aixiang, Grande, Bruno M., Arthur, Sarah E, Alcaide, Miguel, Ennishi, Daisuke, Jessa, Selin, Pararajalingam, Prasath, Meissner, Barbara, Boyle, Merrill, Chong, Lauren, Lai, Daniel, Davidson, Jordan, Mottok, Anja, Bushell, Kevin R, Sehn, Laurie H., Farinha, Pedro, Shah, Sohrab P, Mungall, Andrew J., Gascoyne, Randy D., Marra, Marco A, Steidl, Christian, Connors, Joseph M, Scott, David W., and Morin, Ryan D.

Published
2017
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213. Genetic Characterization and Clinical Impact of Loss of MHC Class I and II Expression in De Novo Diffuse Large B-Cell Lymphoma

Author

Ennishi, Daisuke, Mottok, Anja, Farinha, Pedro, Chan, Fong Chun, Bashashati, Ali, Saberi, Saeed, Meissner, Barbara, Boyle, Merrill, Ben-Neriah, Susana, Kridel, Robert, Savage, Kerry J, Sehn, Laurie H., Morin, Ryan D., Marra, Marco A, Shah, Sohrab P, Connors, Joseph M, Gascoyne, Randy D., Scott, David W., and Steidl, Christian

Published
2017
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214. Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer

Author

Murtaza, Muhammed, primary, Dawson, Sarah-Jane, additional, Pogrebniak, Katherine, additional, Rueda, Oscar M., additional, Provenzano, Elena, additional, Grant, John, additional, Chin, Suet-Feung, additional, Tsui, Dana W. Y., additional, Marass, Francesco, additional, Gale, Davina, additional, Ali, H. Raza, additional, Shah, Pankti, additional, Contente-Cuomo, Tania, additional, Farahani, Hossein, additional, Shumansky, Karey, additional, Kingsbury, Zoya, additional, Humphray, Sean, additional, Bentley, David, additional, Shah, Sohrab P., additional, Wallis, Matthew, additional, Rosenfeld, Nitzan, additional, and Caldas, Carlos, additional

Published
2015
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215. The genomic landscape of epithelioid sarcoma cell lines and tumours

Author

Jamshidi, Farzad, primary, Bashashati, Ali, additional, Shumansky, Karey, additional, Dickson, Brendan, additional, Gokgoz, Nalan, additional, Wunder, Jay S, additional, Andrulis, Irene L, additional, Lazar, Alexander J, additional, Shah, Sohrab P, additional, Huntsman, David G, additional, and Nielsen, Torsten O, additional

Published
2015
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216. Systematic analysis of somatic mutations impacting gene expression in 12 tumour types

Author

Ding, Jiarui, primary, McConechy, Melissa K., additional, Horlings, Hugo M., additional, Ha, Gavin, additional, Chun Chan, Fong, additional, Funnell, Tyler, additional, Mullaly, Sarah C., additional, Reimand, Jüri, additional, Bashashati, Ali, additional, Bader, Gary D., additional, Huntsman, David, additional, Aparicio, Samuel, additional, Condon, Anne, additional, and Shah, Sohrab P., additional

Published
2015
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217. Abstract AS18: The somatic mutational landscape of endometriosis associated ovarian cancers and precursor lesions

Author

Anglesio, Michael S, primary, Bashashati, Ali, additional, Wang, Yikan, additional, Ha, Gavin, additional, Senz, Janine, additional, Yang, Winnie, additional, Kalloger, Steve E, additional, Prentice, Leah M, additional, Yanagida, Satoshi, additional, Salamanca, Clara, additional, Soukhatcheva, Galina, additional, Kazernis, Anthony, additional, Chang, Hector, additional, Mes-Mason, Anne-Marie, additional, Okamoto, Aikou, additional, Marra, Marco A, additional, Gilks, Blake, additional, Shah, Sohrab P, additional, and Huntsman, David G, additional

Published
2015
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218. Abstract POSTER-BIOL-1327: Small cell carcinoma of the ovary, hypercalcemic type displays frequent inactivating germline and somatic mutations in SMARCA4

Author

Ramos, Pilar, primary, Karnezis, Anthony N., additional, Craig, David W., additional, Sekulic, Aleksandar, additional, Russell, Megan L., additional, Hendricks, William P.D., additional, Corneveaux, Jason J., additional, Barrett, Michael T., additional, Shumansky, Karey, additional, Yang, Yidong, additional, Shah, Sohrab P., additional, Prentice, Leah M., additional, Marra, Marco A., additional, Kiefer, Jeffrey, additional, Zismann, Victoria L., additional, McEachron, Troy A., additional, Salhia, Bodour, additional, Prat, Jaime, additional, Clarke, Blaise A., additional, Pressey, Joseph G., additional, Farley, John H., additional, Anthony, Stephen P., additional, Roden, Richard B.S., additional, Cunliffe, Heather E., additional, Huntsman, David G., additional, and Trent, Jeffrey M., additional

