title: Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer.
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.
authors: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
authors: Christopher
authors: C
authors: Weier
authors: Michael C
authors: MC
authors: Haffner
authors: Timothy
authors: T
authors: Mosbruger
authors: David M
authors: DM
authors: Esopi
authors: Jessica
authors: J
authors: Hicks
authors: Qizhi
authors: Q
authors: Zheng
authors: Helen
authors: H
authors: Fedor
authors: William B
authors: WB
authors: Isaacs
authors: Angelo M
authors: AM
authors: De Marzo
authors: William G
authors: WG
authors: Nelson
authors: Srinivasan
authors: S
authors: Yegnasubramanian
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009711:Nucleotides / Q000235:genetics; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA; D012697:Serine Endopeptidases / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG
chemical_list: C072312:ERG protein, human; D009711:Nucleotides; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human