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Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer
Christopher Weier1, Michael C Haffner, Timothy Mosbruger
1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
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.
Insights
TMPRSS2-ERG gene fusions are common in prostate cancer. Our study reveals the complex genomic architecture of these rearrangements, implicating specific DNA repair pathways in their formation.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- TMPRSS2-ERG rearrangements are frequent in prostate cancer, occurring in about 50% of cases.
- The genomic architecture and formation mechanisms of these common cancer rearrangements remain poorly understood.
Purpose of the Study:
- To elucidate the genomic architecture of TMPRSS2-ERG rearrangements in prostate cancer.
- To identify the molecular mechanisms underlying the formation of these recurrent genomic alterations.
Main Methods:
- Development of a targeted capture and next-generation sequencing pipeline.
- Analysis of 83 primary prostate cancer specimens to identify rearrangement breakpoints at nucleotide resolution.
Main Results:
- The optimized pipeline achieved >90% sensitivity and specificity for detecting TMPRSS2-ERG rearrangements.
- Identified both known and novel intra- and inter-chromosomal rearrangements involving TMPRSS2 and ERG.
- Found strong clustering of breakpoints in specific intronic regions and complex chromosomal architectures.
- Revealed that ~88% of rearrangements occurred near microhomology regions or involved insertions, implicating NHEJ and MMEJ pathways.
Conclusions:
- TMPRSS2-ERG rearrangements exhibit complex genomic architectures in prostate cancer.
- Non-homologous end joining and microhomology-mediated end joining pathways are likely involved in generating these rearrangements.
- Provides critical insights into the molecular mechanisms driving prostate cancer-specific genomic alterations.
