Conflict of interest statement: AMD is currently employed at Predictive Biosciences, Inc, Lexington, MA, while being part-time adjunct Professor of Pathology, Oncology, and Urology at the Johns Hopkins University School of Medicine. No funding or other support was provided by Predictive Biosciences, Inc for any of the work in this article. The terms of the relationship between AMD and Predictive Biosciences, Inc are managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.
Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer
Article first published online: 13 MAY 2013
Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 230, Issue 2, pages 174–183, June 2013
How to Cite
Weier, C., Haffner, M. C., Mosbruger, T., Esopi, D. M., Hicks, J., Zheng, Q., Fedor, H., Isaacs, W. B., De Marzo, A. M., Nelson, W. G. and Yegnasubramanian, S. (2013), Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer. J. Pathol., 230: 174–183. doi: 10.1002/path.4186
- Issue published online: 13 MAY 2013
- Article first published online: 13 MAY 2013
- Accepted manuscript online: 27 FEB 2013 12:54PM EST
- Manuscript Accepted: 22 FEB 2013
- Manuscript Revised: 8 FEB 2013
- Manuscript Received: 15 OCT 2012
- hybrid capture;
- targeted next-generation sequencing;
- prostate cancer;
- genomic breakpoint detection
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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.