Published
2015
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219. Synchronous Endometrial and Ovarian Carcinomas: Evidence of Clonality

Author

Anglesio, Michael S., primary, Wang, Yi Kan, additional, Maassen, Madlen, additional, Horlings, Hugo M., additional, Bashashati, Ali, additional, Senz, Janine, additional, Mackenzie, Robertson, additional, Grewal, Diljot S., additional, Li-Chang, Hector, additional, Karnezis, Anthony N., additional, Sheffield, Brandon S., additional, McConechy, Melissa K., additional, Kommoss, Friedrich, additional, Taran, Florin A., additional, Staebler, Annette, additional, Shah, Sohrab P., additional, Wallwiener, Diethelm, additional, Brucker, Sara, additional, Gilks, C. Blake, additional, Kommoss, Stefan, additional, and Huntsman, David G., additional

Published
2015
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221. Spatial genomic heterogeneity within localized, multifocal prostate cancer

Author

Boutros, Paul C, primary, Fraser, Michael, additional, Harding, Nicholas J, additional, de Borja, Richard, additional, Trudel, Dominique, additional, Lalonde, Emilie, additional, Meng, Alice, additional, Hennings-Yeomans, Pablo H, additional, McPherson, Andrew, additional, Sabelnykova, Veronica Y, additional, Zia, Amin, additional, Fox, Natalie S, additional, Livingstone, Julie, additional, Shiah, Yu-Jia, additional, Wang, Jianxin, additional, Beck, Timothy A, additional, Have, Cherry L, additional, Chong, Taryne, additional, Sam, Michelle, additional, Johns, Jeremy, additional, Timms, Lee, additional, Buchner, Nicholas, additional, Wong, Ada, additional, Watson, John D, additional, Simmons, Trent T, additional, P'ng, Christine, additional, Zafarana, Gaetano, additional, Nguyen, Francis, additional, Luo, Xuemei, additional, Chu, Kenneth C, additional, Prokopec, Stephenie D, additional, Sykes, Jenna, additional, Dal Pra, Alan, additional, Berlin, Alejandro, additional, Brown, Andrew, additional, Chan-Seng-Yue, Michelle A, additional, Yousif, Fouad, additional, Denroche, Robert E, additional, Chong, Lauren C, additional, Chen, Gregory M, additional, Jung, Esther, additional, Fung, Clement, additional, Starmans, Maud H W, additional, Chen, Hanbo, additional, Govind, Shaylan K, additional, Hawley, James, additional, D'Costa, Alister, additional, Pintilie, Melania, additional, Waggott, Daryl, additional, Hach, Faraz, additional, Lambin, Philippe, additional, Muthuswamy, Lakshmi B, additional, Cooper, Colin, additional, Eeles, Rosalind, additional, Neal, David, additional, Tetu, Bernard, additional, Sahinalp, Cenk, additional, Stein, Lincoln D, additional, Fleshner, Neil, additional, Shah, Sohrab P, additional, Collins, Colin C, additional, Hudson, Thomas J, additional, McPherson, John D, additional, van der Kwast, Theodorus, additional, and Bristow, Robert G, additional

Published
2015
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223. Hereditary Diffuse Gastric Cancer Syndrome

Author

Hansford, Samantha, primary, Kaurah, Pardeep, additional, Li-Chang, Hector, additional, Woo, Michelle, additional, Senz, Janine, additional, Pinheiro, Hugo, additional, Schrader, Kasmintan A., additional, Schaeffer, David F., additional, Shumansky, Karey, additional, Zogopoulos, George, additional, Santos, Teresa Almeida, additional, Claro, Isabel, additional, Carvalho, Joana, additional, Nielsen, Cydney, additional, Padilla, Sarah, additional, Lum, Amy, additional, Talhouk, Aline, additional, Baker-Lange, Katie, additional, Richardson, Sue, additional, Lewis, Ivy, additional, Lindor, Noralane M., additional, Pennell, Erin, additional, MacMillan, Andree, additional, Fernandez, Bridget, additional, Keller, Gisella, additional, Lynch, Henry, additional, Shah, Sohrab P., additional, Guilford, Parry, additional, Gallinger, Steven, additional, Corso, Giovanni, additional, Roviello, Franco, additional, Caldas, Carlos, additional, Oliveira, Carla, additional, Pharoah, Paul D. P., additional, and Huntsman, David G., additional

