Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer

Christopher Weier, Michael C. Haffner, Timothy Mosbruger, David M. Esopi, Jessica Hicks, Qizhi Zheng, Helen Fedor, William B Isaacs, Angelo Michael Demarzo, William G Nelson, S Yegnasubramanian

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)174-183
Number of pages10
JournalJournal of Pathology
Volume230
Issue number2
DOIs
StatePublished - Jun 2013

Fingerprint

Prostatic Neoplasms
Nucleotides
Base Pairing
Cluster Analysis
Sensitivity and Specificity
Neoplasms

Keywords

  • ERG
  • genomic breakpoint detection
  • hybrid capture
  • prostate cancer
  • rearrangement
  • targeted next-generation sequencing
  • TMPRSS2

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer. / Weier, Christopher; Haffner, Michael C.; Mosbruger, Timothy; Esopi, David M.; Hicks, Jessica; Zheng, Qizhi; Fedor, Helen; Isaacs, William B; Demarzo, Angelo Michael; Nelson, William G; Yegnasubramanian, S.

In: Journal of Pathology, Vol. 230, No. 2, 06.2013, p. 174-183.

Research output: Contribution to journalArticle

Weier C, Haffner MC, Mosbruger T, Esopi DM, Hicks J, Zheng Q et al. Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer. Journal of Pathology. 2013 Jun;230(2):174-183. https://doi.org/10.1002/path.4186
Weier, Christopher ; Haffner, Michael C. ; Mosbruger, Timothy ; Esopi, David M. ; Hicks, Jessica ; Zheng, Qizhi ; Fedor, Helen ; Isaacs, William B ; Demarzo, Angelo Michael ; Nelson, William G ; Yegnasubramanian, S. / Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer. In: Journal of Pathology. 2013 ; Vol. 230, No. 2. pp. 174-183.
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