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The landscape of somatic mutations i...

Baca, Sylvan Charles.

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The landscape of somatic mutations in primary prostate adenocarcinoma.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	The landscape of somatic mutations in primary prostate adenocarcinoma./
Author:	Baca, Sylvan Charles.
Description:	186 p.
Notes:	Source: Dissertation Abstracts International, Volume: 74-10(E), Section: B.
Contained By:	Dissertation Abstracts International74-10B(E).
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3566808
ISBN:	9781303183478

The landscape of somatic mutations in primary prostate adenocarcinoma.
Baca, Sylvan Charles.

The landscape of somatic mutations in primary prostate adenocarcinoma. - 186 p.

Source: Dissertation Abstracts International, Volume: 74-10(E), Section: B.

Thesis (Ph.D.)--Harvard University, 2013.

Prostate cancer is the second leading cause of cancer deaths among men. Targeted analyses of DNA from prostate cancers have identified recurrent somatic alterations that promote tumor growth and survival. Only recently, however, has the comprehensive analysis of cancer genomes become possible due to rapid advances in DNA sequencing technology.

ISBN: 9781303183478Subjects--Topical Terms:

1017719
Biology, Molecular.

The landscape of somatic mutations in primary prostate adenocarcinoma.
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020 $a 9781303183478
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100 1 $a Baca, Sylvan Charles. $3 2101633
245 1 4 $a The landscape of somatic mutations in primary prostate adenocarcinoma.
300 $a 186 p.
500 $a Source: Dissertation Abstracts International, Volume: 74-10(E), Section: B.
500 $a Includes supplementary digital materials.
500 $a Adviser: Levi A. Garraway.
502 $a Thesis (Ph.D.)--Harvard University, 2013.
520 $a Prostate cancer is the second leading cause of cancer deaths among men. Targeted analyses of DNA from prostate cancers have identified recurrent somatic alterations that promote tumor growth and survival. Only recently, however, has the comprehensive analysis of cancer genomes become possible due to rapid advances in DNA sequencing technology.
520 $a To identify somatic mutations that may drive prostate cancer, we sequenced the protein-coding DNA of 112 prostate tumor/normal tissue pairs enriched for aggressive localized disease. We identified novel recurrent mutations in several genes, including MED12 and FOXA1. The most frequently mutated gene was SPOP, which encodes a ubiquitin ligase complex subunit. Mutations altered the substrate-binding cleft of the SPOP protein in 6-15% of tumors across multiple independent cohorts. SPOP-mutant prostate cancers lacked ETS gene rearrangements and exhibited a distinct pattern of genomic alterations, including frequent deletion of the chromatin modifying enzyme gene CHD1. Transcriptome profiling of prostate epithelial cells suggested that SPOP mutations and CHD1 loss may promote invasive cellular growth and genomic instability, respectively. Thus, SPOP mutations appear to define a new molecular subtype of ETS-negative prostate cancer.
520 $a In order to characterize the landscape of somatic alterations across the entire genome in prostate cancer, we also sequenced the full complement of DNA from 57 prostate tumors and matched normal tissue. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly interdependent manner. This phenomenon, which we term "chromoplexy", frequently accounts for the dysregulation of prostate cancer genes and appears to disrupt multiple cancer genes coordinately. Our modeling suggests that chromoplexy may induce considerable genomic derangement over relatively few events in prostate cancer and other neoplasms, supporting a model of punctuated cancer evolution. Together, the studies described in this thesis point toward novel prostate cancer genes and suggest a refined model of prostate tumor evolution.
590 $a School code: 0084.
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Biology, Bioinformatics. $3 1018415
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690 $a 0715
710 2 $a Harvard University. $b Biology: Medical Sciences, Division of. $3 2097738
773 0 $t Dissertation Abstracts International $g 74-10B(E).
790 $a 0084
791 $a Ph.D.
792 $a 2013
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3566808