Published
2015
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224. Recurrent genomic rearrangements in primary testicular lymphoma

Author

Twa, David DW, primary, Mottok, Anja, additional, Chan, Fong Chun, additional, Ben‐Neriah, Susana, additional, Woolcock, Bruce W, additional, Tan, King L, additional, Mungall, Andrew J, additional, McDonald, Helen, additional, Zhao, Yongjun, additional, Lim, Raymond S, additional, Nelson, Brad H, additional, Milne, Katy, additional, Shah, Sohrab P, additional, Morin, Ryan D, additional, Marra, Marco A, additional, Scott, David W, additional, Gascoyne, Randy D, additional, and Steidl, Christian, additional

Published
2015
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225. Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden

Author

Anglesio, Michael S, primary, Bashashati, Ali, additional, Wang, Yi Kan, additional, Senz, Janine, additional, Ha, Gavin, additional, Yang, Winnie, additional, Aniba, Mohamed R, additional, Prentice, Leah M, additional, Farahani, Hossein, additional, Li Chang, Hector, additional, Karnezis, Anthony N, additional, Marra, Marco A, additional, Yong, Paul J, additional, Hirst, Martin, additional, Gilks, Blake, additional, Shah, Sohrab P, additional, and Huntsman, David G, additional

Published
2015
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226. An RCOR1 loss–associated gene expression signature identifies a prognostically significant DLBCL subgroup

Author

Chan, Fong Chun, primary, Telenius, Adele, additional, Healy, Shannon, additional, Ben-Neriah, Susana, additional, Mottok, Anja, additional, Lim, Raymond, additional, Drake, Marie, additional, Hu, Sandy, additional, Ding, Jiarui, additional, Ha, Gavin, additional, Scott, David W., additional, Kridel, Robert, additional, Bashashati, Ali, additional, Rogic, Sanja, additional, Johnson, Nathalie, additional, Morin, Ryan D., additional, Rimsza, Lisa M., additional, Sehn, Laurie, additional, Connors, Joseph M., additional, Marra, Marco A., additional, Gascoyne, Randy D., additional, Shah, Sohrab P., additional, and Steidl, Christian, additional

Published
2015
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227. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4.

Author

Ramos, Pilar, Ramos, Pilar, Karnezis, Anthony N, Craig, David W, Sekulic, Aleksandar, Russell, Megan L, Hendricks, William PD, Corneveaux, Jason J, Barrett, Michael T, Shumansky, Karey, Yang, Yidong, Shah, Sohrab P, Prentice, Leah M, Marra, Marco A, Kiefer, Jeffrey, Zismann, Victoria L, McEachron, Troy A, Salhia, Bodour, Prat, Jaime, D'Angelo, Emanuela, Clarke, Blaise A, Pressey, Joseph G, Farley, John H, Anthony, Stephen P, Roden, Richard BS, Cunliffe, Heather E, Huntsman, David G, Trent, Jeffrey M, Ramos, Pilar, Ramos, Pilar, Karnezis, Anthony N, Craig, David W, Sekulic, Aleksandar, Russell, Megan L, Hendricks, William PD, Corneveaux, Jason J, Barrett, Michael T, Shumansky, Karey, Yang, Yidong, Shah, Sohrab P, Prentice, Leah M, Marra, Marco A, Kiefer, Jeffrey, Zismann, Victoria L, McEachron, Troy A, Salhia, Bodour, Prat, Jaime, D'Angelo, Emanuela, Clarke, Blaise A, Pressey, Joseph G, Farley, John H, Anthony, Stephen P, Roden, Richard BS, Cunliffe, Heather E, Huntsman, David G, and Trent, Jeffrey M

Abstract

Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT cases in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors but in only 0.4% (2/485) of other primary ovarian tumors. These data implicate SMARCA4 in SCCOHT oncogenesis.

Published
2014

229. Model based approaches to array CGH data analysis

Author

Shah, Sohrab P.

