Document Detail

Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer.
MedLine Citation:
PMID:  23447416     Owner:  NLM     Status:  MEDLINE    
TMPRSS2-ERG rearrangements occur in approximately 50% of prostate cancers and therefore represent one of the most frequently observed structural rearrangements in all cancers. However, little is known about the genomic architecture of such rearrangements. We therefore designed and optimized a pipeline involving target capture of TMPRSS2 and ERG genomic sequences coupled with paired-end next-generation sequencing to resolve genomic rearrangement breakpoints in TMPRSS2 and ERG at nucleotide resolution in a large series of primary prostate cancer specimens (n = 83). This strategy showed > 90% sensitivity and specificity in identifying TMPRSS2-ERG rearrangements, and allowed identification of intra- and inter-chromosomal rearrangements involving TMPRSS2 and ERG with known and novel fusion partners. Our results indicate that rearrangement breakpoints show strong clustering in specific intronic regions of TMPRSS2 and ERG. The observed TMPRSS2-ERG rearrangements often exhibited complex chromosomal architecture associated with several intra- and inter-chromosomal rearrangements. Nucleotide resolution analysis of breakpoint junctions revealed that the majority of TMPRSS2 and ERG rearrangements (~88%) occurred at or near regions of microhomology or involved insertions of one or more base pairs. This architecture implicates non-homologous end joining (NHEJ) and microhomology-mediated end joining (MMEJ) pathways in the generation of such rearrangements. These analyses have provided important insights into the molecular mechanisms involved in generating prostate cancer-specific recurrent rearrangements.
Christopher Weier; Michael C Haffner; Timothy Mosbruger; David M Esopi; Jessica Hicks; Qizhi Zheng; Helen Fedor; William B Isaacs; Angelo M De Marzo; William G Nelson; Srinivasan Yegnasubramanian
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  The Journal of pathology     Volume:  230     ISSN:  1096-9896     ISO Abbreviation:  J. Pathol.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-05-14     Completed Date:  2013-07-16     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  England    
Other Details:
Languages:  eng     Pagination:  174-83     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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MeSH Terms
Adenocarcinoma / genetics*,  pathology
Gene Expression Regulation, Neoplastic
Gene Rearrangement*
High-Throughput Nucleotide Sequencing
Nucleotides / genetics
Prostatic Neoplasms / genetics*,  pathology
Sensitivity and Specificity
Sequence Analysis, DNA
Serine Endopeptidases / genetics*
Trans-Activators / genetics*
Grant Support
P30 CA006973/CA/NCI NIH HHS; P50 CA058236/CA/NCI NIH HHS; P50CA58236/CA/NCI NIH HHS; R01 CA070196/CA/NCI NIH HHS; R01CA070196/CA/NCI NIH HHS
Reg. No./Substance:
0/ERG protein, human; 0/Nucleotides; 0/Trans-Activators; EC 3.4.21.-/Serine Endopeptidases; EC 3.4.21.-/TMPRSS2 protein, human

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