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The long tail of oncogenic drivers in prostate cancer

by Schultz, Nikolaus , Han, G. Celine , Pritchard, Colin , Sawyers, Charles L. , Bielski, Craig M. , Scher, Howard I. , Penson, Alexander V. , Kantoff, Philip W. , Rubin, Mark A. , Armenia, Joshua , Robinson, Dan , Abida, Wassim , Liu, David , Kundra, Ritika , Miranda, Susana , Lonigro, Robert , Sboner, Andrea , Wu, Yi Mi , Wankowicz, Stephanie A. M. , Barbieri, Christopher E. , Taplin, Mary-Ellen , Zafeiriou, Zafeiris , Coleman, Ilsa , Chatila, Walid K. , Van Allen, Eliezer M. , Montgomery, Bruce , Demichelis, Francesca , Chakravarty, Debyani , Huang, Franklin W. , Tolonen, Charlotte , Taylor, Barry S. , Nelson, Peter S. , Beltran, Himisha , Chinnaiyan, Arul M. , Reznik, Ed , Garraway, Levi A. , Morrissey, Colm , Gao, Jianjiong , de Bono, Johann S.

in 1-Phosphatidylinositol 3-kinase / 45/23 / 631/114 / 631/67/589/466 / Agriculture / Analysis / Androgens / Androgens - genetics / Animal Genetics and Genomics / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cancer genetics / Cancer metastasis / Cancer Research / Carcinogenesis - genetics / Care and treatment / Cullin Proteins - genetics / Data processing / Deoxyribonucleic acid / DNA / DNA repair / Epigenesis, Genetic / Epigenetic inheritance / Epigenetics / ETS protein / Exome - genetics / Exome sequencing / Gene frequency / Gene Function / Gene mutation / Gene sequencing / Genes / Genetic aspects / Genetic research / Genetic transformation / Genomic analysis / Genomics / Homeodomain Proteins - genetics / Human Genetics / Humans / Kinases / Letter / Ligases / Male / Metastases / Metastasis / Motor vehicle drivers / Mutation / Mutation - genetics / Oncogenes / Phosphatidylinositol 3-Kinases - genetics / Prostate cancer / Prostatic Neoplasms - genetics / Recurrence (Disease) / Regulators / Signal transduction / Signaling / Spliceosomes - genetics / Transcription Factors - genetics / Tumors / Ubiquitin / Ubiquitin-protein ligase

2018

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2018

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2018

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Journal Article

The long tail of oncogenic drivers in prostate cancer

Schultz, Nikolaus,

Han, G. Celine,

Pritchard, Colin,

Sawyers, Charles L.,

Bielski, Craig M.,

Scher, Howard I.,

Penson, Alexander V.,

Kantoff, Philip W.,

Rubin, Mark A.,

Armenia, Joshua,

Robinson, Dan,

Abida, Wassim,

Liu, David,

Kundra, Ritika,

Miranda, Susana,

Lonigro, Robert,

Sboner, Andrea,

Wu, Yi Mi,

Wankowicz, Stephanie A. M.,

Barbieri, Christopher E.,

Taplin, Mary-Ellen,

Zafeiriou, Zafeiris,

Coleman, Ilsa,

Chatila, Walid K.,

Van Allen, Eliezer M.,

Montgomery, Bruce,

Demichelis, Francesca,

Chakravarty, Debyani,

Huang, Franklin W.,

Tolonen, Charlotte,

Taylor, Barry S.,

Nelson, Peter S.,

Beltran, Himisha,

Chinnaiyan, Arul M.,

Reznik, Ed,

Garraway, Levi A.,

Morrissey, Colm,

Gao, Jianjiong,

de Bono, Johann S.

2018

Overview

Comprehensive genomic characterization of prostate cancer has identified recurrent alterations in genes involved in androgen signaling, DNA repair, and PI3K signaling, among others. However, larger and uniform genomic analysis may identify additional recurrently mutated genes at lower frequencies. Here we aggregate and uniformly analyze exome sequencing data from 1,013 prostate cancers. We identify and validate a new class of E26 transformation-specific ( ETS )-fusion-negative tumors defined by mutations in epigenetic regulators, as well as alterations in pathways not previously implicated in prostate cancer, such as the spliceosome pathway. We find that the incidence of significantly mutated genes (SMGs) follows a long-tail distribution, with many genes mutated in less than 3% of cases. We identify a total of 97 SMGs, including 70 not previously implicated in prostate cancer, such as the ubiquitin ligase CUL3 and the transcription factor SPEN . Finally, comparing primary and metastatic prostate cancer identifies a set of genomic markers that may inform risk stratification. Meta-analysis of exome sequencing data identifies new recurrently mutated driver genes for prostate cancer. Comparison of primary and metastatic tumors further identifies genomic markers for advanced prostate cancer that may inform risk stratification.

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Publisher

Nature Publishing Group US,Nature Publishing Group

Subject

1-Phosphatidylinositol 3-kinase

/ 45/23

/ 631/114