Abstract

DNA copy number alterations (CNAs) are genetic changes that can produce adverse effects in numerous human diseases, including cancer. CNAs are segments of DNA that have been deleted or amplified and can range in size from one kilobases to whole chromosome arms. Development of array comparative genomic hybridization (aCGH) technology enables CNAs to be measured at sub-megabase resolution using tens of thousands of probes. However, aCGH data are noisy and result in continuous valued measurements of the discrete CNAs. Consequently, the data must be processed through algorithmic and statistical techniques in order to derive meaningful biological insights. We introduce model-based approaches to analysis of aCGH data and develop state-of-the-art solutions to three distinct analytical problems. In the simplest scenario, the task is to infer CNAs from a single aCGH experiment. We apply a hidden Markov model (HMM) to accurately identify CNAs from aCGH data. We show that borrowing statistical strength across chromosomes and explicitly modeling outliers in the data, improves on baseline models. In the second scenario, we wish to identify recurrent CNAs in a set of aCGH data derived from a patient cohort. These are locations in the genome altered in many patients, providing evidence for CNAs that may be playing important molecular roles in the disease. We develop a novel hierarchical HMM profiling method that explicitly models both statistical and biological noise in the data and is capable of producing a representative profile for a set of aCGH experiments. We demonstrate that our method is more accurate than simpler baselines on synthetic data, and show our model produces output that is more interpretable than other methods. Finally, we develop a model based clustering framework to stratify a patient cohort, expected to be composed of a fixed set of molecular subtypes. We introduce a model that jointly infers CNAs, assigns patients to subgroups and infers the profiles that represent each subgroup. We show our model to be more accurate on synthetic data, and show in two patient cohorts how the model discovers putative novel subtypes and clinically relevant subgroups.

Published
2008
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230. Prognostic Model to Predict Post-Autologous Stem-Cell Transplantation Outcomes in Classical Hodgkin Lymphoma.

Author

Fong Chun Chan, Mottok, Anja, Gerrie, Alina S., Power, Maryse, Nijland, Marcel, Diepstra, Arjan, van den Berg, Anke, Kamper, Peter, d'Amore, Francesco, d'Amore, Alexander Lindholm, Hamilton-Dutoit, Stephen, Savage, Kerry J., Shah, Sohrab P., Connors, Joseph M., Gascoyne, Randy D., Scott, David W., Steidl, Christian, and Chan, Fong Chun

Published
2017
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231. Kronos: a workflow assembler for genome analytics and informatics.

Author

Taghiyar, M. Jafar, Rosner, Jamie, Grewal, Diljot, Grande, Bruno M., Aniba, Radhouane, Grewal, Jasleen, Boutros, Paul C., Morin, Ryan D., Bashashati, Ali, and Shah, Sohrab P.

Subjects
BIOINFORMATICS, NUCLEOTIDE sequencing
Abstract

Background: The field of next-generation sequencing informatics has matured to a point where algorithmic advances in sequence alignment and individual feature detection methods have stabilized. Practical and robust implementation of complex analytical workflows (where such tools are structured into "best practices" for automated analysis of next-generation sequencing datasets) still requires significant programming investment and expertise. Results: We present Kronos, a software platform for facilitating the development and execution of modular, auditable, and distributable bioinformatics workflows. Kronos obviates the need for explicit coding of workflows by compiling a text configuration file into executable Python applications. Making analysis modules would still require programming. The framework of each workflow includes a run manager to execute the encoded workflows locally (or on a cluster or cloud), parallelize tasks, and log all runtime events. The resulting workflows are highly modular and configurable by construction, facilitating flexible and extensible meta-applications that can be modified easily through configuration file editing. The workflows are fully encoded for ease of distribution and can be instantiated on external systems, a step toward reproducible research and comparative analyses. We introduce a framework for building Kronos components that function as shareable, modular nodes in Kronos workflows. Conclusions: The Kronos platform provides a standard framework for developers to implement custom tools, reuse existing tools, and contribute to the community at large. Kronos is shipped with both Docker and Amazon Web Services Machine Images. It is free, open source, and available through the Python Package Index and at https://github.com/jtaghiyar/kronos. [ABSTRACT FROM AUTHOR]

Published
2017
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232. Enhancing knowledge discovery from cancer genomics data with Galaxy.

Author

Albuquerque, Marco A., Grande, Bruno M., Ritch, Elie J., Pararajalingam, Prasath, Jessa, Selin, Krzywinski, Martin, Grewal, Jasleen K., Shah, Sohrab P., Boutros, Paul C., and Morin, Ryan D.

Subjects
CANCER genetics, GENE expression
Abstract

The field of cancer genomics has demonstrated the power of massively parallel sequencing techniques to inform on the genes and specific alterations that drive tumor onset and progression. Although large comprehensive sequence data sets continue to be made increasingly available, data analysis remains an ongoing challenge, particularly for laboratories lacking dedicated resources and bioinformatics expertise. To address this, we have produced a collection of Galaxy tools that represent many popular algorithms for detecting somatic genetic alterations from cancer genome and exome data. We developed new methods for parallelization of these tools within Galaxy to accelerate runtime and have demonstrated their usability and summarized their runtimes on multiple cloud service providers. Some tools represent extensions or refinement of existing toolkits to yield visualizations suited to cohort-wide cancer genomic analysis. For example, we present Oncocircos and Oncoprintplus, which generate data-rich summaries of exome-derived somatic mutation. Workflows that integrate these to achieve data integration and visualizations are demonstrated on a cohort of 96 diffuse large B-cell lymphomas and enabled the discovery of multiple candidate lymphoma-related genes. Our toolkit is available from our GitHub repository as Galaxy tool and dependency definitions and has been deployed using virtualization on multiple platforms including Docker. [ABSTRACT FROM AUTHOR]

