Journal
JOURNAL OF PATHOLOGY
Volume 230, Issue 2, Pages 174-183Publisher
WILEY-BLACKWELL
DOI: 10.1002/path.4186
Keywords
TMPRSS2; ERG; rearrangement; hybrid capture; targeted next-generation sequencing; prostate cancer; genomic breakpoint detection
Funding
- NCI/Prostate SPORE [P50CA58236]
- National Institutes of Health/National Cancer Institute [P50CA058236, R01CA070196]
- Department of Defense [W81XWH-08-1-0049]
- Prostate Cancer Foundation
- V Foundation for Cancer Research
- Helen B Masenhimer Fellowship
- Irving A Hansen Memorial Foundation
Ask authors/readers for more resources
TMPRSS2ERG 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 TMPRSS2ERG 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 TMPRSS2ERG 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 (approximate to 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. Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available