Published
2017
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233. Detecting common secondary structure elements in RNA sequences

Author

Shah, Sohrab P

Abstract

As evidence for the important and diverse roles of RNA molecules in our cellular machinery continues to grow, there is an increasing interest in developing computational methods to analyse RNA sequences. Sets of evolutionarily related RNA sequences contain signals at both the sequence and secondary structure levels that can be exploited to detect motifs common to all or a portion of those sequences. Motifs conserved in evolution are believed to be functionally important and therefore detection of such motifs could yield novel functional RNA sequences. We developed an algorithm called DISCO to detect conserved motifs in a set of unaligned RNA sequences. Our algorithm uses a powerful probabilistic formalism called covariance models (CM) to model motifs. We introduce a novel approach to initialise a CM using pairwise and multiple sequence alignment. The CM is then iteratively refined using expectation maximisation. Our initialisation method can operate on sequence signals alone using only a portion of the input sequences to initialise a CM to recover the remaining motif instances. We tested our algorithm on 26 data sets derived from Rfam seed alignments of microRNA (miRNA) precursors and conserved elements in the untranslated regions of mRNAs (UTR elements). By three measures of specificity and positive predictive value, our algorithm performed well on the miRNA data sets and showed a bi-modal distribution for the UTR element data sets where the motif was completely missed, or very accurately predicted. In a comparison test with a competing algorithm, DISCO outperformed RNAProfile in measures of sensitivity and positive predictive value, although the running time of RNAProfile was considerably faster. The accuracy of our algorithm was unaffected by average percent pairwise sequence identity, overall length or number of sequences in the input data, indicating that DISCO could be run with similar accuracy on diverse data sets. The running time of DISCO is 0(W³ + L²W² + L³) where W is the width of the motif and L is the length of the longest sequence in the input data. This is an improvement on SLASH, the only other RNA motif finding algorithm in the literature that uses CMs.

Published
2005
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234. Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution

Author

Eirew, Peter, primary, Steif, Adi, additional, Khattra, Jaswinder, additional, Ha, Gavin, additional, Yap, Damian, additional, Farahani, Hossein, additional, Gelmon, Karen, additional, Chia, Stephen, additional, Mar, Colin, additional, Wan, Adrian, additional, Laks, Emma, additional, Biele, Justina, additional, Shumansky, Karey, additional, Rosner, Jamie, additional, McPherson, Andrew, additional, Nielsen, Cydney, additional, Roth, Andrew J. L., additional, Lefebvre, Calvin, additional, Bashashati, Ali, additional, de Souza, Camila, additional, Siu, Celia, additional, Aniba, Radhouane, additional, Brimhall, Jazmine, additional, Oloumi, Arusha, additional, Osako, Tomo, additional, Bruna, Alejandra, additional, Sandoval, Jose L., additional, Algara, Teresa, additional, Greenwood, Wendy, additional, Leung, Kaston, additional, Cheng, Hongwei, additional, Xue, Hui, additional, Wang, Yuzhuo, additional, Lin, Dong, additional, Mungall, Andrew J., additional, Moore, Richard, additional, Zhao, Yongjun, additional, Lorette, Julie, additional, Nguyen, Long, additional, Huntsman, David, additional, Eaves, Connie J., additional, Hansen, Carl, additional, Marra, Marco A., additional, Caldas, Carlos, additional, Shah, Sohrab P., additional, and Aparicio, Samuel, additional

Published
2014
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235. TITAN: inference of copy number architectures in clonal cell populations from tumor whole-genome sequence data

Author

Ha, Gavin, primary, Roth, Andrew, additional, Khattra, Jaswinder, additional, Ho, Julie, additional, Yap, Damian, additional, Prentice, Leah M., additional, Melnyk, Nataliya, additional, McPherson, Andrew, additional, Bashashati, Ali, additional, Laks, Emma, additional, Biele, Justina, additional, Ding, Jiarui, additional, Le, Alan, additional, Rosner, Jamie, additional, Shumansky, Karey, additional, Marra, Marco A., additional, Gilks, C. Blake, additional, Huntsman, David G., additional, McAlpine, Jessica N., additional, Aparicio, Samuel, additional, and Shah, Sohrab P., additional

Published
2014
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236. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4

Author

Ramos, Pilar, primary, Karnezis, Anthony N, additional, Craig, David W, additional, Sekulic, Aleksandar, additional, Russell, Megan L, additional, Hendricks, William P D, additional, Corneveaux, Jason J, additional, Barrett, Michael T, additional, Shumansky, Karey, additional, Yang, Yidong, additional, Shah, Sohrab P, additional, Prentice, Leah M, additional, Marra, Marco A, additional, Kiefer, Jeffrey, additional, Zismann, Victoria L, additional, McEachron, Troy A, additional, Salhia, Bodour, additional, Prat, Jaime, additional, D'Angelo, Emanuela, additional, Clarke, Blaise A, additional, Pressey, Joseph G, additional, Farley, John H, additional, Anthony, Stephen P, additional, Roden, Richard B S, additional, Cunliffe, Heather E, additional, Huntsman, David G, additional, and Trent, Jeffrey M, additional

Published
2014
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238. Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma

Author

Gunawardana, Jay, primary, Chan, Fong Chun, additional, Telenius, Adèle, additional, Woolcock, Bruce, additional, Kridel, Robert, additional, Tan, King L, additional, Ben-Neriah, Susana, additional, Mottok, Anja, additional, Lim, Raymond S, additional, Boyle, Merrill, additional, Rogic, Sanja, additional, Rimsza, Lisa M, additional, Guiter, Chrystelle, additional, Leroy, Karen, additional, Gaulard, Philippe, additional, Haioun, Corinne, additional, Marra, Marco A, additional, Savage, Kerry J, additional, Connors, Joseph M, additional, Shah, Sohrab P, additional, Gascoyne, Randy D, additional, and Steidl, Christian, additional

Published
2014
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239. Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN mutation profiles

Author

McConechy, Melissa K, primary, Ding, Jiarui, additional, Senz, Janine, additional, Yang, Winnie, additional, Melnyk, Nataliya, additional, Tone, Alicia A, additional, Prentice, Leah M, additional, Wiegand, Kimberly C, additional, McAlpine, Jessica N, additional, Shah, Sohrab P, additional, Lee, Cheng-Han, additional, Goodfellow, Paul J, additional, Gilks, C Blake, additional, and Huntsman, David G, additional

Published
2014
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240. TERTpromoter mutation in adult granulosa cell tumor of the ovary

Author

Pilsworth, Jessica, Cochrane, Dawn, Xia, Zhouchunyang, Aubert, Geraldine, Färkkilä, Anniina, Horlings, Hugo, Yanagida, Satoshi, Yang, Winnie, Lim, Jamie, Wang, Yi, Bashashati, Ali, Keul, Jacqueline, Wong, Adele, Norris, Kevin, Brucker, Sara, Taran, Florin-Andrei, Krämer, Bernhard, Staebler, Annette, van Meurs, Hannah, Oliva, Esther, Shah, Sohrab, Kommoss, Stefan, Kommoss, Friedrich, Gilks, C., Baird, Duncan, and Huntsman, David

Abstract

The telomerase reverse transcriptase (TERT) gene is highly expressed in stem cells and silenced upon differentiation. Cancer cells can attain immortality by activating TERTto maintain telomere length and telomerase activity, which is a crucial step of tumorigenesis. Two somatic mutations in the TERTpromoter (C228T; C250T) have been identified as gain-of-function mutations that promote transcriptional activation of TERTin multiple cancers, such as melanoma and glioblastoma. A recent study investigating TERTpromoter mutations in ovarian carcinomas found C228T and C250T mutations in 15.9% of clear cell carcinomas. However, it is unknown whether these mutations are frequent in other ovarian cancer subtypes, in particular, sex cord-stromal tumors including adult granulosa cell tumors. We performed whole-genome sequencing on ten adult granulosa cell tumors with matched normal blood and identified a TERTC228T promoter mutation in 50% of tumors. We found that adult granulosa cell tumors with mutated TERTpromoter have increased expression of TERTmRNA and exhibited significantly longer telomeres compared to those with wild-type TERTpromoter. Extension cohort analysis using allelic discrimination revealed the TERTC228T mutation in 51 of 229 primary adult granulosa cell tumors (22%), 24 of 58 recurrent adult granulosa cell tumors (41%), and 1 of 22 other sex cord-stromal tumors (5%). There was a significant difference in overall survival between patients with TERTC228T promoter mutation in the primary tumors and those without it (p = 0.00253, log-rank test). In seven adult granulosa cell tumors, we found the TERTC228T mutation present in recurrent tumors and absent in the corresponding primary tumor. Our data suggest that TERTC228T promoter mutations may have an important role in progression of adult granulosa cell tumors.

Published
2018
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242. Protein Tyrosine Phosphatase Type-1 (PTPN1) Is Frequently Mutated In Primary Mediastinal B Cell Lymphoma and Hodgkin Lymphoma

Author

Gunawardana, Jay, primary, Chan, Fong Chun, additional, Telenius, Adele, additional, Woolcock, Bruce W., additional, Kridel, Robert, additional, Tan, King L., additional, Ben Neriah, Susana, additional, Lim, Raymond S., additional, Rogic, Sanja, additional, Boyle, Merrill, additional, Guiter, Chrystelle, additional, Leroy, Karen, additional, Haioun, Corinne, additional, Rimsza, Lisa M., additional, Gaulard, Philippe, additional, Savage, Kerry J., additional, Connors, Joseph M., additional, Marra, Marco A., additional, Shah, Sohrab P., additional, Gascoyne, Randy D., additional, and Steidl, Christian, additional

Published
2013
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243. Genomic Rearrangements Involving Programmed Death Ligands Are Recurrent In Primary Mediastinal Large B-Cell Lymphoma

Author

Twa, David D. W., primary, Chan, Fong Chun, additional, Ben-Neriah, Susana, additional, Woolcock, Bruce W., additional, Tan, King L., additional, Slack, Graham W., additional, Gunawardana, Jay, additional, Lim, Raymond S., additional, McPherson, Andrew W., additional, Kridel, Robert, additional, Telenius, Adele, additional, Scott, David W., additional, Savage, Kerry J., additional, Shah, Sohrab P., additional, Gascoyne, Randy D., additional, and Steidl, Christian, additional

Published
2013
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244. Correction: Type-Specific Cell Line Models for Type-Specific Ovarian Cancer Research

Author

Anglesio, Michael S., primary, Wiegand, Kimberly C., additional, Melnyk, Nataliya, additional, Chow, Christine, additional, Salamanca, Clara, additional, Prentice, Leah M., additional, Senz, Janine, additional, Yang, Winnie, additional, Spillman, Monique A., additional, Cochrane, Dawn R., additional, Shumansky, Karey, additional, Shah, Sohrab P., additional, Kalloger, Steve E., additional, and Huntsman, David G., additional

Published
2013
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245. Type-Specific Cell Line Models for Type-Specific Ovarian Cancer Research

Author

Anglesio, Michael S., primary, Wiegand, Kimberly C., additional, Melnyk, Nataliya, additional, Chow, Christine, additional, Salamanca, Clara, additional, Prentice, Leah M., additional, Senz, Janine, additional, Yang, Winnie, additional, Spillman, Monique A., additional, Cochrane, Dawn R., additional, Shumansky, Karey, additional, Shah, Sohrab P., additional, Kalloger, Steve E., additional, and Huntsman, David G., additional

Published
2013
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246. Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer.

Author

Duffy, Supipi, Hok Khim Fam, Yi Kan Wang, Styles, Erin B., Jung-Hyun Kim, Ang, J. Sidney, Singh, Tejomayee, Larionov, Vladimir, Shah, Sohrab P., Andrews, Brenda, Boerkoel, Cornelius F., and Hieter, Philip

Subjects
GENETIC overexpression, GENE expression, CANCER cells, CHROMOSOMES, PHENOTYPES, RHABDOMYOSARCOMA
Abstract

Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDPI and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors. [ABSTRACT FROM AUTHOR]

Published
2016
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247. Robust high-performance nanoliter-volume single-cell multiple displacement amplification on planar substrates.

Author

Leung, Kaston, Klaus, Anders, Lin, Bill K., Laks, Emma, Biele, Justina, Lai, Daniel, Bashashati, Ali, Yi-Fei Huang, Aniba, Radhouane, Moksa, Michelle, Steif, Adi, Mes-Masson, Anne-Marie, Hirst, Martin, Shah, Sohrab P., Aparicio, Samuel, and Hansen, Carl L.

Subjects
BIOCHEMICAL substrates, GENOMES, GENE amplification, NUCLEOTIDES, DNA copy number variations
Abstract

The genomes of large numbers of single cells must be sequenced to further understanding of the biological significance of genomic heterogeneity in complex systems. Whole genome amplification (WGA) of single cells is generally the first step in such studies, but is prone to nonuniformity that can compromise genomic measurement accuracy. Despite recent advances, robust performance in highthroughput single-cell WGA remains elusive. Here, we introduce droplet multiple displacement amplification (MDA), a method that uses commercially available liquid dispensing to perform highthroughput single-cell MDA in nanoliter volumes. The performance of droplet MDA is characterized using a large dataset of 129 normal diploid cells, and is shown to exceed previously reported single-cell WGA methods in amplification uniformity, genome coverage, and/or robustness. We achieve up to 80% coverage of a single-cell genome at 5× sequencing depth, and demonstrate excellent single-nucleotide variant (SNV) detection using targeted sequencing of droplet MDA product to achieve a median allelic dropout of 15%, and using whole genome sequencing to achieve false and true positive rates of 9.66 × 10-6 and 68.8%, respectively, in a G1-phase cell. We further show that droplet MDA allows for the detection of copy number variants (CNVs) as small as 30 kb in single cells of an ovarian cancer cell line and as small as 9 Mb in two high-grade serous ovarian cancer samples using only 0.02× depth. Droplet MDA provides an accessible and scalable method for performing robust and accurate CNV and SNV measurements on large numbers of single cells. [ABSTRACT FROM AUTHOR]

Published
2016
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248. Synchronous Endometrial and Ovarian Carcinomas: Evidence of Clonality.

Author

Anglesio, Michael S., Yi Kan Wang, Maassen, Madlen, Horlings, Hugo M., Bashashati, Ali, Senz, Janine, Mackenzie, Robertson, Grewal, Diljot S., Li-Chang, Hector, Karnezis, Anthony N., Sheffield, Brandon S., McConechy, Melissa K., Kommoss, Friedrich, Taran, Florin A., Staebler, Annette, Shah, Sohrab P., Wallwiener, Diethelm, Brucker, Sara, Gilks, C. Blake, and Kommoss, Stefan

Subjects
DNA analysis, CELLS, EPITHELIAL cell tumors, GENOMES, MULTIPLE tumors, OVARIAN tumors, TUMOR classification, ENDOMETRIAL tumors, SAMPLE size (Statistics), SEQUENCE analysis, TUMOR grading
Abstract

Many women with ovarian endometrioid carcinoma present with concurrent endometrial carcinoma. Organ-confined and low-grade synchronous endometrial and ovarian tumors (SEOs) clinically behave as independent primary tumors rather than a single advanced-stage carcinoma. We used 18 SEOs to investigate the ancestral relationship between the endometrial and ovarian components. Based on both targeted and exome sequencing, 17 of 18 patient cases of simultaneous cancer of the endometrium and ovary from our series showed evidence of a clonal relationship, ie, primary tumor and metastasis. Eleven patient cases fulfilled clinicopathological criteria that would lead to classification as independent endometrial and ovarian primary carcinomas, including being of FIGO stage T1a/1A, with organ-restricted growth and without surface involvement; 10 of 11 of these cases showed evidence of clonality. Our observations suggest that the disseminating cells amongst SEOs are restricted to physically accessible and microenvironment-compatible sites yet remain indolent, without the capacity for further dissemination. [ABSTRACT FROM AUTHOR]

Published
2016
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250. The genomic landscape of epithelioid sarcoma cell lines and tumours.

Author

Jamshidi, Farzad, Bashashati, Ali, Shumansky, Karey, Dickson, Brendan, Gokgoz, Nalan, Wunder, Jay S, Andrulis, Irene L, Lazar, Alexander J, Shah, Sohrab P, Huntsman, David G, and Nielsen, Torsten O

Abstract

We carried out whole genome and transcriptome sequencing on four tumour/normal pairs of epithelioid sarcoma. These index cases were supplemented with whole transcriptome sequencing of three additional tumours and three cell lines. Unlike rhabdoid tumour (the other major group of SMARCB1-negative cancers), epithelioid sarcoma shows a complex genome with a higher mutational rate, comparable to that of ovarian carcinoma. Despite this mutational burden, SMARCB1 mutations remain the most frequently recurring event and are probably critical drivers of tumour formation. Several cases show heterozygous SMARCB1 mutations without inactivation of the second allele, and we explore this further in vitro. Finding CDKN2A deletions in our discovery cohort, we evaluated CDKN2A protein expression in a tissue microarray. Six out of 16 cases had lost CDKN2A in greater than or equal to 90% of cells, while the remaining cases had retained the protein. Expression analysis of epithelioid sarcoma cell lines by transcriptome sequencing shows a unique profile that does not cluster with any particular tissue type or with other SWI/ SNF-aberrant lines. Evaluation of the levels of members of the SWI/ SNF complex other than SMARCB1 revealed that these proteins are expressed as part of a residual complex, similarly to previously studied rhabdoid tumour lines. This residual SWI/ SNF is susceptible to synthetic lethality and may therefore indicate a therapeutic opportunity. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Published
2016
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